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Abstract
Pregnant rats were exposed to an acute or a repeated stress (presence of a cat) either at the 10th or the 14th gestational day, and the development of their offspring was studied during the first 2 weeks of life. Motor development was measured by different tests: rooting reflex, vibrissae placing response, righting reflex, negative geotaxis. Other landmarks such as eye opening and spontaneous locomotor activity were also recorded. The results showed that, except for the rooting reflex which was most often enhanced (while not significantly) in prenatally stressed rats, the development of the vibrissae placing response, the righting reflex and the negative geotaxis behavior was delayed in the offspring of dams stressed at the 10th gestational day and not (or almost not) in the offspring of dams stressed at the 14th gestational day, the delay being more severe when the prenatal stress was repeated than when it was acutely administered. The spontaneous motor activity was also altered in repeatedly prenatally stressed rats, whatever the day of pregnancy when it was administered, while it was unaffected in acutely prenatally stressed animals. The delay in motor reflexes development was interpreted as alterations in maturation of nervous structures sustaining motor skills, while permanent decrease of spontaneous motor activity was explained by emotional and motivational alterations due to prenatal stress.
... Li et al., (2021) postulated that LTD occurrence in corticostriatal connections is a marker of synaptic maturation. A similar phenomenon may occur within M1, and may explain the behavioural delays in motor maturation reported in rodents following PNS (Patin et al., 2004). ...
... Studies who evaluate the impact of stress often reported impaired motor learning in Rodents following PNS. Patin et al. (2004) observed that PNS delayed motor development in rat pups, which, according to these authors, may result from maturation alteration of neuronal structures involved in motor functions. Interestingly the delay in motor development was more severe following a repeated PNS over several gestation days compared to a single time PNS, highlighting the probable influence of PNS protocol parameters on its outcomes. ...
... Li et ses collaborateurs (2021) ont mis en évidence un tel décalage dans la maturation des synapses corticostriatales suite à un stress prénatal, reflété par l'incapacité de ces synapses à exprimer une LTD caractéristique des connexions matures. Cette immaturité de la transmission inhibitrice au sein du système moteur pourrait induire un retard développemental des structures impliquées dans la motricité, et être en cause dans les délais observés de la maturation motrice suite à un stress prénatal, chez les rongeurs comme chez les primates humains et non humains(DiPietro et al., 2006;Grace et al., 2016;Huizink et al., 2003;Patin et al., 2004;Schneider et Coe, 1993).Sur les interneurones GABAergiquesL'effet du stress aigu sur les INs localisés dans le M1 des animaux SOD tend, de façon inattendue, à diminuer l'excitabilité des INs du cluster 1, tout en augmentant celle des neurones provenant du cluster 4. Cet effet spécifique du stress entre les souris WT et SOD pourrait provenir du fait que l'excitabilité basale des neurones du cluster 1 diffère entre ces animaux. Ces INs étant possiblement impliqués dans la régulation de la réponse au stress, il est envisageable qu'une diminution de leur excitabilité soit nécessaire au processus adaptatif faisant suite au stress. ...
Le stress est une réponse spontanée d’adaptation de l’organisme, visant à mobiliser les ressources nécessaires pour faire face à une situation perçue comme menaçante. Son influence a majoritairement été décrite au sein de structures limbiques. Or, en tant que processus adaptatif, il module les comportements et impacterait les structures impliquées dans la motricité, dont le cortex moteur primaire (M1). Cette aire cérébrale, à l’origine de la commande motrice volontaire, partage en effet des connexions avec des structures clés de l’axe corticotrope. Peu de données existent cependant, quant à la relation entre le stress et le M1. Une meilleure compréhension de l’impact du stress sur le fonctionnement du réseau neuronal au sein du M1 en conditions physiologiques, permettrait de mieux apprécier ses effets en cas de réseau cortical moteur altéré, comme observé dans le cas de la sclérose latérale amyotrophique (SLA). Ce travail de recherche visait ainsi à définir chez la souris adulte, l’influence du stress sur l’excitabilité et la plasticité du M1 de souris en conditions physiologiques, et d’en évaluer les conséquences dans le cadre de la SLA, en utilisant un modèle murin de la pathologie, la souris SOD1G93A (SOD). Dans un premier temps, les enregistrements électrophysiologiques in vitro et in vivo respectivement de l’excitabilité des interneurones du M1, et de la plasticité du réseau formé par les M1 des deux hémisphères cérébraux (M1-M1) ont révélé qu’un stress aigu tend à promouvoir une augmentation de l’activité globale du M1 chez les WT, mais au contraire à favoriser une diminution de cette activité chez les SOD. Une approche immunohistochimique a également montré suite au stress, des modifications dans le M1 de l’expression de KCC2 et NKCC1, deux cotransporteurs au chlorure régulant l’efficacité de la transmission GABAergique inhibitrice, avec une augmentation de l’expression de KCC2 chez les WT et de NKCC1 chez les SOD. La modification du ratio KCC2/NKCC1 pourrait suggérer une modulation différentielle de la transmission inhibitrice entre ces deux groupes. Dans un second temps, en utilisant les mêmes techniques d’électrophysiologie in vivo et d’immunohistochimie nous avons mis en évidence qu’un stress prénatal favorisait également l’augmentation de l’activité neuronale au sein du M1 des WT, et sa réduction chez les SOD, associé à une augmentation de l’expression de KCC2 et NKCC1 quel que soit le génotype, qui pourraient être en lien avec leurs rôles respectifs dans la formation d’épines dendritiques de novo et la régulation de l’inflammation. Dans un troisième temps, l’utilisation d’une batterie de tests comportementaux a démontré que les souris stressées (stress aigu ou prénatal) WT et SOD, présentaient des déficits cognitifs. En revanche seules les souris soumises à un stress prénatal ont démontré une diminution des performances motrices, suggérant une possible relation entre les changements de la plasticité observés suite à un stress prénatal et les apprentissages moteurs. Enfin, bien que le stress prénatal n’ait pas influencé la survie des animaux SOD, il semble légèrement précipiter l’apparition des symptômes de la SLA. Dans l’ensemble, ces données démontrent l’influence du stress sur l’activité et la plasticité du M1 et pointe vers la nécessité d’une meilleure compréhension de l’implication de ces changements dans la réponse au stress mais également dans l’évolution de la SLA.
... PS has been shown to modulate neuronal development of the frontal cortex [44] and thus it may also potentially affect the motor cortex and voluntary motor control [57]. Further experimental rodent and non-human primate studies indicated that an adverse intrauterine environment during pregnancy impairs neuromotor behavioural development in offspring [13,37,47]. PS-induced motor deficits may include disabilities in fine motor skills [50], reflexes [37] and disturbed coordination and balance [7]. ...
... Further experimental rodent and non-human primate studies indicated that an adverse intrauterine environment during pregnancy impairs neuromotor behavioural development in offspring [13,37,47]. PS-induced motor deficits may include disabilities in fine motor skills [50], reflexes [37] and disturbed coordination and balance [7]. ...
... Defects in CST function and associated systems may be one mechanism to explain these impairments. Reduced CST integrity has been linked to loss of skilled movement capacity [48], and gross and skilled movement impairments have been associated with PS [7,37]. In turn, beneficial experience, such as housing in an enriched environment (EE) that provides animals with rich social, motor, cognitive and sensory stimulation, has been shown to reverse neuromorphological deficits due to stress [4,31]. ...
Background:
An adverse fetal environment in utero has been associated with long-term alterations in brain structure and function, and a higher risk of neurological disorders in later life. A common consequence of early adverse experience is impaired motor system function. A causal relationship for stress-associated impairments and a suitable therapy, however, have not been determined yet.
Objective:
To investigate the impact of ancestral stress on corticospinal tract (CST) morphology and fine motor performance in rats, and to determine if adverse programming by ancestral stress can be mitigated by environmental enrichment therapy in rats.
Methods:
The study examined F3 offspring generated by three lineages; one with prenatal stress only in the F1 generation, one with compounding effects of multigenerational prenatal stress, and a non-stress control lineage. F3 offspring from each lineage were injected with biotinylated dextran amine (BDA) into the motor cortex for anterograde tracing of the CST.
Results:
Examination of the CST revealed reduced axonal density in the ancestrally stressed lineages. These anatomical changes were associated with significant impairments in skilled walking, as indicated by reduced foot placement accuracy and disturbed inter-limb coordination. Therapeutic intervention by environmental enrichment reduced the neuromorphological consequences of ancestral stress and restored skilled walking ability.
Conclusions:
The data suggest a causal relationship between stress-induced abnormal CST function and loss of fine motor performance. Thus, ancestral stress may be a determinant of motor system development and motor skill. Environmental enrichment may represent an effective intervention for the adverse programming by ancestral stress and trauma.
... Pups of both experimental groups showed a decrease in the latency time of this reflex, they had a delay in the disappearance of the reflex, which could suggest that the treatment has some effects in the nervous system maturation for these animals, but further studies are necessary to examine this notion more specifically. Regarding righting reflex, newborn animals take more time to return to the normal position, and as the animal grows, the time needed for the execution of this reflex gradually decreases [35]. This reflex emerges soon after birth in the rat (PN1-PN3), and matures during the first week of development [21,33]. ...
... Soon after the onset of the righting reflex, rat pups achieve the ability of orienting themselves upward in the inclined plane; as an unlearned response to gravitational cues, negative geotaxis, achieved on PN6-PN8 has been considered diagnostic of vestibular and/or proprioceptive function [37]. Negative geotaxis reflex and surface righting are two of the responses reflecting function of the cerebellar and vestibular systems [38], and they are involved with the spatial relation of the animal [35]. A delay in the maturation of the negative geotaxis reflex, as occurred with pups of mothers exposed to the venom on GD16, suggests a delay in the maturation of the CNS structures involved with the motor ability, in particular in the cerebellum [35]. ...
... Negative geotaxis reflex and surface righting are two of the responses reflecting function of the cerebellar and vestibular systems [38], and they are involved with the spatial relation of the animal [35]. A delay in the maturation of the negative geotaxis reflex, as occurred with pups of mothers exposed to the venom on GD16, suggests a delay in the maturation of the CNS structures involved with the motor ability, in particular in the cerebellum [35]. As to the righting reflex, a delay in its development could indicate a delay in myelination [39]. ...
Scorpion envenoming is a public health problem. In Brazil, the scorpion Tityus serrulatus is considered the most dangerous, but a large number of exposures also occur with Tityus bahiensis. There are quite a few studies in literature about the toxic effects of this venom but it is not known if the venom causes malformations or behavioral defects to the offspring of mothers exposed to the venom during pregnancy. The objective of this work was to determine, in rats, the possible toxic effects of T. bahiensis venom on offspring when injected into rats during different periods of fetal development. Rats were assigned to one of three groups: one control group and two experimental groups that were subcutaneously injected with venom (2.5 mg/kg) on the 10th (GD10) or on 16th day (GD16) of gestation. Pups were evaluated for changes in physical and behavioral development. GD10 treatment group offspring showed an increase in body weight gain, earlier ear unfolding, incisor tooth eruption and vaginal opening. A decrease in the time of palmar grasp and surface-righting reflexes was observed only for males. In GD16 treatment group, earlier ear unfolding, incisor tooth eruption, and delay in eye opening were observed in the offspring. In female pups a decrease in weight gain and in time for palmar grasp reflex, and an increase in time for negative geotaxis were observed. In male pups a delay in the testis descent, decrease in the time of palmar grasp, increase in the time of negative geotaxis reflex and in the general and locomotor activities could be noticed. Therefore, we concluded that a moderate dose of scorpion venom administered to pregnant rats was able to elicit alterations in physical and behavioral development in the offspring during the postnatal period.
... The increase in maternal corticosterone reaches the fetus via the placenta, enhancing the concentration of this hormone in the fetus circulation (Weinstock, 2005). Some studies report that the offspring of stressed mothers shows delay in the development of motor reflex, in addition to low weight at birth, which has been associated to depressive behaviors in adulthood (Drago et al., 1999; Emack et al., 2008; Gale and Martyn, 2004; Hauser et al., 2006; Meek et al., 2000; Patin et al., 2004; Van Den Hove et al., 2006). Besides the influence of prenatal events, the postnatal environment can influence early development and, in some cases, even reverse the deleterious effects of PNS. ...
... Despite the changes in the mothers' body weight induced by stress and/or diet, the litter size was not affected. These data are in line with other studies showing the effects of PNS on the mother and the litter (D'Mello and Liu, 2006; Morley-Fletcher et al., 2003; Patin et al., 2004; Smith et al., 2004; Van Den Hove et al., 2005). Our data on the mothers' corticosterone levels during pregnancy showed that the stressor induced a greater secretion of the hormone than the control situation on the first and last days of exposure, indicating a lack of adaptation to the stressor and corroborating previous studies (D'Mello and Liu, 2006; Zagron and Weinstock, 2006). ...
... Particularly, these findings guaranteed that the prenatal manipulation was effective in raising corticosterone levels in the mothers. Numerous studies have shown the impact of prenatal stress on juvenile and adult behavior (Burlet et al., 2005; Drago et al., 1999; Meek et al., 2000; Patin et al., 2004; Suchecki and Palermo Neto, 1991 ), but few have explored its effects or those of nutritional factors on the development of the litter until weaning. Our results showed that the righting reflex of male and female neonates was altered by diet, inasmuch as fish oil retarded and coconut fat accelerated this reflex, and by stress, since PNS pups tended to exhibit longer time to right their bodies than their control counterparts. ...
Adequate development of the central nervous system depends on prenatal and postnatal factors. On one hand, prenatal stress (PNS) has been implicated in impaired development of the offspring. On other hand, nutritional factors during pregnancy and lactation can influence fetal and postnatal growth. This study assessed the postnatal development of rat offspring exposed to PNS, which consisted of restraint and bright lights, 3 times/day, from days 14 to 20 of pregnancy, whose mothers were fed different diets during pregnancy and lactation: regular diet, diet supplemented with coconut fat or fish oil. When pregnancy was confirmed, they were distributed into control (CTL) or PNS groups. At birth, PNS males and females weighed less than those in the group CTL. At 21 days of age, this alteration was no longer observed with fish oil and coconut fat groups. PNS and coconut fat diet induced increased locomotor activity in 13 day old male and female pups, and this effect was prevented by fish oil supplementation only in females. In conclusion, postnatal development from birth to weaning was influenced by PNS and diet and some of those alterations were prevented by coconut fat and fish oil.
... Similar results were obtained in our study using chronic stress throughout gestation. Patin et al. (2004) demonstrated that the effects of PS on the offspring depend largely on the stage of fetal development and, in particular, on the development stage of the central nervous system. In this study, pregnant female rats were exposed to acute or repeated stress (cat presence) on the 10th (when the neural tube was being formed) or 14th (when gross structures of the central nervous system began to differentiate) days of gestation. ...
... Acquisition of the pups' precocious reflexes was delayed when the dams were subjected to the stressor at the 10th gestational day and, in most cases, was not when they were subjected to the stressor at the 14th gestational day. Repetitive stress had a greater effect than acute stress (Patin et al., 2004). ...
Fetal development is susceptible to environmental factors. One such factor is exposure to stress during pregnancy. The present study aimed to investigate the effects of chronic prenatal stress (PS) on the development and behavior of rat offspring during infancy and juvenile ages. Existing approaches to modeling prenatal stress on animals do not correlate with the main type of stress in pregnant women, namely psychological stress. We used a new stress paradigm in the experiment, namely, stress induced by exposure to variable frequency ultrasound (US), which acted on pregnant Wistar rats on gestational days 1–21. This type of stress in rodents can be comparable to psychological stress in humans. We assessed physical development, reflex maturation, motor ability development, anxious behavior, response to social novelty, and social play behavior in male and female offspring. Additionally, we investigated maternal behavior and the effect of neonatal handling (NH) on behavior. Prenatal stress did not affect postnatal developmental characteristics in rat pups, but prenatally stressed rats had higher body weight in early and adult age than controls. Prenatal exposure to a stressor increased anxiety in the open-field test (OF), changed social preferences in the social novelty test (SN), and impaired social play behavior in males. Neonatal handling reduced anxiety and restored social behavior, but evoked hyperactive behavior in rat pups. Maternal behavior did not change. Our study demonstrated for the first time that exposure to variable frequency ultrasound during pregnancy influences offspring development and impairs behavior, correlating with the effects of other types of stress during pregnancy in rodents. This supports the idea of using this exposure to model prenatal stress.
... Studies however are not all agreeing on the effects due to developmental stress exposure. As an example, some studies show an increase (Weller et al 1988), a decrease (Lehmann et al 2000, Patin et al 2004 or no change (Koenig et al 2005) delayed motor development (Patin et al 2004), deficits in learning and spatial learning (Lemaire et al 2000) and reduced cognitive flexibility (Thomas et al 2016) have also been described. Studies in rats also show that pups subjected to maternal deprivation display inhbited hippocampal plasticity due to hypersensitivity to glucocorticoids when they reach adulthood (Mirescu et al 2004). ...
... Studies however are not all agreeing on the effects due to developmental stress exposure. As an example, some studies show an increase (Weller et al 1988), a decrease (Lehmann et al 2000, Patin et al 2004 or no change (Koenig et al 2005) delayed motor development (Patin et al 2004), deficits in learning and spatial learning (Lemaire et al 2000) and reduced cognitive flexibility (Thomas et al 2016) have also been described. Studies in rats also show that pups subjected to maternal deprivation display inhbited hippocampal plasticity due to hypersensitivity to glucocorticoids when they reach adulthood (Mirescu et al 2004). ...
Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are disorders of mostly unknown etiopathogenesis, for which both genetic and environmental influences are expected to contribute to the phenotype observed in patients. Changes at all levels of brain function, from network connectivity between brain areas, over neuronal survival, synaptic connectivity and axonal growth, down to molecular changes and epigenetic modifications are suspected to play a key roles in these diseases, resulting in life-long behavioural changes. Genome-wide association as well as copy-number variation studies have linked cadherin-13 (CDH13) as a novel genetic risk factor to neuropsychiatric and neurodevelopmental disorders. CDH13 is highly expressed during embryonic brain development, as well as in the adult brain, where it is present in regions including the hippocampus, striatum and thalamus (among others) and is upregulated in response to chronic stress exposure. It is however unclear how CDH13 interacts with environmentally relevant cues, including stressful triggers, in the formation of long-lasting behavioural and molecular changes. It is currently unknown how the environment influences CDH13 and which long term changes in behaviour and gene expression are caused by their interaction. This work therefore investigates the interaction between CDH13 deficiency and neonatal maternal separation (MS) in mice with the aim to elucidate the function of CDH13 and its role in the response to early-life stress (ELS). For this purpose, mixed litters of wild-type (Cdh13+/+), heterozygous (Cdh13+/-) and homozygous knockout (Cdh13-/-) mice were maternally separated from postnatal day 1 (PN1) to postnatal day 14 (PN14) for 3 hours each day (180MS; PN1-PN14). In a first series of experiments, these mice were subjected to a battery of behavioural tests starting at 8 weeks of age in order to assess motor activity, memory functions as well as measures of anxiety. Subsequently, expression of RNA in various brain regions was measured using quantitativ real-time polymerase chain reaction (qRT-PCR). A second cohort of mice was exposed to the same MS procedure, but was not behaviourally tested, to assess molecular changes in hippocampus using RNA sequencing. Behavioural analysis revealed that MS had an overall anxiolytic-like effect, with mice after MS spending more time in the open arms of the elevated-plus-maze (EPM) and the light compartment in the light-dark box (LDB). As a notable exception, Cdh13-/- mice did not show an increase of time spent in the light compartment after MS compared to Cdh13+/+ and Cdh13+/- MS mice. During the Barnes-maze learning task, mice of most groups showed a similar ability in learning the location of the escape hole, both in terms of primary latency and primary errors. Cdh13-/- control (CTRL) mice however committed more primary errors than Cdh13-/- MS mice. In the contextual fear conditioning (cFC) test, Cdh13-/- mice showed more freezing responses during the extinction recall, indicating a reduced extinction of fear memory. In the step-down test, an impulsivity task, Cdh13-/- mice had a tendency to wait longer before stepping down from the platform, indicative of more hesitant behaviour. In the same animals, qRT-PCR of several brain areas revealed changes in the GABAergic and glutamatergic systems, while also highlighting changes in the gatekeeper enzyme Glykogensynthase-Kinase 3 (Gsk3a), both in relation to Cdh13 deficiency and MS. Results from the RNA sequencing study and subsequent gene-set enrichment analysis revealed changes in adhesion and developmental genes due to Cdh13 deficiency, while also highlighting a strong link between CDH13 and endoplasmatic reticulum function. In addition, some results suggest that MS increased pro-survival pathways, while a gene x environment analysis showed alterations in apoptotic pathways and migration, as well as immune factors and membrane metabolism. An analysis of the overlap between gene and environment, as well as their interaction, highlighted an effect on cell adhesion factors, underscoring their importance for adaptation to the environment. Overall, the stress model resulted in increased stress resilience in Cdh13+/+ and Cdh13+/- mice, a change absent in Cdh13-/- mice, suggesting a role of CDH13 during programming and adaptation to early-life experiences, that can results in long-lasting consequences on brain functions and associated behaviours. These changes were also visible in the RNA sequencing, where key pathways for cell-cell adhesion, neuronal survival and cell-stress adaptation were altered. In conclusion, these findings further highlight the role of CDH13 during brain development, while also shedding light on its function in the adaptation and response during (early life) environmental challenges.
... PS animals often show reduced dendritic spine density and dendritic atrophy in both ACC and OFC (Murmu et al. 2006). These anatomical changes induced by PS are associated with cognitive impairments, such as learning and memory deficits (Lemaire et al. 2000;Welberg and Seckl 2001;Bowman et al. 2004;Weinstock 2008;Glover 2011;Harris and Seckl 2011), delayed motor reflex development (Patin et al. 2004), and reduced motor ability and strength in later life (Kofman 2002;Canu et al. 2007;Cao et al. 2014) in both experimental animals and humans. ...
... Additionally, PS induces memory and learning impairments in males, while it improves these cognitive functions in females (Lemaire et al. 2000;Bowman et al. 2004;Son et al. 2006;Darnaudery and Maccari 2008). Human studies have reported greater motor deficits in male than the female PS offspring (Patin et al. 2004;Cao et al. 2014). Importantly, a particular outcome of PS may affect behavioral laterality in a sexually dimorphic manner, with males being more susceptible to laterality changes than females (Alonso et al. 1991(Alonso et al. , 1997Tang and Verstynen 2002). ...
In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate
new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations
differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching
and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational
stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted
paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled
walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the
shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater
spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness
and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral
traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.
... The test was performed on PN4, PN6, PN8 and PN10. The evaluations were performed according to the method of Patin et al. [29]. ...
... The test was carried out on PN6, PN8, PN10 and PN12. The evaluations were performed according to the method of Patin et al. [29]. ...
... There is an abundance of evidence illustrating the negative consequences associated with stress early in life (McCormick et al., 1995;Lemaire et al., 2000;Huizink et al., 2003;Patin et al., 2004;Lee et al., 2007). But there is also evidence suggesting that mild stress may be beneficial. ...
... Although the skills required to complete the negative geotaxis task are not fully understood, the task is often used as a milestone for early sensorimotor development in rats (Alberts et al., 2004;Patin et al., 2004). The current results suggest that prenatal stress alters sensorimotor development. ...
There is a general consensus that prenatal stress alters offspring brain development, however, the details are often inconsistent. Hypothesizing that variation to the level of stress would produce different maternal experiences; this study was designed to examine offspring outcomes following a single prenatal stress paradigm at two different intensities. Pregnant Long Evans rats received mild, high, or no-stress from gestational days 12-16. Offspring underwent early behavioural testing and global methylation patterns were analysed from brain tissue of the frontal cortex and hippocampus. The two different prenatal stress intensities produced significantly different and often, opposite effects in the developing brain. Mild prenatal stress decreased brain weight in both males and females, whereas extreme stress increased female brain weight. Mild prenatal stress slowed development of sensorimotor abilities and decreased locomotion, whereas high prenatal stress also slowed development of sensorimotor learning but increased locomotion. Finally, mild prenatal stress increased global DNA methylation levels in the frontal cortex and hippocampus whereas high prenatal stress was associated with a dramatic decrease. The data from this study provide evidence to support a dose-dependent effect of prenatal stress on multiple aspects of brain development, potentially contributing to long-term outcomes.
... The presentation of these reflexes in newborns is altered by exposure to stressful situations in the dams, showing full development 14 days post-parturition. This shows how the prenatal stage influences not only the response from the mother but the offspring as well [32]. To compensate for the delayed maturation, murine mothers spend approximately a total of 10.6% of their time in the first week of life grooming and licking the pups [33]. ...
Mother–young bonding is a type of early learning where the female and their newborn recognize each other through a series of neurobiological mechanisms and neurotransmitters that establish a behavioral preference for filial individuals. This process is essential to promote their welfare by providing maternal care, particularly in altricial species, animals that require extended parental care due to their limited neurodevelopment at birth. Olfactory, auditory, tactile, and visual stimuli trigger the neural integration of multimodal sensory and conditioned affective associations in mammals. This review aims to discuss the neurobiological aspects of bonding processes in altricial mammals, with a focus on the brain structures and neurotransmitters involved and how these influence the signaling during the first days of the life of newborns.
... Offspring exposed to stress during gestational development miss neurological development milestones (Mesquita et al., 2007), specifically those related to motor function development. Offspring then will also exhibit stunted motor function at adulthood (Patin, Vincent, Lordi, & Caston, 2004). Specifically, protein deficiency (Woodward, 1998) during gestation results in smaller body size, gene expression changes in the liver and muscle tissue, hyperinsulinemia, hypertension, severe brain development delay, and endocrine changes (Almeida & Mandarim-de-Lacerda, 2005;Boersma & Tamashiro, 2015;Dahri, Snoeck, Reusens-Billen, Remacle, & Hote, 1991;Fernandez-Twinn et al., 2005;Gonzalez, Lotto, & Hallgrímsson, 2014;Gressens et al., 1997;Langley-Evans, Welham, & Jackson, 1999;Langley-Evans, Welham, Sherman, & Jackson, 1996;Mortensen et al., 2010). ...
Maternal malnutrition during gestation and lactation is known to have adverse effects on offspring. We evaluate the impact of maternal diet on offspring bony labyrinth morphology. The bony labyrinth develops early and is thought to be stable to protect vital sensory organs within. For these reasons, bony labyrinth morphology has been used extensively to assess locomotion, hearing function, and phylogeny in primates and numerous other taxa. While variation related to these parameters has been documented, there is still a component of intraspecific variation that is unexplained. Although the labyrinthine developmental window is small, it may provide the opportunity for developmental instability to produce corresponding shape differences, as measured by fluctuating asymmetry (FA). We hypothesized that (a) offspring with poor maternal diet would exhibit increased FA, but (b) no unilateral shape difference. To test these hypotheses, we used two groups of rats (Rattus norvegicus; Crl:WI[Han] strain), one control group and one group exposed to a isocaloric, protein‐restricted maternal diet during gestation and suckling. Individuals were sampled at weaning, sexual maturity, and old age. A Procrustes analysis of variance identified statistically significant FA in all diet‐age subgroups. No differences in level of FA were identified among the subgroups, rejecting our first hypothesis. A principal components analysis identified no unilateral shape differences, supporting our second hypothesis. These results indicate that bony labyrinth morphology is remarkably stable and likely protected from a poor maternal diet during development. In light of this result, other factors must be explored to explain intraspecific variation in labyrinthine shape.
... Others report no or little effect of stress (Chapman and Stern, 1979;Van den Hove et al., 2005), or even opposite effects according to sex (Alonso et al., 1991). The majority of studies however, find decreases in movement and "exploration" in the offspring of females subjected to a variety of stressors during pregnancy (Hockman, 1961;Fride et al., 1986;Suchecki and Neto, 1991;Poltyrev et al., 1996;Vallee et al., 1997;Fujioka et al., 2001;Patin et al., 2004). Thus it seems that cuttlefish may differ in this respect from most vertebrate models and could therefore serve as a means to explore the Frontiers in Physiology | www.frontiersin.org ...
Ette thèse est centrée sur les capacités sensorielles, cognitives et sur les effets du stress chez deux espèces de seiche : Sepia officinalis et Sepia pharaonis. Nous avons d’abord démontré que les embryons répondent à différents stimuli environnementaux (lumière, proies, prédateurs, encre de seiche) mettant en évidence que l'information sensorielle passe à travers la capsule de l'œuf, ce qui permet une continuité sensorielle transnatale. De telles réponses sont possibles puisque leur système chimiosensoriel et visuel sont fonctionnels avant l'éclosion. Nous avons également montré que les embryons des deux espèces sont capables d'apprentissage simple (empreinte alimentaire) et associatif (conditionnement classique) et que ces capacités précoces pourraient augmenter leurs chances de survie avant et après l'éclosion en permettant la reconnaissance des proies et des prédateurs. Enfin, nous avons montré que le stress embryonnaire naturel (odeur de prédateur) et artificiel (lumière) ont des effets modérés voire nuls sur les capacités d’apprentissage périnatal. Ces résultats comportementaux ont été observés sans grande différence entre les deux espèces qui vivent pourtant dans des environnements très éloignés. Pris ensemble, ces résultats démontrent que les embryons de seiche ne sont pas isolés de leur environnement mais détectent et traitent les informations environnementales qui modulent leur comportement après l’éclosion.
... Prenatal stress (PS) signifies the exposure of a pregnant mother to distress and can lead to neurological disorders in offspring (Berger, Barros, Sarchi, Tarazi, & Antonelli, 2002;Patin, Lordi, & Caston, 2004). In humans, fetal exposure to chronically high levels of endogenous maternal corticosteroids (Takahashi, Turner, & Kalin, 1998) has been associated with adverse birth outcomes, including preterm birth (Stott, 1973), fetal growth retardation (Cliver et al., 1992), delays in early motor development (Sandman, Wadhwa, Chicz-DeMet, Dunkel-Schetter, & Porto, 1997), behavioral abnormalities (Trautman, Meyer-Bahlburg, Postelnek, & New, 1995), sleep disturbances (Weinstock, 1997), the development of psychiatric disorders, such schizophrenia and depression, in later life (Huttenen & Niskanem, 1978;Meier, 1985), and epileptic seizures (Gholipoor et al., 2017;Thébault-Dagher et al., 2017). ...
Stress during gestation has been shown to affect susceptibility and intensity of seizures in offspring. Environmental stimuli, such as maternal physical exercise, have shown to be beneficial for brain development. Although studies have demonstrated the deleterious influence of stress during pregnancy on seizure manifestation in offspring, very little is known on how to minimize these effects. This study verified whether physical exercise during the pregnancy associated with prenatal stress minimizes seizure susceptibility in offspring at the beginning of postnatal development. Pregnant rats and male pups were divided into the following groups: control, stress, stress/forced exercise, and stress/voluntary exercise. Behavioral manifestations were analyzed after injection of pentylenetetrazol (PTZ; 45 and 60 mg/kg) at ages P15 and P25. Increased behavioral manifestations and seizure severity was observed in the stress group compared with the control group at both ages. At the dose of 45 mg/kg, offspring of stressed mothers who performed both physical exercise models showed an increase in latency for the first manifestation and decrease in the seizures severity at both ages compared with the mothers groups who were only stressed. Prenatal restraint stress potentiated PTZ‐induced seizure behavior, and both forced and voluntary exercise during gestation attenuates the negative effects of PTZ‐induced offspring.
... The effects of prenatal stress on activity have been studied most extensively in rodents, especially rats, and results are mixed. Some authors (Hilakivi, Ota, and Lister 1989;Masterpasqua, Chapman, and Lore 1976;Peters 1986;Sandi, Venero, and Guaza 1996 The majority of studies however, find decreases in movement and "exploration" in the offspring of females subjected to a variety of stressors during pregnancy (Fride et al. 1986;Fujioka et al. 2001;Hockman 1961;Patin et al. 2004;Poltyrev et al. 1996;Suchecki and Neto 1991;Vallee et al. 1997). Thus it seems that cuttlefish may differ in this respect from most vertebrate models and could therefore serve as a means to explore the factors driving the evolution of this response in different animal groups. ...
Prenatal stress is a subject of growing ethological interest due to its effects on human health and animal welfare. This Ph.D. thesis utilizes the cuttlefish Sepia officinalis, a convenient model in which developing offspring can be separated from their mothers to examine various potential sources of stress in experimental isolation. Several categories of stressors were applied to cuttlefish and cuttlefish eggs and the resulting offspring were tested in a range of physiological and behavioral tests. The goal was to determine if various types of prenatal stress affect cuttlefish, and if so, how these effects are transmitted. The data presented demonstrate that both stressors applied to reproducing females (maternal stress), as well as stressors applied directly to embryos (embryonic stress), affected post-natal behavior (including body patterning, brain lateralization, predation and activity patterns), learning, memory and/or neurobiology (including monoamine concentrations and turnover, the size of various brain lobes and cell division). The results highlight the presence of three pathways by which stress can exert effects: on the number of offspring produced by the female, transmission from the female to her offspring and directly on the offspring themselves. The experiments also demonstrated that a completely artificial stressor (bright light) affected a wider range of behaviors in offspring than a natural-occurring one (predator odor). Finally, the data showed that incubation and spawning environment can also affect offspring, and thus deserve attention in the formulation and interpretation of experiments with this species. These findings inform both welfare practices for cuttlefish and other cephalopods (e.g. reduce handling to maximize reproduction) as well as elucidating and reinforcing ethological principles that apply to animal stress in general (e.g. the transmission of stress effects from mother to offspring). Given the insight provided here and in numerous other studies, cuttlefish and other cephalopods should continue to serve as behavioral models in ethology and biology in general.
... Others report no or little effect of stress (Chapman and Stern, 1979;Van den Hove et al., 2005), or even opposite effects according to sex (Alonso et al., 1991). The majority of studies however, find decreases in movement and "exploration" in the offspring of females subjected to a variety of stressors during pregnancy (Hockman, 1961;Fride et al., 1986;Suchecki and Neto, 1991;Poltyrev et al., 1996;Vallee et al., 1997;Fujioka et al., 2001;Patin et al., 2004). Thus it seems that cuttlefish may differ in this respect from most vertebrate models and could therefore serve as a means to explore the factors driving the evolution of this response in different animal groups. ...
Stress experienced during prenatal development—either applied to reproducing females (maternal stress), directly to developing offspring (embryonic stress) or in combination—is associated with a range of post-natal behavioral effects in numerous organisms. We conducted an experiment to discern if maternal and embryonic stressors affect the behavior of hatchlings of the cuttlefish Sepia officinalis, a species with features that allow for the examination of these stress types in isolation. Separating the impact of stress transmitted through the mother vs. stress experienced by the embryo itself will help clarify the behavioral findings in viviparous species for which it is impossible to disentangle these effects. We also compared the effect of a naturally-occurring (predator cue) and an “artificial” (bright, randomly-occurring LED light) embryonic stressor. This allowed us to test the hypothesis that a threat commonly faced by a species (natural threat) would be met with a genetically-programmed and adaptive response while a novel one would confound innate defense mechanisms and lead to maladaptive effects. We found that the maternal stressor was associated with significant differences in body patterning and activity patterns. By contrast, embryonic exposure to stressors increased the proportion of individuals that pursued prey. From these results, it appears that in cuttlefish, maternal and embryonic stressors affect different post-natal behavior in offspring. In addition, the effect of the artificial stressor suggests that organisms can sometimes react adaptively to a stressor even if it is not one that has been encountered during the evolutionary history of the species.
... In a study on pregnant rats exposed to an acute or a repeated stress (presence of a cat) either at the gestational day (GD) 10 or 14, the development of the vibrissae placing response, the righting reflex, and the negative geotaxis behavior was delayed, particularly with a repeated stressor, in the offspring of dams stressed at the GD 10 when offspring were assessed through the first two weeks of life. The delay in motor development was interpreted as an alteration in maturation of nervous structures due to prenatal stress 69 . Another study revealed that hindlimb unloading, a ground-based model widely used to plan the absence of weight support on hindlimbs, severely impaired motor activity and skilled walking in rats. ...
Noise stress is a common environmental pollutant whose adverse effect on offspring performance has been less studied. This study was novel in terms of using “noise” as a prenatal stress compared with physical stress to explore the effect of stress during gestation on HPA axis activation, cognitive performance, and motor coordination, as well as in investigating the effect of behavioral assessments on the corticosterone (CORT) levels. Three groups of C57BL/6 mice with a gestational history of either noise stress (NS), physical stress (PS), or no stress were examined in several behavioral tests. Plasma CORT level was significantly higher before starting the behavioral tests in NS group than the two other groups. It was significantly increased after the behavioral tests in both prenatal stressed groups relative to the controls. Stress caused anxiety-like behavior and reduced learning and memory performance in both stressed groups compared to the controls, as well as decreased motor coordination in the NS group relative to the other groups. The findings suggested that: prenatal NS severely changes the HPA axis; both prenatal stressors, and particularly NS, negatively impair the offspring’s cognitive and motor performance; and, they also cause a strong susceptibility to interpret environmental experiences as stressful conditions.
... The stress protocol was conducted from GND14 to GND20 as described by Cassim et al. 17 Stress was introduced on GND14 because this is when gross neural structures of the CNS start specializing and also because the placental barrier becomes less active, thus the foetus is exposed to maternal stress hormones. 18,19 Postnatal handling Febrile seizure induction. Following birth, the pups remained with their dams until postnatal day (PND) 14. ...
Febrile seizures are childhood convulsions resulting from an infection that leads to an inflammatory response and subsequent convulsions. Prenatal stress has been shown to heighten the progression and intensity of febrile seizures. Current medications are costly and have adverse effects associated with prolonged use. Quercetin flavonoid exhibits anti-inflammatory, anti-convulsant, and anti-stress effects. This study was aimed to investigate the therapeutic effect of quercetin in a prenatally stressed rat model of febrile seizures. We hypothesized that quercetin will alleviate the effects of prenatal stress in a febrile seizure rat model. On gestational day 13, Sprague-Dawley rat dams were subjected to restraint stress for 1 hour/d for 7 days. Febrile seizures were induced on postnatal day 14 on rat pups by intraperitoneally injecting lipopolysaccharide followed by kainic acid and quercetin on seizure onset. Hippocampal tissue was harvested to profile cytokine concentrations. Our results show that quercetin suppresses prenatal stress–induced pro-inflammatory marker (interleukin 1 beta) levels, subsequently attenuating febrile seizures. This shows that quercetin can be therapeutic for febrile seizures in prenatally stressed individuals.
... It has been observed that prenatal stress (PS) generates effects on the brain, affecting structures like the cortex ( (Ulupinar & Yucel, 2005), hippocampus (Bock, Murmu, Biala, Weinstock, & Braun, 2011;Bustamante et al., 2010;Fujioka et al., 2006;Hayashi et al., 1998;Hosseini-sharifabad and Hadinedoushan, 2007;Jia et al., 2010;Martínez-Téllez, Hernández-Torres, Gamboa, & Flores, 2009;Mychasiuk et al., 2011), accumbens nucleus (Hayashi et al., 1998;Muhammad et al., 2012), and amygdala (Salm et al., 2004). Moreover, PS clinically affects cognitive, social and neuromotor development in offspring (Canu, Darnaudéry, Falempin, Maccari, & Viltart, 2007;Gué et al., 2004;Lee, Brady, Shapiro, Dorsa, & Koenig, 2007;Patin, Vincent, Lordi, & Caston, 2004;Vallée et al., 1999). Both the hippocampus and amygdala are rich in glucocorticoid receptors, making them a target for the HPA axis (Tottenham & Sheridam, 2010). ...
... Em roedores, diversos protocolos estressores aplicados durante o período gestacional têm como objetivo recriar alguns dos muitos distúrbios já mencionados. Entre os mais comumente utilizados incluem: o estresse variado não previsível (KINNUNEN;KOENIG;BILBE, 2003;KOENIG et al., 2005); estresse com a presença de predador natural (PATIN et al., 2002;PATIN et al., 2004) e o estresse por contenção (CHAMPAGNE; MEANEY, 2006). O Estresse por contenção tem sido mais amplamente usado por provocar alterações comportamentais e neuroendócrinas mais significativas quando comparado a outros protocolos (RICHARDSON et al., 2006;GRAIGNIC-PHILIPPE et al., 2014). ...
... Ainsi, une modification de la réactivité émotionnelle a été mise en évidence à de nombreuses reprises chez les rongeurs, cette modification de la réactivité se traduisant le plus souvent par une diminution du comportement locomoteur des jeunes et une augmentation de leur néophobie (Braastad 1998). Des retards dans le développement moteur sont également observés chez les ratons issus de mères stressées par un chat pendant la gestation (Patin et al 2004). Le stress prénatal modifie les capacités d'apprentissage des jeunes rats et souris, soit en les diminuant soit en les facilitant (Archer et Blackman 1971). ...
Stress that occurs during pregnancy can have consequences on the behaviour of offspring such as increased emotional reactivity, impaired learning ability and feminisation of male sexual behaviour. A modification of the hypothalamo-pituitary axis is often observed, for example, an increase in basal glucocorticoid concentrations and a higher secretion rate after a stressful event. Immune responses can also be modified, and birth-weight reduced. However, there is a high level of variability in the effects of prenatal stress. This may be due to the type of stressor, its intensity and period of application during pregnancy. The effect may also differ according to the gender of the offspring, with females appearing to be more affected than males. Stress experienced by a dam during pregnancy could have consequences on neuroendocrine development in the foetus. Maternal hormones secreted during stress, which can cross the placental barrier, could be one of the mechanisms explaining these effects. Modification of maternal behaviour due to chronic stress may also be involved in the effect on the behaviour of the offspring. Most studies have been performed on rodents and primates but the few experiments involving farm animals tend to show that the consequences can be important.
... The second type consists of regimens of unpredictable/variable stressors usually over the last week of gestation. There are widespread effects of prenatal stress on virtually all aspects of physiology: immune function (Götz et al., 2007;Llorente et al., 2002), sensorimotor function (Canu et al., 2007;Patin et al., 2004), cardiovascular system (Igosheva et al., 2007, responses to pain (Butkevich et al., 2007;Kinsley et al., 1988), and changes in sleep (Rao et al., 1999). One of the most marked effects of maternal stress is that it results in altered development of the HPA axis of offspring. ...
Through all stages of life, the function of the central nervous system is shaped by the hypothalamic-pituitary-adrenal (HPA) axis. As such, the extent to which HPA function is modified during sensitive periods of development has lifelong consequences for the individual. Here we describe fetal and neonatal development of the HPA axis and how maternal physiology and maternal behavior moderate this development. The specific factors discussed are the consequences to the developing fetus and neonate of elevations in maternal glucocorticoids through her experience of stress, of variation in maternal diet and nutrition, and of variations in naturally occurring maternal care and neglect. Also discussed is the lasting impact of altered perinatal development for the animal in later stages of life and for its offspring (intergenerational effects). Lastly, development of the HPA axis is considered with respect to windows of vulnerability for mental pathologies and metabolic disorders in adulthood.
... Ainsi, une modification de la réactivité émotionnelle a été mise en évidence à de nombreuses reprises chez les rongeurs, cette modification de la réactivité se traduisant le plus souvent par une diminution du comportement locomoteur des jeunes et une augmentation de leur néophobie (Braastad 1998). Des retards dans le développement moteur sont également observés chez les ratons issus de mères stressées par un chat pendant la gestation (Patin et al 2004). Le stress prénatal modifie les capacités d'apprentissage des jeunes rats et souris, soit en les diminuant soit en les facilitant (Archer et Blackman 1971). ...
Stress that occurs during pregnancy can have consequences on the behaviour of offspring such as increased emotional reactivity, impaired learning ability and feminisation of male sexual behaviour. A modification of the hypothalamo-pituitary axis is often observed, for example, an increase in basal glucocorticoid concentrations and a higher secretion rate after a stressful event. Immune responses can also be modified, and birth-weight reduced. However, there is a high level of variability in the effects of prenatal stress. This may be due to the type of stressor, its intensity and period of application during pregnancy. The effect may also differ according to the gender of the offspring, with females appearing to be more affected than males. Stress experienced by a dam during pregnancy could have consequences on neuroendocrine development in the foetus. Maternal hormones secreted during stress, which can cross the placental barrier, could be one of the mechanisms explaining these effects. Modification of maternal behaviour due to chronic stress may also be involved in the effect on the behaviour of the offspring. Most studies have been performed on rodents and primates but the few experiments involving farm animals tend to show that the consequences can be important.
... The non-stressed rats were left undisturbed in their home cages. The stressed rats were taken to a different room and placed in rodent restrainers for 45 min, 3 times a day at 3 h intervals, starting at 09 h 00 (Patin et al., 2004;Wilson et al., 2013). The rats were returned to the housing room at the end of each stress period. ...
It is estimated that more than 80% of patients with epilepsy live in developing countries with 50-60% of them being children. This high prevalence is perpetuated by low socio-economic challenges, poor health care facilities and lack of drug affordability. Searsia chirindensis formerly known as rhus chirindensis and commonly known as 'Red Current' is a popular traditional medicinal plant, which has been used to treat a number of illnesses such as heart complaints and neurological disorders. The aim of this study is to investigate the effects of Searsia chirindensis on the development of febrile seizure in a prenatally stressed rat. Febrile seizures were induced by administering lipopolysaccharide to 14 day old rat pups followed by kainic acid. A subset of the rats was treated with Searsia after induction of febrile seizures. Interleukin-1β (IL-1β) levels were measured in plasma. Lipid peroxidation was determined in liver tissue. Our data shows that treatment with Searsia reduced interleukin-1β levels in plasma of the febrile seizure rats and prevented lipid oxidation in the liver. Prenatal stress is dampened by the beneficial effects of Searsia on seizure development in rat pups. These results highlight the potentiating effects of Searsia in the reversal of febrile seizures and prenatal stress effects.
Copyright © 2015. Published by Elsevier Ireland Ltd.
... As the hydrocephalus developing in the C57BL/6J background of KO mice, but at most slightly enlarged ventricles in the 129Sv background, demonstrates, the strain can make decisive contributions to the manifestation of effects (Dahme et al., 1997;Demyanenko et al., 1999). In addition, different handling of mice influences performance of mice in all sorts of paradigms, even those measuring locomotor ability (Patin et al., 2004). Anyway, the motor impairment of KO mice that has been reported as a personal observation (Fransen et al., 1998a), could be better determined and quantified in this study by using the pole test. ...
... Both male and female offspring in the maternal enrichment group exhibited a reduction in the amount of time spent upwards on the negative geotaxis platform. Although the skills needed to complete this task are not fully understood, it is often used as a milestone for sensorimotor development in young rats [28,29]. It is possible that offspring in this group demonstrate decreased performance on the task because maternal enrichment during pregnancy is slowing brain maturation of offspring, which should promote greater plasticity later in life. ...
Environmental enrichment has been shown to have profound effects on the healthy adult brain and as a remedial tool for brains compromised by injury, disease, or negative experience. Based upon these findings and evidence from the prenatal stress literature, we ventured an exploratory study to examine the effects of parental enrichment on offspring development. Using Long Evans rats, paternal enrichment was achieved by housing sires in enriched environments for 28 days prior to mating with a control female. For the maternal enrichment paradigm, female rats were also housed in enriched environments for 28 days (7 days prior to conception and for the duration of pregnancy). Increased size, multiple levels for exploration, an abundance of stimulating toys, and numerous cagemates for social interaction were characteristic of the enriched environments. Offspring were assessed using two early behavioral tests and then sacrificed at postnatal day 21 (P21). Brain tissue from the frontal cortex and hippocampus was harvested for global DNA methylation analysis. Parental enrichment, preconceptionally and prena-tally, altered offspring behavior on the negative geotaxis task and openfield exploratory behavior task. Paternal enrichment significantly decreased offspring brain weight at P21. Additionally, both environmental enrichment paradigms significantly decreased global methylation levels in the hippocampus and frontal cortex of male and female offspring. This study demonstrates that positive prenatal experiences; preconceptionally in fathers and prenatally in mothers, have the ability to significantly alter offspring developmental trajectories.
... With regard to behavioral modification, parental manipulations either negative, as food restriction, benzodioxin exposure or maternal stress, or positive, as environmental enrichment, alter the maturation of reflexes and motor coordination as well as the cognitive and emotional offspring development (Patin et al., 2004;Nishijo et al., 2007;Zhang et al., 2010;Mychasiuk et al., 2011Mychasiuk et al., , 2012Qin et al., 2011). Namely, several reports describe the effects of prenatal EE exposure, using different rat strains, schedules and protocols of environmental enrichment, and various behavioral tests (McKim and Thompson, 1975;Kiyono et al., 1985;Koo et al., 2003;Mychasiuk et al., 2012;Rosenfeld and Weller, 2012). ...
Environmental enrichment is usually applied immediately after weaning or in adulthood, with strong effects on CNS anatomy and behavior. To examine the hypothesis that a pre-reproductive environmental enrichment of females could affect the motor development of their offspring, female rats were reared in an enriched environment from weaning to sexual maturity, while other female rats used as controls were reared under standard conditions. Following mating with standard-reared males, all females were housed individually. To evaluate the eventual transgenerational influence of positive pre-reproductive maternal experiences, postural and motor development of male pups was analyzed from birth to weaning. Moreover, expression of Brain Derived Neurotrophic Factor and Nerve Growth Factor in different brain regions was evaluated at birth and weaning. Pre-reproductive environmental enrichment of females affected the offspring motor development, as indicated by the earlier acquisition of complex motor abilities displayed by the pups of enriched females. The earlier acquisition of motor abilities was associated with enhanced neurotrophin levels in striatum and cerebellum. In conclusion, maternal positive experiences were transgenerationally transmitted, and influenced offspring phenotype at both behavioral and biochemical levels.
... Locomotor Activity-Developmental exposures to MeHg as well as to PS have previously been reported to alter motor activity (Emack and Matthews, 2011;Franco et al., 2006;Goulet et al., 2003;Kim et al., 2000;Montgomery et al., 2008;Patin et al., 2004), and such alterations could influence FI and/or NOR performance. Therefore, locomotor activity was measured in an automated open field arena (43.2 cm × 43.2 cm × 30.5 cm; Med Associates Inc., St. Albans, Vermont) housed in sound-attenuated enclosures ventilated by a fan for a 60 min period. ...
Methylmercury (MeHg) and prenatal stress (PS) are risk factors for neurotoxicity that may co-occur in human populations. Because they also share biological substrates and can produce common behavioral deficits, this study examined their joint effects on behavioral and neurochemical effects in male and female rats. Dams had access to 0, 0.5 or 2.5 ppm MeHg chloride drinking water from two weeks prior to breeding through weaning. Half of the dams in each of these treatment groups also underwent PS on gestational days 16-17. This yielded 6 groups/gender: 0-NS, 0-PS, 0.5-NS, 0.5-PS, 2.5-NS, and 2.5-PS. Behavioral testing began in young adulthood and included Fixed Interval (FI) schedule-controlled behavior, novel object recognition (NOR) and locomotor activity, behaviors previously demonstrated to be sensitive to MeHg and/or mediated by brain mesocorticolimbic dopamine glutamate systems targeted by both MeHg and PS. Behavioral deficits were more pronounced in females and included impaired NOR recognition memory only under conditions of combined MeHg and PS, while non-monotonic reductions in FI response rates occurred, with greatest effects at the 0.5 ppm concentration; the less reduced 2.5 ppm FI response rates were further reduced under conditions of PS (2.5-PS). Correspondingly, many neurochemical changes produced by MeHg were only seen under conditions of PS, particularly in striatum in males and in hippocampus and nucleus accumbens in females, regions of significance to the mediation of FI and NOR performance. Collectively these findings demonstrate sex-dependent and non-monotonic effects of developmental MeHg exposure that can be unmasked or enhanced by PS, particularly for behavioral outcomes in females but for both sexes in neurochemical changes, that were observed at MeHg exposure concentrations that did not influence either reproductive outcomes or maternal behavior. Thus, assessment of risks associated with MeHg may be underestimated in the absence of other extant risk factors with which it may share common substrates and effects.
... negative geotaxis task have not been fully appreciated, the paradigm has been reliably used as a measure of sensorimotor development (Alberts et al., 2004;Patin et al., 2004). Offspring of fathers who experienced chronic stress were significantly impaired at the negative geotaxis task when tested on P9, but had recovered by P10 and were indistinguishable from control offspring. ...
Although there has been an abundance of research focused on offspring outcomes associated with maternal experiences, there has been limited examination of the relationship between paternal experiences and offspring brain development. As spermatogenesis is a continuous process, experiences that have the ability to alter epigenetic regulation in fathers may actually change developmental trajectories of offspring. The purpose of this study was to examine the effects of paternal stress prior to conception on behaviour and the epigenome of both male and female developing rat offspring. Male Long-Evans rats were stressed for 27 consecutive days and then mated with control female rats. Early behaviour was tested in offspring using the negative geotaxis task and the open field. At P21 offspring were sacrificed and global DNA methylation levels in the hippocampus and frontal cortex were analyzed. Paternal stress prior to conception altered behaviour of all offspring on the negative geotaxis task, delaying acquisition of the task. In addition, male offspring demonstrated a reduction in stress reactivity in the open field paradigm spending more time than expected in the centre of the open field. Paternal stress also altered DNA methylation patterns in offspring at P21, global methylation was reduced in the frontal cortex of female offspring, but increased in the hippocampus of both male and female offspring. The results from this study clearly demonstrate that paternal stress during spermatogenesis can influence offspring behaviour and DNA methylation patterns, and these affects occur in a sex-dependent manner. Development takes place in the centre of a complex interaction between maternal, paternal, and environmental influences, which combine to produce the various phenotypes and individual differences that we perceive.
... Des troubles de l'humeur sont également retrouvés dans la progéniture, se traduisant par des phénotypes anxiodépressifs, avec une réduction du comportement exploratoire et de la motivation [11]. On note aussi une majoration de l'anxiété sous-tendue par des mécanismes moléculaires, comme la réduction de l'expression des récepteurs de la sérotonine [12]. ...
Depuis deux décennies, la recherche expérimentale s’est efforcée de modéliser le stress périnatal et ses conséquences cliniques
et biologiques. En laboratoire, l’effet du stress s’apparente à celui d’une programmation développementale et peut rendre
compte de la survenue ultérieure de pathologies neuropsychologiques. Si un tel niveau de preuve n’est pas établi en clinique
humaine, plusieurs observations suggèrent l’intervention modulatrice du stress périnatal dans le développement à court et
long terme de l’enfant, ainsi qu’une vulnérabilité accrue aux troubles psychopathologiques. Après avoir rappelé les principaux
modèles, cette revue présente quelques stratégies cliniques intégrant la gestion du stress dans l’objectif d’en limiter le
retentissement.
Over the past 20 years, experimental researchers have attempted to experimentally model perinatal stress in order to determine
its clinical and biological consequences. In the laboratory, the effect of stress appears similar to that of developmental
programming and could account for the subsequent occurrence of neuropsychological pathologies. Although this level of proof
has not been clinically established, several observations suggest that perinatal stress has a modulating effect on the infant’s
short- and long-term development, with an increased vulnerability for psychiatric disorders. This review considers the principal
models and then presents some of the clinical strategies that integrate stress management in order to limit its repercussions.
Mots clésDéveloppement neuropsychologique-Lien mère-enfant-Pathologie développementale-Soins de développement-Stress périnatal
KeywordsDevelopmental origin of adult disease-Developmental care-Mother-infant bond-Neuropsychological development-Perinatal stress
... Both male and female offspring in the maternal enrichment group exhibited a reduction in the amount of time spent upwards on the negative geotaxis platform. Although the skills needed to complete this task are not fully understood, it is often used as a milestone for sensorimotor development in young rats [28,29]. It is possible that offspring in this group demonstrate decreased performance on the task because maternal enrichment during pregnancy is slowing brain maturation of offspring, which should promote greater plasticity later in life. ...
Environmental enrichment has been shown to have profound effects on the healthy adult brain and as a remedial tool for brains compromised by injury, disease, or negative experience. Based upon these findings and evidence from the prenatal stress literature, we ventured an exploratory study to examine the effects of parental enrichment on offspring development. Using Long Evans rats, paternal enrichment was achieved by housing sires in enriched environments for 28 days prior to mating with a control female. For the maternal enrichment paradigm, female rats were also housed in enriched environments for 28 days (7 days prior to conception and for the duration of pregnancy). Increased size, multiple levels for exploration, an abundance of stimulating toys, and numerous cagemates for social interaction were characteristic of the enriched environments. Offspring were assessed using two early behavioral tests and then sacrificed at postnatal day 21 (P21). Brain tissue from the frontal cortex and hippocampus was harvested for global DNA methylation analysis. Parental enrichment, preconceptionally and prenatally, altered offspring behavior on the negative geotaxis task and openfield exploratory behavior task. Paternal enrichment significantly decreased offspring brain weight at P21. Additionally, both environmental enrichment paradigms significantly decreased global methylation levels in the hippocampus and frontal cortex of male and female offspring. This study demonstrates that positive prenatal experiences; preconceptionally in fathers and prenatally in mothers, have the ability to significantly alter offspring developmental trajectories.
... Aversive events during pregnancy impair fetal development and produce short-and long-term alterations (Barbazanges et al., 1996;Burlet et al., 2005;Drago et al., 1999;Emack et al., 2008;Lemaire et al., 2006;Morley-Fletcher et al., 2003a;Morley-Fletcher et al., 2003b;Weinstock, 1997). These changes, that have been claimed to result from the exposure to high levels of corticosterone (Catalani et al., 2000;Maccari et al., 2003;Zagron and Weinstock, 2006), include low birth weight, delay in growth and motor development and behavioral impairment in novel situations (Burlet et al., 2005;Drago et al., 1999;Emack et al., 2008;Hauser et al., 2006;Patin et al., 2004;Secoli and Teixeira, 1998). Corticosterone secretion can be modulated by nutritional factors, provided either pre-or post-natally. ...
Prenatal stress (PNS) during critical periods of brain development has been associated with numerous behavioral and/or mood disorders in later life. These outcomes may result from changes in the hypothalamic-pituitary-adrenal (HPA) axis activity, which, in turn, can be modulated by environmental factors, such as nutritional status. In this study, the adult male offspring of dams exposed to restraint stress during the last semester of pregnancy and fed different diets were evaluated for depressive-like behavior in the forced swimming test and for the corticosterone response to the test. Female Wistar rats were allocated to one of three groups: regular diet, diet supplemented with coconut fat or with fish oil, offered during pregnancy and lactation. When pregnancy was confirmed, they were distributed into control or stress groups. Stress consisted of restraint and bright light for 45 min, three times per day, in the last week of pregnancy. The body weight of the adult offspring submitted to PNS was lower than that of controls. In the forced swimming test, time of immobility was reduced and swimming was increased in PNS rats fed fish oil and plasma corticosterone levels immediately after the forced swimming test were lower in PNS rats fed regular diet than their control counterparts; this response was reduced in control rats whose mothers were fed fish oil and coconut fat. The present results indicate that coconut fat and fish oil influenced behavioral and hormonal responses to the forced swimming test in both control and PNS adult male rats.
Background
Febrile seizures (FS) are a neurological abnormality which occur following a fever that has resulted from a systemic infection and are characterized by convulsions. These convulsions occur due to abnormally increased signalling of interleukin-1 beta, resulting in increased neuronal hyper-excitability. Furthermore, exposure to prenatal stress has been shown to exacerbate seizure duration, elicit anxiety-like behaviour and corticosterone levels. Oxytocin is a neuropeptide with anxiolytic, social bonding, and stress regulation effects. Therefore, the aim of the study was to assess whether oxytocin can attenuate the anxiety-like behaviour and increased corticosterone in rat offspring exposed to prenatal stress and FS.
Method
Sprague Dawley rats were mated. On GND14, prenatal stress was induced on pregnant dams for 1 hr/7 days. On PND 14, rat pups were injected with lipopolysaccharide (LPS, 200 μg/kg, i.p.) followed 2.5 h later by an i.p. injection of kainic acid (KA, 1.75 mg/kg). Oxytocin (1 mg/kg) was induced via different routes (intraperitoneal or intranasal) as well an enriched environment between PND 22-26. The enriched environment included larger cages (1560 cm²) with only 4 pups per cage, compared to those groups not receiving enrichment (646 cm²), as well as cardboard rolls and plastic toys. On PND 27-33 the light/dark box and elevated plus maze were used to assess anxiety-like behaviour. On PND 34 all rats were euthanized using a sharp guillotine, trunk blood and hypothalamic tissue were collected for neurochemical analysis (ELISA kit).
Results
Our findings confirmed that exposure to both prenatal stress and febrile seizures resulted anxiety-like behaviour and significantly higher plasma corticosterone concentrations compared to their counterparts. Environmental enrichment was significantly effective in attenuating the increased basal corticosterone levels and anxiety-like behaviour seen in the prenatally stressed FS rat. Although direct administration of oxytocin showed higher significance in reducing corticosterone plasma levels when compared to the enriched environment. Furthermore, hypothalamic oxytocin levels were not significant in rat exposed to environmental enrichment while oxytocin treatment showed a significant effect when compared to their counterparts.
Conclusion
Therefore, oxytocin administration during early postnatal development shows great potential in reversing the effects of prenatal stress and its subsequent exacerbation of FS.
The aim of this review was to present the main parameters used for the assessment of neurotoxicity during the initial period of life of rodents until puberty and to carry out a review of the most current literature on the toxic effects of pesticides, medications, licit and illicit drugs, toxins and environmental agents in rodent offspring. The bibliographic survey was done through the PubMed database; the terms used were postnatal development, toxicity, rodents and physical and reflexological parameters. The filters included were: 1) English language; 2) species: rats and mice; 3) review and original articles; 4) publications between 2000 and 2020. The selected works showed the main parameters of physical development and innate reflexes used for the assessment of neurotoxicity during the initial period of a rodent's life until puberty; these parameters may point out behavioral and neurological changes in adulthood. The eye and vaginal opening were the most cited physical milestones, and the surface righting reflex and negative geotaxis were the most used reflexes. The results showed the different toxic agents capable of altering the development of rodent pups, causing reversible and, in some cases, irreversible damage in these animals. These agents have an economic interest, as they are used as pesticides, medications and legal and illegal drugs, in addition to being toxins and environmental contaminants. Thus, this review contributes to the safe use of these agents during the gestational and lactation period, crucial periods for the correct development of a living being.
Ipomoea carnea is a toxic plant found in Brazil and other tropical countries. The plant contains the alkaloids calystegines and swainsonine, which inhibit key cellular enzymes and cause systematic cell death. It is known that swainsonine is excreted in the amniotic fluid of dams exposed to the plant. Thus, the aim of this study was to verify whether the toxic effect of I. carnea on fetuses is due to exclusively the passage of the active principle of the plant through the placenta, or if the placentotoxic effect of swainsonine could collaborate in the adverse effects observed in the fetus. The teratogenic effects of exposure to the toxic principles of I. carnea were evaluated not only using the conventional protocol but also at later stages in the postnatal developmental period. Females were treated, from gestation day (GD) 6 until GD19, with 0.0, 1.0, 3.0 or 7.0 g/kg body weight of I. carnea dry leaves. The plant did not induce changes in reproductive performance or biochemical profile of the dams. Dams that received the highest dose of I. carnea showed cytoplasmic vacuolization in the liver, kidney and placental tissue. I. carnea promoted different lectin binding patterns in different areas of placental tissue. No fetal skeletal or visceral malformations was observed. The postnatal evaluation revealed a lower litter weight and a lower pup body weight one day after birth in the group that received the highest dose of I. carnea. Physical milestones were unaffected by the treatments. Female pups from all experimental groups exhibited a delay in achieving a negative geotaxis response. The results show that the toxic principle of I. carnea produces injury in utero in mothers and fetuses, but these deleterious effects were better demonstrated using postnatal evaluation.
Maple Syrup Urine Disease (MSUD) is caused by a severe deficiency in the branched‐chain keto acid dehydrogenase complex activity. Patients MSUD accumulate the branched‐chain amino acids leucine (Leu), isoleucine, valine in blood, and other tissues. Leu and/or their branched‐chain α‐keto acids are linked to neurological damage in MSUD. When immediately diagnosed and treated, patients develop normally. Inflammation in MSUD can elicit a metabolic decompensation crisis. There are few cases of pregnancy in MSUD women, and little is known about the effect of maternal hyperleucinemia on the neurodevelopment of their babies. During pregnancy, some intercurrences like maternal infection or inflammation may affect fetal development and are linked to neurologic diseases. Lipopolysaccharide is widely accepted as a model of maternal inflammation. We analyzed the effects of maternal hyperleucinemia and inflammation and the possible positive impact the use of ibuprofen in Wistar rats on a battery of physics (ear unfolding, hair growing, incisors eruption, eye‐opening and auditive channel opening) and neurological reflexes (palmar grasp, surface righting, negative geotaxis, air‐righting, and auditory‐startle response) maturation parameters in the offspring. Maternal hyperleucinemia and inflammation delayed some physical parameters and neurological reflexes, indicating that both situations may be harmful to fetuses, and ibuprofen reversed some settings.
Maternal stress, especially during early pregnancy, predisposes offspring to neuropsychiatric disorders. We hypothesized that maternal psychosocial stress (MPS) during pregnancy affects fetal structural neurodevelopment depending on the gestational age of exposure. Fetal sheep brains were harvested at 130 days gestation (dG, term 150 dG) from ewes frequently isolated from flock-mates during early gestation (first and second trimester; n = 10) or late gestation (third trimester; n = 10), or from control flock-mates (n = 8). Immunohistochemistry for formation of neuronal processes, myelination, synaptic density, cell proliferation and programed cell death was performed on brain tissue sections. Sections of the cortical gray matter, the hippocampal CA3 region and the superficial, subcortical and deep white matter were examined morphometrically. Stress effects depended on the brain region and time of exposure. Stress during early gestation but not during late gestation reduced the amount of neuronal processes in the cerebral cortex and hippocampus by 36.9 ± 10.1% (p < 0.05, mean ± SEM) and 36.9 ± 15.8% (p < 0.05), respectively, accompanied by a decrease in synaptic density in the cerebral cortex and hippocampus by 39.8 ± 23.1% (p < 0.05) and 32.9 ± 13.4% (p < 0.01). Myelination was decreased in white matter layers on average by 44.8 ± 11.7% (p < 0.05) accompanied by reduced (glial) cell proliferation in the deep white matter by 83.6 ± 12.4% (p < 0.05). In contrast, stress during the third trimester had no effect in any brain region. Chronic MPS during the first and second trimester induced prolonged effects on neuronal network and myelin formation which might contribute to disturbed neurobehavioral, cognitive and motor development in offspring of stressed mothers.
• Lay summary
• Many women are exposed to stressful events during pregnancy. Maternal stress especially during early pregnancy predisposes for offspring’s neuropsychiatric disorders. In our sheep study, we show that disturbance of fetal brain development is a potential mechanism and is worst during 1st and 2nd trimester.
Fish are sensitive to temperature, but the intergenerational consequences of maternal exposure to high temperature on offspring behavioural plasticity and underlying mechanisms are unknown. Here we show that a thermal maternal stress induces impaired emotional and cognitive responses in offspring rainbow trout ( Oncorhynchus mykiss ). Thermal stress in mothers triggered the inhibition of locomotor fear-related responses upon exposure to a novel environment and decreased spatial learning abilities in progeny. Impaired behavioural phenotypes were associated with the dysregulation of several genes known to play major roles in neurodevelopment, including auts2 (autism susceptibility candidate 2), a key gene for neurodevelopment, more specifically neuronal migration and neurite extension, and critical for the acquisition of neurocognitive function. In addition, our analysis revealed the dysregulation of another neurodevelopment gene ( dpysl5 ) as well as genes associated with human cognitive disorders ( arv1 , plp2 ). We observed major differences in maternal mRNA abundance in the eggs following maternal exposure to high temperature indicating that some of the observed intergenerational effects are mediated by maternally-inherited mRNAs accumulated in the egg. Together, our observations shed new light on the intergenerational determinism of fish behaviour and associated underlying mechanisms. They also stress the importance of maternal history on fish behavioural plasticity.
Fish are sensitive to temperature, but the intergenerational consequences of maternal exposure to high temperature on offspring adaptive behaviour and underlying mechanisms are unknown. Here we show that a thermal maternal stress induces emotional and cognitive disorders in offspring. Thermal stress in mothers triggered the inhibition of fear responses and decreased spatial learning abilities in progeny. Impaired behavioural phenotypes were associated with the dysregulation of several genes known to play major roles in neurodevelopment, including auts2 , a key gene for neurodevelopment, more specifically neuronal migration and neurite extension, and critical for the acquisition of neurocognitive function. In addition, our analysis revealed the dysregulation of another neurodevelopment gene ( dpysl5 ) as well as genes associated with human cognitive disorders ( arv1 , plp2 ). We observed major differences in maternal mRNA abundance in the eggs following maternal exposure to high temperature indicating that some of the observed intergenerational effects are mediated by maternally-inherited mRNAs accumulated in the egg. Together, our observations shed new light on the intergenerational determinism of fish behaviour and associated underlying mechanisms. They also stress the importance of maternal history on fish adaptive capacities in a context of global climate changes.
La pollution atmosphérique est omniprésente du fait de nombreuses sources émettrices de composés chimiques. Dans ce contexte, les Hydrocarbures Aromatiques Polycycliques (HAP) sont largement diffusés dans l’air et ont déjà montré des effets délétères sur la santé.Ce travail a consisté en l’évaluation de la neurotoxicité du fluorène, composé choisi comme molécule représentative de la pollution liée aux HAP, chez le rat adulte exposé par voie i.p., par voie orale ou par inhalation. Le modèle d’exposition par inhalation a ensuite été appliqué à l’étude des effets du polluant sur le développement sensori-moteur et l’activité comportementale de l’animal exposé in utero ou au cours de la lactation.Ces études ont montré que le fluorène était susceptible d’affecter le niveau d’anxiété et l’activité locomotrice du rat adulte exposé directement et indirectement au polluant, et n’avait aucun effet sur les capacités d’apprentissage. En revanche, aucune atteinte majeure de la maturation des fonctions sensori-motrices n’a été mise en évidence. L’analyse de la présence du composé et de trois de ses métabolites a par ailleurs montré que le polluant était capable de traverser la barrière hémato-encéphalique et d’être métabolisé au niveau du cerveau. Les réponses physiologiques et comportementales étant variables entre les études, les effets induits par le fluorène dépendent donc de la voie d’entrée, du niveau de contamination et du moment d’exposition.Ces résultats ont ainsi révélé chez l’animal la toxicité comportementale du fluorène à des niveaux de contamination réalistes, confirmant ainsi le risque sanitaire de l’exposition aux HAP tout au long de la vie des individus
Cerebral traces of infantile trauma and future psychopathology
The affective, relational, but also the cognitive development of children is linked very early in life to the quality of relationships, investment and security of their care-givers. The perinatal period appears to be a moment when cerebral development is very sensitive to stress. When such stress is chronic and associated with a prolonged secretion of cortisol, it is particularly likely to leave a neurobiological trace which can influence the entire life of the individual. These modifications in neuronal architecture can bring about an alteration of the development of intellectual functions and physical development (psychogenic dwarfism), troubles of the system of affectivity, emotions and memory. Early toxic stress can provoke later hyper-reactivity to minor stresses with mental and physical consequences which last into adult life. The psychopathological risk of depression, anxiety, post-traumatic stress but also metabolic syndrome and cardiovascular diseases will also be greater.
This paper engages with questions of logic and its politics to explore how those of us in early childhood education can become critical consumers of ‘brain research’. The research truths we use to construct classroom practices decide the meanings of our actions, thoughts and feelings and our interactions with children. Following Foucault (1980), I see these truths as intimately connected with power and its effects on us.
Several preclinical and clinical studies have shown that prenatal stress alters neuronal dendritic development in the prefrontal cortex, together with behavioral disturbances (anxiety). Nevertheless, neither whether these alterations are present during the lactation period, nor whether such findings may reflect the onset of anxiety disorders observed in childhood and adulthood has been studied. The central aim of the present study was to determine the effects of prenatal stress on the neuronal development and behavior of mice offspring during lactation (postnatal days 14 and 21). We studied 24 CF-1 male mice, grouped as follows: (i) control P14 (n=6), (ii) stressed P14 (n=6), (iii) control P21 (n=6) and (iv) stressed P21 (n=6). On the corresponding days, animals were evaluated with the open field test and sacrificed. Their brains were then stained in Golgi-Cox solution for 30 days. The morphological analysis dealt with the study of 96 pyramidal neurons. The results showed, first, that prenatal stress resulted in a significant (i) decrease in the apical dendritic length of pyramidal neurons in the orbitofrontal cortex at postnatal day 14, (ii) increase in the apical dendritic length of pyramidal neurons in the orbitofrontal cortex at postnatal day 21, and (iii) reduction in exploratory behavior at postnatal day 14 and 21.
Individual response to stress is orchestrated by hypothalamus-pituitary axis corticosteroids, although critically modulated by the central endocannabinoid (eCB) system. Whilst the role of the eCB system in stress response and emotional homeostasis in adult animals has been extensively studied, it has only been scarcely investigated in developing animals. Herein, we aimed to investigate the participation of eCB ligands in the stress responses of neonate rats. Twelve days-old Wistar male rats were exposed to a social challenge (repeated brief isolations from dam and littermates), which resulted in a significant increase in serum corticosterone levels. This stressful social challenge also decreased spontaneous rat pups' behaviours and augmented isolation-induced ultrasonic vocalizations. Notably, a specific decrease in anandamide content (not 2-AG) was observed within the hippocampus (not in the striatum). However, the enhancement of eCB signalling by URB597 administration (0.1mg/kg) did not affect the adrenocortical and behavioural responses to this postnatal social challenge. The influence of gestational stress was also evaluated in the infant offspring of rats dams exposed to restraint stress (PRS, three episodes/day, on gestation days 14 till delivery); however, PRS did not modify neonate responses to this postnatal challenge. Present findings provide evidence for the participation of the eCB system in the acute response to a social challenge in infant male rats. However, the lack of evidences from the pharmacological study encourages the investigation of alternative and/or indirect mechanisms that may participate in the behavioural and endocrine response to stress in developing animals. Further experiments are still needed to clarify the interactions between the HPA axis and the eCB system in stress reactivity at early postnatal stages.
During the prenatal period, development of individual is influenced by the environmental factors. In mammals, 5-hydroxytryptamine (5-HT) is a central neurotransmitter that regulates behavioral functions in the vertebrate brain. Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the 5-HT synthesis. Various stresses are known to modulate the 5-HT synthesis and the TPH expression. In the present study, the influence of prenatal noise and music aplication on the 5-HT synthesis and the TPH expression in the dorsal and median raphe of young rats was investigated. Prenatal noise application increased the 5-HT synthesis and the TPH expression in the dorsal and median raphe nuclei of offspring. Prenatal music application, in contrast, decreased the 5-HT synthesis and the TPH expression in the dorsal and median raphe nuclei of offspring. The present study suggests that prenatal stimuli including noise and music may affect the emotional state of offspring.
In a world in which athletic skill is often valued more highly than intellectual prowess, we know surprisingly little about
the development of the human motor system. Even less is known about how an adverse intrauterine event or environment might
program motor learning, memory and function throughout the lifespan. We are only beginning to investigate how events during
development of the brain and central nervous system might predispose some individuals to older age onset of some common neurological
disorders such as Parkinson’s and Alzheimer’s diseases. Anecdotal and empirical evidence suggests that one or more adverse
events occurring in utero may result in long-term changes in neuromotor development. These changes may be evident from infancy,
or not become apparent until later in life. This chapter reviews this evidence. We suggest that the research focus must shift
towards neurophysiological rather than neurodevelopmental paradigms, if these programmed changes in neuromotor function and
the mechanisms responsible are to be fully understood. We also introduce the idea that the impact on the individual of maladaptive
neuromotor programming might be reduced by the development of early intervention therapies, which utilise the developing nervous
system’s capacity for plastic change.
A febrile seizure is a neurological disorder that occurs following an infection that results in a rapid rise in body temperature. It commonly affects 3-5% of children between the ages of 3 months and 5 years. Interleukin-1 beta IL-1β a pro-inflammatory cytokine has been suggested to play a role in the manifestation of febrile seizures. There is evidence suggesting that neurological disorders can be exacerbated in an offspring that was exposed to stress prenatally. The aim of our study was therefore to investigate whether febrile seizures are exacerbated in the offspring of rats that were prenatally stressed. The offspring of pregnant Sprague-Dawley dams were used in the study. Prenatal stress consisted of exposing the pregnant dams to 45 min of restraint, 3 times per day with 3 h intervals in-between, for 7 days starting on gestational day 14 (GND14). On postnatal day (PND) 14, the pups were injected with lipopolysaccharide (LPS, 200 μg/kg, i.p.) followed 2.5 h later by an i.p. injection of kainic acid (KA, 1.75 mg/kg). All the animals were decapitated on PND 21. Trunk blood was collected to detect plasma interleukin-1beta (IL-1β) levels in the various groups. Our data showed that i.p. injections of LPS followed by KA led to the development of seizure activity that was associated with increased plasma IL-1β levels. Prior exposure to prenatal stress resulted in the development of advanced stages of seizure development, leading to an exaggerated seizure response. Prenatal stress alone also led to elevated plasma IL-1β levels, while previously stressed animals receiving LPS and KA yielded the highest plasma levels of IL-1β levels. Our data therefore shows that IL-1β levels may play an important role in the development of febrile seizures.
We previously reported that the developing rat cerebellum is affected by exposure to hypergravity. In the present study, we explored the hypothesis that the changes in cerebellar structure in hypergravity-exposed rat neonates may affect their motor coordination. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravitational loading. To test this hypothesis, we compared motor behavior, cerebellar structure, and protein expression in rat neonates exposed to 1.5–1.75G on a 24-ft centrifuge daily for 22.5 h starting on gestational day (G) 10, through birth on G22/G23 and through postnatal day (P) 21. Exposure to hypergravity impacted the neurodevelopmental process as indicated by: (1) impaired righting response on P3, more than doubling the righting time at 1.75G, and (2) delayed onset of the startle response by one day, from P9 in controls to P10 in hypergravity-exposed pups. Hypergravity exposure resulted in impaired motor functions as evidenced by performance on a rotarod on P21; the duration of the stay on the rotarod recorded for 1.75G pups of both sexes was one tenth that of the stationary control (SC) pups. These changes in motor behavior were associated with cerebellar changes: (1) cerebellar mass on P6 was decreased by 7.5% in 1.5G-exposed male pups, 27.5% in 1.75G-exposed male pups, 17.5% in 1.5G-exposed female pups, and 22.5% in 1.75G female pups and (2) changes in the expression of glial and neuronal proteins. The results of this study suggest that perinatal exposure to hypergravity affects cerebellar development as evidenced by decreased cerebellar mass and altered cerebellar protein expression; cerebellar changes observed in hypergravity-exposed rat neonates are associated with impaired motor behavior. Furthermore, the response to hypergravity appears to be different in male and female neonates. If one accepts that the hypergravity paradigm is a useful animal model with which to predict those biological processes in the CNS affected by microgravity, and because males and females were shown to respond differently to hypergravity, it can be surmised that males and females may respond differently to the microgravity encountered in space.
The prenatal environment, including prenatal stress, has been extensively studied in laboratory animals and humans. However, studies of the prenatal environment usually directly stress pregnant females, but stress may come 'indirectly', through stress to a cage-mate. The current study used indirect prenatal bystander stress and investigated the effects on the gross morphology, pre-weaning behavior, and epigenome of rat offspring. Pregnant Long-Evans rats were housed with another female rat that underwent elevated platform stress from gestational days 12 to 16. We found that ultrasonic vocalizations of female cage-mates were disrupted following the stress procedure. After birth, offspring were tested on two behavioral tasks and sacrificed at postnatal day 21 (p21). Frontal cortex and hippocampal tissue was used to measure global DNA methylation and gene expression changes. At p21, bystander-stressed female offspring exhibited increased body weight. Offspring behavior on the negative geotaxis task was altered by prenatal bystander stress, and locomotor behavior was reduced in female offspring. Global DNA methylation increased in the frontal cortex and hippocampus of bystander-stressed offspring. Microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. These alterations in gene expression were associated with overrepresentation of 36 biological processes and 34 canonical pathways. Prenatal stress thus does not have to be experienced by the mother herself to influence offspring brain development. Furthermore, this type of 'indirect' prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior.
The objectives of the present study were to explore whether maternal psychosocial factors, mental health and work stress around delivery, are related to the behavior of 2-year-old children.
In a prospective cohort study design, pregnant women attending the National Taiwan University Hospital for delivery and post-partum care from April 2004 to January 2005 were recruited and their children were observed at 24 months. A total of 186 mother-term-born child dyads completed the measurement. The five-item Mental Health Index (MHI-5) self-report data of maternal psychosocial factors were selected from the Taiwanese version of the short form 36 (SF-36). The Child Behavior Checklist for age 1½-5 (CBCL/1½-5) was completed by the parents when the child was 2 years old.
The mean score of mental health around delivery was 68.11. The proportion of mothers with work stress seldom and always was 61.8% and 24.7%, respectively. The mean of the total CBCL score, and internalizing, externalizing behavior and sleep problems scores was 45.95, 11.89, 15.59 and 4.23, respectively. After adjusting for the potential confounders, maternal work stress around delivery was found to have a significant effect on the total CBCL and externalizing, attention and aggressive, behavioral problems of 2-year old children. Maternal mental health around delivery, however, did not show significant effects on child behavior.
Work stress around delivery seems to aggravate children's externalizing behavior problems at 2 years old. It is therefore important to improve the psychosocial health and reduce the stress of pregnant women.
It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.
The cerebellum, the deep cerebellar nuclei, and the inferior olivary nucleus of the heterozygote Lurcher mutant mouse have been compared with the same structures in normal littermates. The comparison was made using light and electron microscopic methods for qualitative observations and light microscopic methods for quantitative observations. The study included the newborn period from 4 days of age up to 730 days, which is old age for a mouse. The cerebellum of the normal mouse is similar to that of many other species though apparently minor structural differences are seen. Amongst these was the similarity between the mouse climbing fibre and mossy fibre glomeruli which contrasts with the rat where they can be distinguished by the high density of synaptic vesicles and central cluster of mitochondria in the climbing fibres. In Golgi stained material the inferior olivary nucleus of the normal mouse showed cells with highly ramified dendrites and cells with simple dendrite patterns. In the adult Lurcher mouse the cerebellum is much smaller than is normal. There are no Purkinje cells and the internal granule cell layer is reduced in thickness and density. Examination of younger animals shows that Purkinje cells are present and that they undergo degeneration. In Golgi stained material from younger animals Purkinje cells often show more than one primary dendrite, sometimes as many as five, and somatic spines persist well beyond the first week of life. Cytoplasmic organelles often have a random orientation and the mitochondria are rounded rather like those seen in the nervous mutant. Granule cells in the adult Lurcher mutant are reduced in number and during the developmental period degenerative changes are seen. The Golgi cells and stellate cells are relatively normal and some cells, identified as basket cells, are seen. The inferior olivary nucleus is found with ease in the Lurcher mutant and is as extensive as in the normal mouse. However, in Golgi stained material only cells with highly ramified dendrites are seen. In addition the total number of neurons is reduced. It is possible that the neurons with a simple dendrite pattern have climbing fibres which pass only to the Purkinje cells. The deep cerebellar nuclei in the normal mouse cannot be separated easily into their three subdivisions, lateral, interpositus and medial. In the Lurcher mutant the neurons are of similar size to those of the normal mouse but they are crowded more closely together than is normal. In the Lurcher mutant as in the normal adult the neuronal cell bodies are covered with synapses and not with glial cells. Estimates of total cell numbers were made in order to obtain evidence about the time course of the development of the changes in structure and to make a detailed comparison between the normal mouse and the Lurcher mutant with respect to Purkinje cells, granule cells, olive neurons, and deep cerebellar nuclei neurons. In the normal mouse the mean number of Purkinje cells between 10 and 730 days was 177 000, s.d. ± 11 600, n = 12. The number of granule cells probably reached a peak at about 17 days. At 26 days post-natal the number estimated was 27 million and at 730 days 28 million. The mean number of olive neurons between 14 and 730 days post-natal was 32 700, s.d. ± 1900, n = 9; the mean number of deep cerebellar neurons counted at three adult ages was 17 600, s.d. ± 1800. In the adult the ratio of Purkinje cells to olive cells is ca. 5.4:1, of granule cells to Purkinje cells is ca. 170:1, of Purkinje cells to deep cerebellar nuclei neurons is ca. 10:1, and of olive neurons to deep cerebellar nuclei neurons is ca. 1.85:1. This last would chiefly be of interest if there are olive neurons projecting solely to deep cerebellar neurons. In the Lurcher mutant the number of Purkinje cells falls below normal from 8 days post-natally, reaches 10% of normal at 26 days and probably falls to zero at around 90 days. At this point such are the changes in the overall structure that confusion of Purkinje cells with Golgi cells may occur. At 4 days post-natal age the number of granule cells is smaller than normal by 25% and this difference increases with age to a reduction of ca. 90%. The number of olive cells is close to normal until 8 days of age, is only 60% of normal at 15 days when the highest number is reached, and is 25% of normal at 121 days. The deep cerebellar nuclei neuron numbers were the same as those in the normal. Included in the discussion is a detailed critical comparison of these results from the normal mouse with all previous estimates of cell numbers in the cerebellum. The lesion in Lurcher is compared with that found in the other mouse cerebellar mutants and with experimentally evoked lesions of the cerebellum. For the Lurcher mutant the tentative conclusion is that the primary lesion may arise in the Purkinje cells.
It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.
Pregnant rats were exposed to differents schedules of noise and light stress, and the developmement of their offspring was studied during the first 2 weeks of life.
Motor development was measured by different tests: Righting reflex (Days 2–4); Cliff avoidance (Days 4–10); turning on an inclined plane (Days 5–10); and swimming behavior (Days 6–10). Development of motivation-involved behavior was measured with a home-seeking test (Days 6–16). Other developmental landmarks such ss acoustic response (Days 12–14) and eye-opening (Days 14–17) were also recorded.
Thrice-weekly random stress resulted in a delay in the devlopment of all behaviors studied. Daily stress exposure throughtout pregnancy resulted in smaller litters with heavier pups, but otherwise normal behavioral and physical development. Rats exposed to daily stress during the last week of pregnancy only produced litters that did not differ in size and body weight, but that displayed accelerated development of all parameters (except for eye-opening) from Day 6 onward.
It is concluded that the unpredictabel nature of prenatal stress is responsible for delays in behavior of offspring.
It is suggested that drug addiction is more likely to develop in individuals who are particularly sensitive to the reinforcing effects of drugs. Animal studies of intravenous drug self-administration (SA) have shown that rats display a large range of individual differences in the propensity to develop drug-seeking. Predisposed animals are characterized by a higher locomotor reactivity to both novelty and psychostimulants. In this report, we show that prenatal stress (restraint of the mother during the last week of pregnancy) may contribute to an individual's vulnerability to develop amphetamine self-administration. The adult offspring of stressed mothers exhibited: (i) a higher locomotor response to novelty and to an injection of amphetamine (0.3 mg/kg, i.v.); (ii) a higher level of amphetamine self-administration. The data indicate that individual predisposition to drug-seeking in the adult may be induced by prenatal events.
Prenatal stress enhanced lordotic behavior potentials in male rats but did not feminize patterns of active avoidance acquisition or open-field performance. These results suggest that prenatal stress selectively feminizes some but not all behavior patterns shown to differentiate under the influence of perinatal gonadal hormones. In the rat, the critical period for the differentiation of active avoidance behavior appears to span prenatal and early neonatal ontogeny.
This prospective study investigated whether mild maternal stress during pregnancy could influence performance on a variety of developmental measures in rhesus monkey infants (Macaca mulatta). Twenty-four infants were tested during the first month of life for interactive, neuromotor, and temperamental characteristics and capabilities using instruments adapted directly from human neonatal assessments. Twelve infants were derived from mothers exposed during pregnancy to a mild stressor in the form of a daily 10-min removal from home cage and exposure to three unpredictable noise stimuli. Twelve infants were derived from mothers undisturbed during pregnancy. Prenatally stressed infants had lower birthweights, were delayed in self-feeding, were more distractible, and had lower scores on a Motor Maturity composite score when compared to offspring from undisturbed pregnancies. Close inspection of the Motor Maturity score revealed that low muscle tonus, poor coordination, and slow response speed characterized the prenatally stressed offspring.
This study investigated the hypotheses that unpredictable prenatal stress (1) has effects on the offspring, similar to those induced by perinatal administration of glucocorticoids and (2) increases the vulnerability to stressful situations at adulthood. Rats were exposed to random noise and light stress throughout pregnancy. Offspring were tested for the development of spontaneous alternation behavior (SA) and at adulthood, their response to novel or aversive situations, open field, extinction and punishment following acquisition of an appetitive response and two-way active avoidance, were assessed. In prenatally stressed rats, the development of SA was significantly delayed. On repeated exposure to an open field they were less active; control rats had elevated plasma corticosterone (CCS) on days 2 and 4 of open field exposure, while prenatally stressed rats had significantly raised plasma CCS after each exposure (days 1–8). Furthermore, punishment-induced suppression of an appetitive response was enhanced. Acquisition of active avoidance was faciliated in female but reduced in male prenatally stressed offspring. It is suggested that random prenatal noise and light stress may cause impairment of development of hippocampal function which lasts into adulthood. This impairment is manifested as an increase in vulnerability and a decrease in habituation to stressful stimuli.
Young rats, old enough to creep well but before the eyelids are open, orient and move upward upon an inclined surface. The angle of geotropic orientation on such a surface (theta) is proportional to the logarithm of the component of gravity parallel to the inclined plane. This result is compared with the scanty information available for other animals; there is indication that it may be generally valid. The precision of the orientation, measured by the percentage dispersion of the individual measurements, also increases in proportion to the logarithm of this component. The cosine of the angle of orientation decreases very nearly in proportion to the sine of the angle of inclination. A possible interpretation of this is given as involving the idea that upward orientation ceases when the differential pull of the body weight upon the opposed legs reaches a threshold value. Attaching weights (W) to the tail causes theta to increase, and in proportion to log W.
Electric foot shock administered to pregnant rats altered the ontogeny of spontaneous motor activity in their pups. Prenatally stimulated (PMS) offspring were more active than controls on Days 1-10 but less active during the 3rd postpartum week. The age of peak activity, a major developmental landmark, occurred in PMS pups around 10 days of age; in controls maximum activity was not seen until the 3rd week. This effect was independent of the gender of the offspring and the timing of the gestational stimulation. Its appearance in both cross-fostered and fostered pups indicated the prenatal origin of the effect. The maturation of spontaneous alternation behavior and several reflexes and the appearance of physical features were not affected by prenatal stimulation. Moreover, both PMS and control groups exhibited an age-related increase in brain concentrations of norepinephrine, serotonin, and 5-hydroxyindoleacetic acid. These findings indicate that spontaneous motor activity is uniquely sensitive to PMS, and as far as can be determined here, PMS produces no generalized alteration in behavioral and physical ontogeny.
During the last trimester of gestation, pregnant rats were exposed to crowded living conditions, or to immobilization combined with intense illumination. In adulthood, male offspring of mothers exposed to either condition of stress showed increased readiness to display feminine sexual behaviour (lordosis) while no deficits were observed in their masculine sexual behaviour. It was concluded that prenatal stress adversely affects sexual differentiation by causing a feminization but not a demasculinization of male offspring.
Stress during gestation significantly increased estrous cycle length in female offspring as adults, primarily by lengthening the estrus-metestrus stage. Therefore, prenatal stress may disturb the hormonal milieu of the female fetus during a critical hypothalamic differentiation stage.
Female rats subjected to prenatal stress later experienced fewer conceptions, more spontaneous abortions and vaginal hemorrhaging, longer pregnancies, and fewer viable young than nonstressed rats. The offspring of the prenatally stressed rats were lighter in weight and less likely to survive the neonatal period. Prenatal stress may influence the balance of adrenal and gonadal hormones during a critical stage of fetal hypothalamic differentiation, thereby producing a variety of reproductive dysfunctions in adulthood.
During the last trimester of pregnancy, rat mothers were exposed to various forms of stress including immobilization-illumination, crowding and cold. At birth, male offspring from all experimental groups showed a shortened anogenital distance. In addition, offspring of mothers exposed to immobilization-illumination or cold showed reduced weight of body, testis and adrenals. It was suggested that corticosteroids secreted by the stressed mother suppressed gonadal secretions of the male fetus, thereby interfering with the sexual differentiation.
Rats were subjected to restraint stress for nine hours daily, on three consecutive days, at various stages of pregnancy from days 9–20, and the postnatal development and behaviour of the offspring assessed on a wide-ranging battery of tests. Stress at any of the stages of pregnancy investigated caused a significant decrease in offspring body weight persisting up to 6 weeks of age, and delayed the appearance of certain developmental landmarks such as ear opening, auditory startle and cliff avoidance responses. Postnatal mortality and impairment of ability to orient to the home cage were also significantly increased in the offspring from rats stressed on days 18–20 of pregnancy. In a second experiment, the effects of restraint stress on days 18–20 were investigated in more detail. At birth, stressed and control offspring were fostered onto mothers from the same treatment group or cross-fostered onto mothers from the opposite treatment group and assessed as before, to determine whether the adverse effects observed in the first experiment were prenatally or postnatally mediated. The effects were most marked in prenatally stressed pups reared by stressed mothers and least marked in controls reared by controls, with the other two cross-fostered groups being intermediate; this indicates that the effects were induced partly prenatally at the time of treatment and partly postnatally by the rearing mothers that had been stressed.
In laboratory rats (Rattus norvegicus) aged 1 to 21 days emergence of postural and locomotor skills was studied in the open field and in experimental situations with homing used as motivation. Righting is mediated initially by curving and rocking of the trunk, later head and shoulder are rotated, and lastly the hindlimbs turn and provide co-ordinated support. Pivoting prodominates during the second half of the first week, crawling during most of the second week, and walking or running by the end of the second week. Balancing on narrow paths and compensating for lateral displacement on rotating rods mature later, as do various skills (climbing up or down on inclined surfaces, rods and ropes, and jumping across gaps) that require substantial hindlimb co-ordiantion.
Previous studies demonstrated that throughout the preweaning period prenatally stressed rats have an overactive hypothalamic-pituitary-adrenal (HPA) system. This increased HPA activity was accompanied by an increase in defensive behavior. This study examined whether these alterations in HPA activity and defensive behavior continued into adulthood. Brain catecholamines in the cerebral cortex and locus coeruleus were also measured in prenatally stressed and control rats. Shock-induced levels of defensive freezing were significantly higher in prenatally stressed rats than in controls. However, plasma ACTH and corticosterone concentrations did not differ between groups either in the basal state or after exposure to foot shock. Concentrations of norepinephrine (NE) in the cerebral cortex and locus coeruleus region were significantly reduced in prenatally stressed rats. In addition, concentrations of NE metabolites were significantly elevated in prenatally stressed rats, suggesting an increased turnover of brain NE. Prenatally stressed rats also had, in the locus coeruleus region, significantly reduced dopamine (DA) levels but elevated concentration of DA metabolites. Results indicate that prenatal stress produces an increased behavioral responsiveness to stress that is evident in early life and continues into adulthood. The early hyperactivity of the HPA system in prenatally stressed rats, however, appears to normalize in adulthood. The increased turnover in brain catecholamines measure in the cerebral cortex and locus coeruleus region of prenatally stressed rats may be associated with the heightened expression of stress-induced behavior.
Pregnant female rhesus monkeys were exposed to a 2-week period of adrenocorticotropic hormone (ACTH) to determine whether it would affect the early neuromotor development of their fetuses in a manner similar to that observed after psychological stressors. During the first month after birth, infants were tested on two occasions with a modification of the Brazelton Newborn Behavioral Assessment Scale. Infants derived from ACTH-treated pregnancies showed early impairments in motor coordination and muscle tonicity and shorter attention spans as compared to controls. In addition, on a temperament rating scale, infants from the ACTH condition were more irritable and difficult to console. These findings indicate that a delimited period of endocrine activation during pregnancy can have an adverse effect on infant neurobehavioral development, like that of prenatal stress.
This prospective study investigated whether mild maternal stress during pregnancy could alter the behavioral and affective responses in rhesus monkey infants in a complex, novel environment. Twenty-four rhesus monkey infants were tested on three occasions at 6 months of age in a novel environment. Twelve infants were derived from mothers exposed to a daily 10-min mild stressor from Day 90 to Day 145 postconception, while 12 were derived from mothers undisturbed during pregnancy. Prenatally stressed infants demonstrated more disturbance behavior, and lower levels of gross motor/exploratory behavior. Moreover, half of the prenatally stressed infants showed an abnormal response, falling asleep, while none of the control infants displayed this behavior. Males exhibited more clinging to surrogates, while females spent more time in gross motor/exploratory behaviors, with prenatally stressed males tending to spend the least time in gross motor/exploratory activity.
Previous experiments revealed that 14-day-old prenatally stressed rats have significantly elevated concentrations of plasma adrenocorticotrophic hormone (ACTH) and corticosterone suggesting these animals have an overactive hypothalamic-pituitary-adrenal (HPA) system. In these studies, however, stress-induced hormone levels were determined only immediately after exposure to an acute stressor. Therefore, in the current study, we examined in postnatal days 7, 14 and 21 prenatally stressed rats the stress-induced time course of this pituitary-adrenal hormone elevation. Plasma ACTH and corticosterone were measured in the basal state and at 0.0, 0.5, 1.0, 2.0 and 4.0 h after a 10-min exposure period to foot shocks administered in the context of social isolation. Results indicated that at all 3 ages, plasma ACTH in prenatally stressed rats was significantly elevated. Corticosterone concentrations were also significantly higher in prenatally stressed than in control rats, especially in day 14 rats. Analysis of stress-induced hormone fluctuations over time indicated that by 14 days of age, both prenatally stressed than in control and control rats had significant increases in plasma ACTH and corticosterone after exposure to stress. Furthermore, although prenatally stressed rats had significantly higher pituitary-adrenal hormone concentrations than control animals, the post-stress temporal patterns of decline in ACTH and corticosterone levels were similar between groups. Results suggest that throughout the preweaning period, prenatal stress produces an HPA system that functions in a manner similar to that of controls but at an increased level.
Previous studies have shown that maternal stress modifies 5-hydroxytryptamine (5-HT) receptor binding in several brain regions of the adult offspring and alters the intensity of the behavioral responses to 5-HT receptor agonists. We now report that the same stress, crowding combined with daily saline injections during the final week of pregnancy, elevates maternal plasma free tryptophan level without significantly affecting total tryptophan. The increased maternal plasma tryptophan was associated with significantly increased fetal brain levels of tryptophan, 5-HT and 5-hydroxyindoleacetic acid. These increases were maintained after birth until at least postnatal day 10. Since 5-HT is recognised as having a role in the control of neuron development during the perinatal period, we suggest that the stress-induced increase in fetal brain 5-HT synthesis may play a part in the mechanisms by which prenatal stress alters adult behavior.
In adult lurcher mice, in which virtually all cerebellar Purkinje cells have degenerated as a direct consequence of mutant gene action, the inferior olivary complex suffers a severe retrograde transneuronal atrophy. Our analysis indicates a 63% cell loss in the lurcher inferior olive, homogeneously distributed between the medial and dorsal accessory, and principal olivary subdivisions. Olivary neurons are reduced in cross-sectional area by 30% in lurcher mice, compared to normal controls. All olivary subdivisions morphologically identifiable in normal mice are also found in the lurcher inferior olive. Analysis of olivocerebellar topography by retrograde transport of lectin-conjugated horseradish peroxidase and fluorogold, in both single and double labeling paradigms, reveals no abnormalities in the general organization of this highly ordered projection. This stability may be based on the initial establishment of the topographic pattern in late embryogenesis or early postnatal periods, prior to the onset of lurcher Purkinje cell degeneration, or, alternatively, the lurcher gene may not alter critical afferent and target characteristics at stages when the topographic relationship is being established. Once established, the olivocerebellar projection is apparently not dependent on the Purkinje cell for long-term maintenance of its general topographic organization.
It has been reported that gonadal steroids modulate brain and behavioral sex differentiation during development. Prenatal maternal restraint also alters development by affecting gonadal steroid levels in the fetus. Prenatal maternal restraint of animals decreases sex differences for sexual behavior, locomotion, aggression, etc. In recent work on animal models, we reported that, like humans, laboratory rats show sex differences in depression. From the present study, performed on Sprague-Dawley rats, we conclude that: 1) there are sex differences for depression in two different animal models (swimming-induced immobility and natatory tests); 2) there are also sex differences in open-field behavior; 3) prenatal maternal restraint decreases sex differences for depression but does not affect sex differences in open-field behavior; 4) prenatal maternal restraint affects female but not male behavior in the two depression tests used. These results suggest that: 1) sex differences reported in animal models of depression are under the control of gonadal steroids during prenatal brain development; 2) stress during early phases of development increases the risk for depression in adulthood.
Two cohorts of boys were examined while attending a well-baby clinic and reexamined at the end of the first grade of elementary school. One cohort (n = 57) consisted of boys born in the year of the Six-Day War in 1967. The other cohort was born 2 years later (n = 63). Data on socio-demographic background, early development, behavior at school and at home were obtained from the mothers and the teachers. Statistical analysis showed that the "war children" had significant developmental delays and regressive, non-affiliative and dissocial behavior. The children, who were in their first half year of life at the time of the war, were much more disturbed than those of whom the mothers were pregnant at the time of the war. The findings suggest that a disturbed mother-child relationship existed in the former group.
This chapter reveals prenatal stress effects on functional development of the off spring. The term “psychological stress” is used to denote situations that, although not physically harmful in terms of causing direct tissue damage, evoke behavioral and physiological responses that are characteristic of the “stress” response. Early reports that prenatal psychological stress in human subjects may influence the behavior of the offspring prompted a large number of studies in experimental animals in an attempt to provide more precise information about the nature of the changes induced by such stress and their underlying mechanisms. In the absence of any direct neural connections between the mother and foetus, it has been postulated that hormones (e.g., glucocorticoids, adrenaline) transported from the maternal blood to the placenta are the most likely mediators. The nature of the effect of prenatal stress on early physical development and later behavior appears to depend upon genetic factors, the severity of the stress, and its timing. These in turn determine whether abnormal maternal and foetal hormonal and neuronal activity occurs at a critical period of foetal development.
Pregnant Sprague-Dawley rats were exposed to mild stress treatments during different gestational periods and the offspring were investigated at 60 days of age. In the first study, stress from embryonic day (ED) 11 to ED 20 produced effects similar to those reported following stress throughout pregnancy; increased numbers of 5-HT2 binding sites in cerebral cortex and a reduced intensity of the behavioral syndrome produced by injections of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). In the second study, stress from ED 3 to ED 14 had no significant effect on the intensity of the 5-MeODMT-elicited 5-HT syndrome while stress from ED 15 to ED 20 had a similar effect as stress throughout pregnancy. These data provide evidence that the critical period for prenatal stress-induced changes in brain 5-HT neurons is between ED 15 and birth. This suggests that the mechanism involves an interaction with developmental events occurring within this time span such as the growth of nerve axons and the formation of synaptic contacts. Our findings also provide further evidence that stress during the final trimester of pregnancy may have serious adverse effects on fetal brain development.
The effects of prenatal exposure to stress and to naltrexone on emotional behaviors were studied in CD1 mice during ontogeny and in the adulthood. During ontogeny (a) lower body weights were initially found in pups born by mothers injected with naltrexone; (b) treatments did not affect sensory motor development except in the case of the cliff aversion reflex which occurred earlier in pups prenatally exposed to stress; (c) measures of ultrasonic vocalizations in stressful context showed that the amount of vocalizations emitted by pups born by stressed mothers was significantly higher than that emitted by pups born by naltrexone injected and control mothers (d) an examination of mother-offspring interactions on the very first day of observation indicated a consistent trend in stressed mothers to be more responsive to their pups. In adulthood, ultrasonic calls in courtship after short and long periods of isolation showed a time-dependent decrease of vocalizations in males prenatally exposed to naltrexone. These results indicate that the modifications of emotionality evident during early development are directly related to the reactivity of the mothers to the experimental treatments.
Persistent effects of stress were found in second generation rats bred from females whose own mothers had been stressed during pregnancy. The second generation rats grew more slowly, with a plateau in the growth being reached at the same age as in the controls. This resulted in adult animals of both sexes being permanently smaller than their control counterparts. When these offspring were subjected to short-term stress (one session) in adulthood, the response was not significantly different to that for the controls, indicating an intact emergency response. The male offspring from the stressed group, however, had a significantly ( P < 0·01) higher plasma progesterone concentration, and a significantly ( P < 0·01) lower testicular enzymic 3β-hydroxysteroid dehydrogenase activity at rest, when compared with the control offspring. The fertility of the mature female from the stressed group was not affected as a third generation of litters born did not differ from the controls.
It is suggested that a changed genetic programme in the ovarian germ cells of the first generation and/or a changed uterine environment in the second generation may be implicated.
J. Endocr. (1986) 109, 239–244
Mild maternal stress in the form of chronic daily subcutaneous injections of saline or the vehicle for diazepam to pregnant rats was shown to result in some long term, subtle but reliable, changes in the behavior of the offspring. The same vehicle given for the same period of time in the dam's drinking water, without injection had no effect on the development of later behavior of rat pups. Chronic prenatal injections of saline or vehicle for diazepam, used in many experiments as controls for the evaluation of drug effects were shown to have some long lasting behavioral effects in the offspring of the treated dams. The series of experiments reported here compared the offspring of saline or vehicle injected dams to those of uninjected dams on a variety of developmental measurements, an open field behaviour and on learning performance in a complex brightness discrimination maze.
Pregnant Long-Evans rats were stressed by crowding, and subsequent mother-infant interactions were described after cross-fostering. Prenatally stressed pups elicited less maternal licking from unstressed foster dams than controls, and previously stressed dams licked unstressed foster pups less than controls. No other differences in mother-infant interactions were detected. Adult offspring reared by foster dams that were stressed during pregnancy were more active in an open field than controls, but prenatally stressed and unstressed animals reared by control dams did not differ. Thus, stress during pregnancy can alter the maternal behavior of stressed dams, and the differential maternal stimulation can affect adult open-field behavior. Because prenatally stressed pups elicit different maternal care, cross-fostering does not eliminate the possibility that maternal stimulation may mediate some prenatal stress effects.
Maternal low-level stress was found to produce persistent changes in serotonin (5-HT) receptor binding in several brain regions of the offspring. [3H]5-HT binding was increased in cerebral cortex, decreased in hippocampus and unchanged in pons medulla while [3H]spiperone binding was increased in all three regions at 60 days of age. The binding changes appeared to be due to altered numbers of binding sites with no change in dissociation constants. Regional differences were also found when the ability of nerve terminals to synthesize [14C]5-HT from L-[14C]tryptophan was studied. Prenatal stress reduced the rate of [14C]5-HT synthesis in hippocampus but not in cortex or pons medulla. When younger offspring were studied, binding of [3H]5-HT to cerebrocortical membranes was found to be reduced at 16 days of age and increased at 40 days while [3H]spiperone showed only an increased binding at 40 days. In contrast, prenatal stress resulted in increased nighttime locomotor activity whether measured at 23, 40 or 60 days of age. The present study provides additional evidence that prenatal stress affects the development of serotonergic neurons and it is possible that such changes may underlie the reported behavioural deficits in offspring of stressed female rats.
Maternal licking behavior was observed in 20 Long-Evans rat dams on two consecutive days. Stimulus pups were male and female foster pups from dams that were either housed with 5 adult males during the last trimester of pregnancy (stressed) or housed alone (unstressed). Unstressed male pups received significantly more maternal licking than their female siblings, but prenatally stressed males and females received similar levels of maternal licking, comparable to that directed to unstressed females. In a second study, urine collected from prenatally stressed male pups elicited significantly less investigation from dams in a choice test than urine from age-matched unstressed males. It is concluded that the chemosignals which stimulate dams normally to provide more maternal attention to male than female neonates are deficient in prenatally stressed males. The results raise the possibility that differential maternal care may mediate some effects of prenatal stress on behavioral development in males.
Health nurses interviewed 153 randomly selected mothers during the first month after delivery and obtained data on their pregnancies, and, by periodic visits up to four years of age, on the health, development and behaviour of their children. The object was to explore the relationships between child morbidity and a wide range of possibly noxious factors in pregnancy.
No relationship was found between the children's health and physical illness, accidents, work stresses or dental operations in the mothers. Situational stresses such as the death or severe illness of a family member, or shocks and frights, experienced by the expectant mother were also not significant. On the other hand, stresses involving severe, continuing personal tensions (in particular marital discord) were closely associated with child morbidity in the form of ill‐health, neurological dysfunction, developmental lag and behaviour disturbance. This association could not be attributed to prenatal maternal illness, to short gestation or to complications at delivery. Low socioeconomic status and adverse environment were not significantly related to child morbidity if there was no prenatal personal tension, but they were highly characteristic of the personal tension cases.
It is suggested that the effects of poverty on child development are mediated by prenatal personal tensions.
It is also suggested that continuous personal tension in pregnancy may be characteristic of population pressures, and that their morbid outcome in the children acts as a means of population control in the human race.
RÉSUMÉ
Etude longitudinale depuis la naissance sur les effets des tensions prénatales
Des infirmières de santé ont interrogé 153 mères sélectionnées au hasard sur leurs grossesses durant le premier mois après l'accouchement et au cours de visites périodiques par la suite. Elles purent obtenir des détails sur la santé, le développement et le comportement des enfants juqu'à l'âge de 4 ans. L'objet de l'étude a été d'explorer la relation entre la morbidité infantile et une grande étendue de facteurs nocifs possibles durant la grossesse. Aucune affection physique chez la mère, aucun accident, aucun accident du travail, ni intervention dentaire n'ont joué un tel rôle. Des tensions de situation telle que la mort ou une maladie grave chez un membre de la famille, un choc ou une grande frayeur, que la future mère avait dû surmonter, se montrèrent également sans influence sur la santé des enfants. Inversement, des tensions qui prennent une forme personnelle grave et continuelle—en particulier les discordes conjugales—étaient intimement associées avec la mauvaise santé des enfants, des dysfonctions neurologiques et des troubles du comportement. Cette association n'a pu être attribuée à une maladie maternelle prénatale concomitante, une pré‐maturité ou une complication de la délivrance. Le niveau socio‐économique bas et un environnement défavorable n'étaient pas reliés significativement à une morbidité infantile lorsqu'il n'y avait pas de tension personnelle prénatale chez la mère, mais étaient hautement caractéristiques des cas de tension personnelle. Il est suggéré que la pauvreté atteint le développement de l'enfant à travers ses influences néfastes sur les tensions personnelles de la mère durant la période prénatale.
Il est également suggéré (par analogie avec certaines agressions extéroceptives chez l'animal entrainant une viabilité faible et une mort foetale) que des tensions personnelles continues durant la grossesse sont caractéristiuqes de pressions de population, et que, chez les humains, leurs conséquences morbides agissent comme un moyen de contrôle de population.
ZUSAMMENFASSUNG
Auswirkungen praenataler Stressituationen: Eine Verlaufsstudie von Geburt an
153 willkürlich ausgewählte Mütter wurden während des ersten Monats nach ihrer Entbindung von Gesundheitsfürsorgerinnen über ihre Schwangerschaft befragt und durch wiederholte spätere Besuche wurden Informationen über den Gesundheitszustand, die Entwicklung und das Verhalten ihrer Kinder bis zum Alter von vier Jahren gesammelt.
Es war der Zweck dieser Studie, eine Beziehung zwischen kindlicher Morbidität und einem weiten Spektrum möglicher schädlicher Faktoren während der Schwangerschaft zu finden. Weder organische Krankheiten der Mütter, noch Unfälle, Arbeitsbelastungen, noch Zahnbehandlungen erwiesen sich als solche Faktoren. Psychische Stressituationen wie Tod oder Krankheit eines Familienmitglieds, Schock und Angst, mit denen die Schwangeren fertig wurden, hatten ebenfalls keinen Einfluß auf die kindliche Gesundheit. Jedoch waren Belastungen durch ernsthafte anhaltende persönliche Spannungen, insbesondere eheliche Konflikte eng mit dem Krankheits‐Gesundheitszustand, mit neurologischer Dysfunktion und Verhaltensstörungen der Kinder verbunden. Diese Beziehung konnte jedoch nicht auf begleitende mütterliche Krankheiten, Frühgeburtenraten oder Geburtskomplikationen bezogen werden. Niedriger sozio‐ökonomischer Status, und schlechte Umwelteinflüsse zeigten ohne gleichzeitige mütterliche Spannungen in der Schwangerschaft keine signifikante Beziehung zur kindlichen Morbidität, waren aber sehr charakteristisch für die Fälle mit persönlichen Spannungen. Es wird angenommen, daß Armut die kindliche Entwicklung beeinflußt und zwar durch ihren schlechten Einfluß auf die persönlichen Spannungen der Mutter während der Schwangerschaft.
Es wird weiterhin angenommen (analog zu bestimmten extero‐ceptiven Stressituationen bei Tieren, aus denen eine verminderte Lebensfähigkeit und Früchttod resultiert), daß fortgesetzte persönliche Spannungen während der Schwangerschaft charakteristisch hoher Bevölkerungsdichte sind und daß beim Menschen Häufigkeit und Schwere von Krankheiten als ein Mittel zur Kontrolle der Bevölkerungsdichte wirkt.
RESUMEN
Estudio continuado a partir del nacimiento de los efectos de sufrimientos pre‐natales
Enfermeras sanitarias entrevistaron a 153 madres seleccionadas al azar durante el primer mes después del parto, preguntándoles acerca de sus embarazos, y más adelante a base de visitas periódicas pudieron obtener datos sobre la salud, desarrollo y comportamiento de sus niños hasta la edad de 4 años.
El objeto del estudio fue explorar las relaciones entre la morbilidad infantil y un amplio margen de factores gestacionales posiblemente nocivos. No fueron calificados como tales las enfermedades fisicas de las madres, ni accidentes, stresses de trabajo y operaciones dentales. Stresses situacionales, tales como la muerte o enfermedad grave de un familiar, y shock y sustos que podría sufrir la gestante no tuvieron tampoco influencia en la salud de los niños. De otra parte stresses consecutivos a tensiones personales continuas (sobre todo desacuerdo marital) estaban asociades muy de cerca con la mala salud de los niños, disfunción neurológica y alteraciones en el comportamiento. Esta asociación no podría ser atribuida a enfermedad materna prenatal concomitante, prematuridad o complicaciones del parto. Un nivel socio‐económico bajo y un ambiente adverso no tenían relación significativa con la morbilidad del niño si no había al mismo tiempo tensiones personales prenatales en la madre; sin embargo eran altamente características de los casos con tensión personal. Se sugiere que la pobreza afecta al desarrollo del niño a través de su influencia adversa sobre las tensiones personales prenatales de la madre.
Se sugiere (por analogía con ciertos stresses esteroceptivos en animales que dan lugar a pobre viabilidad y muerte fetal) que las tensiones personales continuadas en la gestación son caracteristicas de presiones de la población y que en los humanos su acción mórbida actúa a la manera de un control de la población.
Male rats were exposed to prenatal or postnatal stress, or both. The prenatally stressed males showed low levels of male copulatory behavior and high rates of female lordotic responding. Postnatal stress had no effect. The modifications are attributed to stress-mediated alterations in the ratio of adrenal to gonadal androgens during critical stages of sexual differentiation. Specifically, it appears that stress causes an increase in the weak adrenal androgen, androstenedione, from the maternal or fetal adrenal cortices, or from both, and a concurrent decrease in the potent gonadal androgen, testosterone.
Two hundred and fourteen normal offspring from 45 litters of mice were studied. Daily examinations employing a spectrum of reflexologic tests as indicators of neurologic development were followed from birth to 4 weeks of age. Five periods of neurologic development were found, each period having reflex responses characteristic of the behaviour and neurologic development of that age. The periods were designatedperinatal (birth to 3 days),neonatal (3 to 9 days),postnatal transition (9 to 15 days),postnatal infantile orpre-juvenile (15 to 26 days), andjuvenile (from 26 days until sexual maturity). These findings were correlated with data from previous studies, and it was confirmed that the end of the Postnatal transition period is the most critical period of development, when all aspects of neural maturation suddenly reach adultlike perfection. It was concluded that reflex tests are useful in assessing the degree of neural maturation in the developing mouse, and are reliable indicators of normal development.
Pregnant rats were subjected to once daily stress treatments consisting of handling and a saline injection. The offspring showed region-specific changes in brain 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in infancy but only the hypothalamus still showed significant changes at 60 days of age. In a reaction-to-stress test 23-day-old offspring in the prenatal stress group showed a greater elevation in plasma corticosterone level but smaller changes in hypothalamic NE and 5-HIAA levels than control offspring suggesting that prenatal stress may have altered the functioning of the hypothalamic-pituitary-adrenal axis. It is suggested that changes in the development of specific monoamine-containing neurons may be associated with the reported behavioral deficits in offspring of female rats stressed during pregnancy.
This incidence of cannibalism was studied in a series of developmental studies (on neonatal lesions, prenatal stress, prenatal surgery, unoperated controls) in which rats were manipulated during either the prenatal or early postnatal periods. Cannibalism during the preweaning period occurred in from 0 to 33% of the litters, depending on the treatment group. It was found in most cases, however, that mothers who cannibalized were also good caretakers of their remaining pups. The same litters were also involved in preweaning tests of mother-young interactions to determine if experimental treatments altered the maternal-filial relationship. It was found that as early as postnatal Day 4, nursing episodes were predominantly pup-initiated in the lesioned litters but mother-initiated in control litters.
The effects of high-anxiety-producing stress administered to rats during pregnancy were studied. The birthweight of offspring of both sexes from the stressed group was found to be significantly lower compared to birthweights of rats from unstressed mothers. The subsequent growth rates, however, were not affected. Mortality rate was significantly higher in the stressed group, although litter size, gestation length and sex ratios were not affected. Mean plasma resting corticosterone levels of the young pups did not differ between the two groups although they rose significantly as they aged in all groups. The offspring of both sexes from stressed mothers responded differently from the controls when subjected to short-term stress (one session) in adulthood. Their increase in plasma corticosterone concentration was significantly below that of the controls. This difference in response was abolished with long-term stress (10 days) when the males, but not the females, had habituated to the stressor. The observed inability to respond adequately to a sudden environmental change suggests a defective emergency response.
Lingering effects due to stressing were also found. Male offspring of a second litter, conceived by the original mothers 8 weeks after the discontinuation of stress, had significantly lower birthweights than those of the controls. The subsequent growth rate of neither sex was affected nor was the response to short-term stress.
J. Endocr. (1984) 100 , 301–306
Experimental female rats were injected with ACTH during the last third of their pregnancy. This treatment resulted in prolongation of gestation and in abnormal development of the young. The number of resorptions, stillbirths, and congenitally malformed pups was increased and those that appeared normal had lower body weights. The experimental treatment also severely affected the ability of the dams to exhibit normal maternal behavior. Significant individual differences were noted in the sensitivity of the dams to the experimental treatment. Cross-fostering experiments revealed that experimental dams exhibited normal maternal behavior towards control foster pups, after an initial delay of 24 h. When experimental pups, born after a prolonged gestation, or delivered by caesarian section after the normal duration of gestation, were given to control mothers, normal maternal behavior was observed, but the survival rate of the young was not increased.
Corticotropin-releasing factor (CRF) is a neuropeptide found throughout the central nervous system that has a proposed role in modulating emotional and behavioral states, including stress and anxiety. The amygdala, which is important in the control of emotional and autonomic responses to stress, contains CRF nerve terminals, CRF cell bodies, and CRF receptors. In rats, exposure to prenatal stress results in offspring that display a hyperemotional state and increased anxiety. In this study the effects of prenatal stress on CRF release was measured in amygdala minces (1 mm3) obtained from adult (8-16 weeks of age) male offspring of dams subjected to daily saline injection (0.1 ml, s.c.) from gestational day 14 to 21. CRF release from amygdala was time- and calcium-dependent, and stimulated by KCl-induced depolarization. Depolarization-induced CRF release was significantly increased by 42% from the amygdala of prenatally stressed offspring versus controls. Prenatally stressed offspring also showed a 49% increase in CRF levels in the amygdala. The increased amounts of CRF released in response to depolarization were likely the consequence of increased tissue content of CRF, as fractional release under basal or KCl-stimulated conditions was not different in the prenatal stress group versus control. This suggests that a long-lasting up-regulation of the CRFergic neurotransmission may occur in the amygdala, which may be important in the generation of hyperemotional offspring after exposure to prenatal stress.
It has been suggested that stress during the initial stages of human life may serve as a predisposing factor to mental illness. Recently, we reported that in pregnant rats, stress induces an increase of behavioral depression in the female offsprings when adult. This article describes the effect of prenatal stress on central dopaminergic transmission during adulthood. The offspring of stressed mothers showed an increase of behavioral depression in the Porsolt test and a reduction of DOPAC, HVA, and DOPAC/DA index in the n. accumbens. The effect on the right accumbens was more marked than on the left. A great body of information exists to suggest that depression is related to a decrease of dopaminergic neurotransmission, and the present data provide new evidence in support of the hypothesis that maternal stress during gestation increases the risk of depression in the offspring. We are also reporting a hitherto uncommented relationship between behavioral depression in the Porsolt test and the decrease of dopamine transmission in the n. accumbens.
Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring.
The present study evaluates the effect of chronic intermittent cold-swimming stress on body weight gain of pregnant rats and subsequent development of the offsprings after birth, till peripubertal stage. When stress was administered during the first half (1-11 days) of gestation, weight gain of pregnant rats was significantly lower at the 9th and 11th days (P < 0.05 vs. control, respectively). No differences of weight gain in comparison with control rats were found at term gestation in pregnant rats exposed to stress continuously. Similarly, stress administered, starting from 12th day till term gestation, had no effect on weight gain. Even though weight gain of pregnant rats during the second half of pregnancy in group stress 1-11 was restored to normal values, a high mortality rate of neonates 1, 2 and 3 weeks after birth was found in this group (P < 0.02, 0.01 and 0.001 vs. controls). There was no significant difference between stressed and control groups with respect to the number or body weight of litters, as well as weight gain of neonates during the first 21 days of life. In addition, in offsprings from all stressed groups, a high number of small for date animals was found after 14 days of life, and 74.4% of these small for date animals died during the peripubertal period. The present data demonstrate that the exposure to stress in utero may induce damaging effects on postnatal development.
Neuromotor responses were assessed in 90 infant squirrel monkeys born from normal and stressed pregnancies. Repeated psychological disturbance during pregnancy, evoked by disruption of the pregnant female's social relationships, significantly altered the performance of the young infant on a standardized battery of neuromotor tests. As compared with infants from undisturbed pregnancies, infants from chronically stressed pregnancies had poorer motor abilities, impaired balance reactions, and reduced postrotary nystagmus. They also had shorter attention spans and looking episodes during the administration of orientation items. In contrast, when only a single stressful period was imposed during midgestation, infants were not significantly different from control subjects. These findings indicate that sustained stress across pregnancy can have deleterious effects on fetal development, but a short period of stress, at least when restricted to midgestation, does not appear to adversely affect neuromotor responses of the young primate infant.
Neonatal handling produces enduring changes in hypothalamic-pituitary-adrenal (HPA) axis activation in response to acute stress presentation. Handled rats display reduced HPA activity in response to stress, which is associated with increased hippocampal glucocorticoid receptor densities and decreased median eminence corticotrophin-releasing hormone (CRH) content. Prenatal stress (PS) also has long-term consequences on HPA responsivity to stress and related behavioral profiles. On the basis of earlier behavioral data suggesting that PS contributed to the expression of handled responses, we investigated how PS and handling might interact to affect median eminence CRH content. Groups of prenatally stressed rats and controls were subjected to a handling procedure or left undisturbed. Adult rats were killed and median eminence CRH levels were assayed as well as plasma corticosterone (CORT). PS and handling did not affect CRH content; however, handled plus PS rats exhibited significantly reduced CRH levels. Handling decreased plasma CORT concentrations, an effect that was absent in the PS rats. We contend that PS can modulate an animal's sensitivity to later environmental manipulations while producing minimal effects on its own. Researchers interested in early environmental conditions and later physiologic and behavioral responses should monitor their subjects' gestational history.
Growth rate of the offspring of female rats stressed by the presence of a cat at the 10th or the 19th gestational day was lower than that of controls whereas footshocks administered at the same periods did not significantly influence growth rate of the young. Whatever the nature of the stress and the time when it was administered to the mother, the death rate of the young rats was much greater than that in controls. When adult, the offspring of stressed mothers exhibited learning and memory impairments in a delayed alternation task as well as in passive avoidance conditioning. Alteration of these cognitive functions is interpreted in terms of subtle dysfunctions in the development of the nervous system through modifications of the hormonal components of the mothers, particularly eventual alterations of the nervous system biochemistry of the offspring.