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Single early prenatal lipopolysaccharide exposure impairs striatal monoamines and maternal care in female rats
Abstract
Aims:
Environmental information received by a mother can induce a phenotype change in her offspring, commonly known as a maternal effect (trans-generational effect). The present work verified the effects of lipopolysaccharide (LPS), which mimics bacterial infection, on maternal care and on the activity of related brain areas in F1 offspring, i.e., female rats that were prenatally exposed to LPS.
Main methods:
Pregnant rats received 100μg/kg of LPS intraperitoneally on gestational day (GD) 9.5. Female offspring of the F1 generation were mated to naïve males and were evaluated during their lactation period for open field, maternal and aggressive behaviors. Striatal and hypothalamic dopamine and serotonin levels and turnover were also evaluated. Furthermore, astrocyte protein expression in the nucleus accumbens (NA) was analyzed in F1 females to assess LPS-induced neuroinflammation.
Key findings:
Prenatal LPS did not change open field behavior but impaired both maternal and maternal aggressive behaviors in the F1 generation. LPS exposure also reduced both striatal levels of dopamine and serotonin and its metabolites, but induced no changes in NA astrocyte expression.
Significance:
We suggested that the observed impairments in the F1 females were a consequence of a motivational change induced by prenatal LPS, as (1) no changes in motor activity were observed, (2) prenatal LPS-exposure was reported by our group to induce motivational impairments in males, and (3) the existence of a strong connection between striatal dopaminergic activity and motivation-oriented activities. The present findings strongly indicate a maternal effect for prenatal LPS, at least for the F1 generation.
... We have shown that prenatal LPS (on gestational day [GD] 9.5) impairs MB in the F1 generation [12]. Thus, if prenatal LPS decreased MB in F1 generation, we asked how prenatal LPS influence the maternal/ predatory selection. ...
... F0 generation treatment LPS (from Escherichia coli, SigmaV R , serotype 0127: B8, catalog L3129-100 mg) was dissolved in saline (50 mg/ ml of LPS in 0.9% Na Cl solution) and was intraperitoneally (i.p.) administered to F0 pregnant rats (PND90-95) at a dose of 100 mg/kg on GD 9.5 (LPS group, n ¼ 12). We applied this treatment because it was previously reported to induce sickness behaviour in the F0 generation [20] and impaired MB in the F1 generation in adulthood [12]. In addition, prenatal treatments with this dose increased the cytokine IL-1 b production at the placental level [11]. ...
... Additionally, both corticosterone and TNF-alpha were not different relative to the S þ S group. Thus, we suggest that prenatal LPS decreased MB and promoted the switch from MB to PB by a reduced motivation, as observed after prenatal LPS exposure [12]. ...
Purpose: The influence of a challenge dose of lipopolysaccharide (LPS) on the behavioural selection between maternal (MB) and predatory behaviours (PB) of female rats prenatally treated with the same endotoxin or saline solution (F1 generation) were studied.
Material and methods: Thus, in adult age, these female rats were mated and, at lactation days 5 or 6, the following groups were formed: (1) LPS + LPS group-female rats prenatally treated with LPS and received an LPS challenge dose; (2) S + LPS group-female rats prenatally treated with saline solution and received a challenge LPS dose (3) S + S group-females rats prenatally treated with saline which received a saline injection. MB, PB to cockroaches, exploratory behaviour, periaqueductal grey (PAG) expression of the astrocytic biomarker glial fibrillary acidic protein (GFAP), and corticosterone and TNF-alpha serum levels were evaluated.
Results: Showed that: (1) relative to the S + S group, the LPS + S group showed decreased MB and slightly increased PB, without inducing sickness behaviour; (2) the LPS + LPS group showed decreased MB but few effects on PB; (3) there was increased sickness behaviour associated with increased TNF-alpha serum levels in the LPS + LPS group; (4) a significant increase in GFAP expression was observed in both LPS groups, which was greater in the LPS + LPS group and (5) no differences in the corticosterone of all groups.
Conclusions: Prenatal LPS impaired the switch from MB to PB in female rats of the LPS + LPS group by increased sickness behaviour as well as an increase in plasmatic TNF-alpha levels inducing PAG astrogliosis.
... Monoamine and monoamine metabolite levels in the hypothalamus and frontal cortex were measured using high-performance liquid chromatography (HPLC, Shimadzu, model Prominence, Kyoto, Japan). Tissue collection and preparation were previously described by our group [29]. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5HIAA), and norepinephrine (NOR) were measured. ...
... Previous data from our group corroborated that GD 9.5 is a critical period. We showed that prenatal treatment with LPS on GD 9.5 in rats induced short-and long-term reproductive, behavioral, and neuroimmune impairments in the offspring [14][15][16][17][18][19]26,29,34,35]. ...
... SAL, prenatal saline injection; LPS, prenatal LPS injection (n = 8 rats/group). The data are expressed as the mean ± SEM. [25][26][27][28][29] have a predominant cognitive component as with reversal learning [40]. The effects of maternal LPS exposure on the developing fetal brain have been suggested to be mediated by the induction of proinflammatory cytokines within the maternal circulation and placenta [42][43][44]. ...
... Lipopolysaccharide (LPS) is an endotoxin that originates in the cell wall of Gram-negative bacteria and mimics bacterial infection, activating the host immune system to release proinflammatory cytokines (Avitsur et al., 1997;Saluk-Juszczak and Wachowicz, 2005). Viral and bacterial infections, including those caused by prenatal LPS exposure, induce short-and long-term changes in behavior and central nervous system activity Boksa, 2010;Golan et al., 2005;Kirsten et al., 2012Kirsten et al., , 2010aKirsten et al., , 2010bMeyer et al., 2009;Penteado et al., 2013;Soto et al., 2013). Previous investigations by our group showed that prenatal LPS exposure (100 μg/kg, intraperitoneally, on gestational day [GD] 9.5) reduced social behavior in F1 males in both infancy and adulthood and decreased striatal dopamine (DA) and DA metabolite levels in the absence of signs that indicate neuroinflammation (Kirsten et al., 2010b). ...
... The reproductive performance was examined because it was reported that prenatal LPS induces spontaneous abortions (Aisemberg et al., 2010;Lee et al., 2013b;Xu et al., 2013) and intrauterine fetal death or embryonic resorption (Paintlia et al., 2008;Xu et al., 2006;Zhao et al., 2008). Since environmental information received by a mother can induce a phenotype change in her offspring, commonly known as a maternal effect (trans-generational effect), the maternal behavior was assessed Soto et al., 2013). General activity of dams in the open field was investigated to exclude that motor interferences on maternal behavior performance. ...
... Immunological challenge in the prenatal or early postnatal period, in the form of either acute interleukin-1 (IL-1) or endotoxin exposure, is capable of producing long lasting changes in neuroendocrine function Granger et al., 1996;Hood et al., 2003;Kirsten et al., 2012Kirsten et al., , 2011aKirsten et al., , 2011bKirsten et al., , 2010aKirsten et al., , 2010bPimentel et al., 2012;Soto et al., 2013). LPS have been shown to induce stress like-responses in the neonate (Spencer et al., 2005), elevating circulating levels of corticotropin-releasing hormone, adrenocorticotropin-releasing hormone, corticosterone, and glucose (Walker et al., 2008(Walker et al., , 2004(Walker et al., , 2006. ...
Objective:
The present study analyzed the effects of lipopolysaccharide (LPS) on maternal behavior during lactation and possible correlations with changes in emotional and immune responses in offspring.
Methods:
Lactating rats received 100 μg/kg LPS, and the control group received saline solution on lactation day (LD) 3. Maternal general activity and maternal behavior were observed on LD5 (i.e. the day that the peak of fever occurred). In male pups, hematological parameters and ultrasonic vocalizations (USVs) were assessed on LD5. At weaning, an additional dose of LPS (50 µg/kg, i.p.) was administered in male pups, and open-field behavior, oxidative burst and phagocytosis were evaluated.
Results:
A reduction in the time in which dams retrieved the pups was observed, whereas no effects on maternal aggressive behavior were found. On LD5, a reduction of the frequency of USVs was observed in pups, but no signs of inflammation were found. At weaning, an increase in immune system activity was observed, but no differences in open-field behavior were found.
Conclusion:
These results indicate that inflammation in lactating mothers disrupted mother/pup interactions and may have produced short- and long-term effects on pup behavior as well as biological pathways that modulate inflammatory responses to bacterial endotoxin challenge in pups.
... Lipopolysaccharide (LPS) is an endotoxin that originates in the cell wall of Gram-negative bacteria and mimics bacterial infection, activating the host immune system to release proinflammatory cytokines (Avitsur et al., 1997; Saluk-Juszczak and Wachowicz, 2005). Viral and bacterial infections, including those caused by prenatal LPS exposure, induce short-and long-term changes in behavior and central nervous system activity (Bernardi et al., 2010; Boksa, 2010; Golan et al., 2005; Kirsten et al., 2012 Kirsten et al., , 2010a Kirsten et al., , 2010b Meyer et al., 2009; Penteado et al., 2013; Soto et al., 2013). Previous investigations by our group showed that prenatal LPS exposure (100 μg/kg, intraperitoneally, on gestational day [GD] 9.5) reduced social behavior in F1 males in both infancy and adulthood and decreased striatal dopamine (DA) and DA metabolite levels in the absence of signs that indicate neuroinflammation (Kirsten et al., 2010b). ...
... The reproductive performance was examined because it was reported that prenatal LPS induces spontaneous abortions (Aisemberg et al., 2010; Lee et al., 2013b; Xu et al., 2013 ) and intrauterine fetal death or embryonic resorption (Paintlia et al., 2008; Xu et al., 2006; Zhao et al., 2008). Since environmental information received by a mother can induce a phenotype change in her offspring, commonly known as a maternal effect (trans-generational effect), the maternal behavior was assessed (Bernardi et al., 2010; Soto et al., 2013). General activity of dams in the open field was investigated to exclude that motor interferences on maternal behavior performance. ...
... Thus, the nest odor preference test was employed to evaluate if pups presents aversion toward its mothers. Immunological challenge in the prenatal or early postnatal period, in the form of either acute interleukin-1 (IL-1) or endotoxin exposure, is capable of producing long lasting changes in neuroendocrine function (Bernardi et al., 2010; Granger et al., 1996; Hood et al., 2003; Kirsten et al., 2012 Kirsten et al., , 2011a Kirsten et al., , 2011b Kirsten et al., , 2010a Kirsten et al., , 2010b Pimentel et al., 2012; Soto et al., 2013). LPS have been shown to induce stress like-responses in the neonate (Spencer et al., 2005), elevating circulating levels of corticotropin-releasing hormone, adrenocorticotropin-releasing hormone, corticosterone, and glucose (Walker et al., 2008Walker et al., , 2004Walker et al., , 2006). ...
... By activating the immune system similarly to infections, LPS can cause several behavioral changes (e.g., an increase in slow-wave sleep, anorexia, and depressive-like behavior) that may be associated with MDD and are referred to as sickness behavior ( (Cohn, Kinoshita, & Palermo-Neto, 2012;Hodes, Kana, Menard, Merad, & Russo, 2015). From an immune-neuroendocrine perspective, LPS triggers the secretion of proinflammatory cytokines by the innate immune system and also increases the activity of the hypothalamic-adrenal-pituitary (HPA) axis, an important system that is known to be responsive to environmental stressors and infections (Leonard, 2001;Leonard & Myint, 2009;Soto et al., 2013b)) (Kirsten et al., 2015) and has been reported to be related to MDD (Munoz, Cuijpers, Smit, Barrera, & Leykin, 2010;Waters et al., 2015;Yang et al., 2015). ...
... Stressful environmental situations, including psychological trauma during the early stages of neonatal development and prenatal exposure to various viral and bacterial infections, can cause short-and long-term changes in behavior and central nervous system activity (Meyer, Yee, & Feldon, 2007;Soto, et al., 2013b). Prenatal infection that is mimicked by LPS exposure causes profound changes in fetal brain development, affecting such areas as the HPA axis and increasing the levels of glucocorticoids and proinflammatory cytokines within the maternal circulation and fetal brain (Ashdown et al., 2006;Meyer, et al., 2007;Urakubo, Jarskog, Lieberman, & Gilmore, 2001). ...
The objective of the present study was to investigate whether prenatal lipopolysaccharide (LPS) administration modifies the expression of depressive and non-depressive-like behavior in male and female mice across two generations. The sexual dimorphism of these mice was also examined in the open-field test. Male and female mice of the parental (F0) generation were selected for depressive- or non-depressive-like behavioral profiles using the tail suspension test (TST). Animals with similar profiles were matched for further mating. On gestation day (GD) 15, pregnant F0 mice received LPS (100μg/kg, i.p.) and were allowed to nurture their offspring freely. Adult male and female of the F1 generation were then selected according to behavioral profiles and observed in the open field. Male and female mice of the two behavioral profiles were then mated to obtain the F2 generation. Adults from the F2 generation were also behaviorally phenotyped, and open field behavior was assessed. Male mice that were selected for depressive- and non-depressive-like behaviors and treated or not with LPS in the parental generation exhibited similar proportions of behavioral profiles in both filial lines, but LPS exposure increased the number of depressive-like behavior. An effect of gender was observed in the F1 and F2 generations, in which male mice were more sensitive to the intergenerational effects of LPS in the TST. These data indicate that prenatal LPS exposure on GD15 in the F0 generation influenced the transmission of depressive- and non-depressive-like behavior across filial lines, with sexual dimorphism between phenotypes.
... Monoamine and monoamine metabolite levels in the hypothalamus and striatum were measured using high-performance liquid chromatography (HPLC) in the same rats that were behaviorally evaluated and had their serum collected. Tissue collection and preparation were previously described by our group [53]. Norepinephrine (Nor) and its metabolites vanillyl mandelic acid (VMA) and 3-methoxy-4-hydrophenylglycol (MHPG), dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5HIAA) were measured using HPLC (Shimadzu, model Prominence, Kyoto, Japan). ...
... Previous data from our group corroborated that GD 9.5 is a critical period. We showed that prenatal treatment with LPS on GD 9.5 in rats induced short-and long-term reproductive, behavioral, and neuroimmune impairments in the offspring [25,26,28,30,31,53]. These impairments were more pronounced in males; prenatal LPS did not alter behavior or corticosterone levels in females [29][30][31]. ...
We previously showed that prenatal lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces behavioral, brain and immunological changes in the offspring. Bacterial infections can also induce changes in the balance of chemical elements (e.g., metals) in our body. For example, proinflammatory cytokines liberated after LPS exposure produces metallothionein, which sequestrates zinc (Zn). Deficient or increased levels of some of those metals can be harmful and toxic to the fetus during pregnancy. Because maternal deficiency of some metals as a result of exposure to LPS may be responsible for damage in offspring, the aim of this study was to measure the concentration of some chemical elements, especially the ones involved in pregnancy and infection/inflammation. We exposed Wistar rats to LPS (100 μg/kg, intraperitoneally) or to saline (vehicle), on gestational day 9.5. 24 h after the treatment we evaluated the maternal serum Zn, magnesium (Mg), copper (Cu), selenium (Se) and manganese (Mn) concentrations with a high resolution inductively coupled plasma mass spectrometry (HR-ICPMS). Our results showed that the concentration of Zn, Mg, Se and Mn was reduced in the LPS group, when compared with their respective controls. In all cases, results were considered significant if p < 0.05. Thus, maternal LPS exposure reduced the concentration of specific chemical elements that are involved in impairments found in the offspring. FAPESP.
... Monoamine and monoamine metabolite levels in the hypothalamus and striatum were measured using high-performance liquid chromatography (HPLC) in the same rats that were behaviorally evaluated and had their serum collected. Tissue collection and preparation were previously described by our group [53]. Norepinephrine (Nor) and its metabolites vanillyl mandelic acid (VMA) and 3-methoxy-4-hydrophenylglycol (MHPG), dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5HIAA) were measured using HPLC (Shimadzu, model Prominence, Kyoto, Japan). ...
... Previous data from our group corroborated that GD 9.5 is a critical period. We showed that prenatal treatment with LPS on GD 9.5 in rats induced short-and long-term reproductive, behavioral, and neuroimmune impairments in the offspring [25,26,28,30,31,53]. These impairments were more pronounced in males; prenatal LPS did not alter behavior or corticosterone levels in females [29][30][31]. ...
... Here, we showed MIA increased pup retrieval latency only in dams that were also exposed to early life RMS, and not in those without early life separation. A previous study shows that in utero lipopolysaccharide (LPS) induced F1 postpartum deficits [56]. Similar to our findings, LPS did not alter nursing or grooming, but only increased retrieval duration. ...
... In opposite , one of the maternal care characteristics, licking-nursing duration, was increased in LPS-treated dams. Somewhat different results were described by Bernardi and colleagues ( Bernardi et al., 2010 ) and Soto and colleagues ( Soto et al., 2013 ), who observed impairment of maternal care behavior in dams treated with 250 μg/kg and 100 μg/kg of LPS, respectively. The difference between the mentioned and present results can be explained by the different dose of LPS, as well as by the different days of gestation when the LPS was administered. ...
Higher risk of depression and schizophrenia in descendants of mothers experienced acute infection during the pregnancy has been reported. Since monoamines are fundamental in mentioned psychopathologies, it is possible that maternal immune activation leads to impaired functioning of serotonin (5-HT), noradrenaline, and dopamine neurons in offspring. To test this hypothesis, we examined the effect of maternal immune activation by lipopolysaccharide (LPS) in rats on the excitability of monoamine-secreting neurons in the offspring. LPS was administered during days 15–19 of the gestation in the rising doses of 20–80 µg/kg; control dams received vehicle. During days 53–63 postpartum, rats were anesthetized and electrodes were inserted into the dorsal raphe nucleus, locus coeruleus, and ventral tegmental area for in vivo excitability assessment of 5-HT, noradrenaline, and dopamine neurons. Maternal immune activation suppressed the firing rate of 5-HT neurons in both sexes and stimulated the firing rate of dopamine neurons in males. Decrease in the firing rate of 5-HT neurons was accompanied with an increase, and increase in the firing rate of dopamine neurons with a decrease, in the density of spontaneously active cells. Maternal immune activation also decreased the variability of interspike intervals in 5-HT and dopamine neurons. It is possible that the alteration of excitability of 5-HT and dopamine neurons by maternal immune activation is involved in the psychopathologies induced by infectious disease during the pregnancy. Stimulation of dopamine excitability in males might be a compensatory mechanism secondary to the maternal immune challenge-induced suppression of 5-HT neurons.
... Each segment was dissected, weighed and stored at − 80 • C until use. Each brain segment was defrost and added to a vial containing perchloric acid solution and homogenized with a sonicator, before being centrifuged (Felicio et al., 1996;Soto et al., 2013). Supernatants were taken and used in the quantification by high performance liquid chromatography coupled to electrochemical detector (HPLC-ECD; Felicio et al., 1996), a sample injector (15 and 20 Al valve) an integrator (Chromatopac, Shimatzu, Japan), a C-18 column (Shimpack; ODS, Kyoto, Japan). ...
Ethnopharmacological relevance
Luffa operculata (L.) Cogn (Cucurbitaceae), is a traditional plant popularly used against sinusitis and as abortive.
Aim of the study
The verification of the effects of BNE prenatal exposure to juvenile male Wistar rats (F1 generation).
Materials and methods
Pregnant female rats (F0 generation) received 1.0 mg/kg BNE, or distilled water (100 mL/kg), by gavage, between gestation days GD17 and GD21. The pups were weaned at PND21, and were kept up to PND60 (juvenile age). Four groups were obtained: control (CG), experimental (EG), stress control (SCG) and stress experimental (SEG), by the “New York subway” stress technique (NYS) After being stressed, the animals were screened for behavioral changes in the open field (OF) and in light-dark box (LDB) apparatuses. They were euthanized, and the liver, kidneys and brain were removed for macroscopic and microscopic analyses, and for quantification of neurotransmitters in the hypothalamus, frontal cortex and striatum.
Results and discussion
SEG showed impairment in locomotion and rearing frequencies and in the grooming. Vanillylmandelic acid, noradrenaline and dopamine in the hypothalamus were reduced, while DOPAC was increased in the hypothalamus, as was the frontal cortex amount of 5-HIAA, indicating that there were alterations in the hypothalamic-hypophysis-adrenal axis. LDB and OF analyses demonstrated that treatment with BNE did not reverse post-stress effects. No macroscopic or histopathological changes were observed in the liver, kidneys, nor in the brain.
Conclusion
the administration of BNE to juvenile male pups diminished spatial exploration and grooming and impaired hypothalamus neurochemistry.
... Substantial evidence using murine models has confirmed that MIA by LPS exposure or pharmacological simulation of viral infection by Poly I:C inoculation efficiently primes defects in dopaminergic neurotransmission in the offspring, recapitulating ASD traits. For instance, LPS and Poly I:C exposure promotes a decrease in the dopamine levels, in the D1DR and D2DR number and in the DAT in NAc, PFC and striatum of ASD people (Kirsten et al. 2010;Soto et al. 2013;Romero et al. 2010;Meyer et al. 2008;Ozawa et al. 2006;Vuillermot et al. 2010). Also, deletion in the dopamine ...
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions that harm function and individual ability to process and respond to external stimuli. Individuals with ASD spend less time engaging in social interaction compared to non‐affected subjects. Studies employing structural and functional magnetic resonance imaging reported morphological and functional abnormalities in the connectivity of the mesocorticolimbic reward pathway between the nucleus accumbens and the ventral tegmental area (VTA) in response to social stimuli, as well as diminished medial prefrontal cortex in response to visual cues, whereas stronger reward system responses for the non‐social realm (e.g., video games) than social rewards (e.g., approval), associated with caudate nucleus responsiveness in ASD children. Defects in the mesocorticolimbic reward pathway have been modulated in transgenic murine models using D2 dopamine receptor heterozygous (D2+/−) or dopamine transporter knockout mice, which exhibit sociability deficits and repetitive behaviors observed in ASD phenotypes. Notably, the mesocorticolimbic reward pathway is modulated by systemic and central inflammation, such as primed microglia, which occurs during obesity or maternal overnutrition. Therefore, we propose that a positive energy balance during obesity/maternal overnutrition coordinates a systemic and central inflammatory crosstalk that modulates the dopaminergic neurotransmission in selective brain areas of the mesocorticolimbic reward pathway. Here, we will describe how obesity/maternal overnutrition may prime microglia, causing abnormalities in dopamine neurotransmission of the mesocorticolimbic reward pathway, postulating a possible immune role in the development of ASD.
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... Monoamine and monoamine metabolite levels in the striatum (Paxinos and Watson, 1998) were measured using high-performance liquid chromatography (HPLC, Shimadzu, model Prominence, Kyoto, Japan). Tissue collection and preparation, as well as the HPLC system, coefficients of variation, and standard linear regression curve values were previously described by our group (Soto et al., 2013). Serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5HIAA), dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. ...
Ivermectin is a human and veterinary antiparasitic drug which is one of the most widely used in the world. Studies from our group have revealed several behavioral and neurochemical impairments induced by therapeutic doses of ivermectin in adult rats. However, the effects on juveniles remain unknown. Ivermectin has been prescribed for juvenile humans, pets and farm animals, which still show remarkable development and postnatal maturation and may be more susceptible to drug interventions. Hence, we studied the behavioral and neurochemical effects of two therapeutical doses (0.2 and 1.0 mg/kg) of ivermectin in juvenile rats. As it is underestimated in prescriptions, the stress factor was also studied. Ivermectin 1.0 mg/kg induced hyperlocomotion in juvenile rats. Association of 1.0 mg/kg ivermectin with stress induced hypolocomotion in rats. Ivermectin 1.0 mg/kg whether or not associated with stress exacerbated socialization of rats. Ivermectin did not induce anxiety-like behavior neither affected corticosterone levels of juvenile rats. The motor/exploratory behavioral findings induced by association of ivermectin and stress seem to be triggered after the increase in the striatal serotonergic system activity. Association of ivermectin with stress increased striatal dopamine levels, which increased (excessive) social play behavior. Our results suggest a review of the prescribed dose of ivermectin for juvenile humans and pets. Moreover, the stress factor should be considered for ivermectin medical prescriptions, since it may exacerbate behavioral and neurochemical disturbances.
... Offspring of these immune-challenged mothers have repeatedly shown significant dysregulation in striatal and prefrontal brain regions, and they serve as ASD preclinical models of inflammation. Adult and peripubertal offspring of LPS-exposed rodents demonstrate consistently attenuated dopamine activity (measured by dopamine directly as well as its metabolites, DOPAC and homovanillic acid (HVA)) within striatal and thalamic brain regions (see Table 1; Kirsten & Bernardi, 2017;Kirsten, Taricano, Flório et al., 2010;Soto et al., 2013). An exception to this trend includes a report of increased dopamine concentrations within the NAcc of adult rats born to LPSexposed mothers (Romero, Guaza, Castellano, & Borrell, 2010). ...
Accumulating evidence suggests that autism spectrum disorder (ASD) may be conceptualized within a framework of reward processing impairments. The Social Motivation Theory of Autism posits that reduced motivation to interact with people and decreased pleasure derived from social interactions may derail typical social development and contribute to the emergence of core social communication deficits in ASD. Neuroinflammation may disrupt the development of mesolimbic dopaminergic systems that are critical for optimal functioning of social reward processing systems. This neuroinflammation-induced disturbance of mesolimbic dopaminergic functioning has been substantiated using maternal immune activation rodent models whose offspring show aberrant dopaminergic corticostriatal function, as well as behavioral characteristics of ASD model systems. Preclinical findings are in turn supported by clinical evidence of increased mesolimbic neuroinflammatory responses in individuals with ASD. This review summarizes evidence for reward processing deficits and neuroinflammatory impairments in ASD and examines how immune inflammatory dysregulation may impair the development of dopaminergic mesolimbic circuitry in ASD. Finally, future research directions examining neuroinflammatory effects on reward processing in ASD are proposed.
... Previous data from our group have corroborated that GD 9.5 is a critical period. We have demonstrated that prenatal exposure to LPS on GD 9.5 in rats induces short- and long-term reproductive, behavioral, and neuroimmune impairments in the offspring [7][8][9]31,[45][46][47]. ...
Autism is characterized by social deficits, communication abnormalities, and repetitive behaviors. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by gram-negative bacteria, induces autistic-like behaviors. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected pioglitazone to block or ease the impairments induced by LPS because although this drug was designed as an anti-diabetic drug (it has an insulin effect), it also exerts anti-inflammatory effects. Juvenile offspring were treated daily with pioglitazone, and the main behaviors related to autism, namely, socialization (play behavior) and communication (50-kHz ultrasonic vocalizations), were studied. Biomarkers linked to autism and/or pioglitazone were also studied to attempt to understand the mechanisms involved, namely, IL-6, TNF-alpha, MCP-1, insulin, and leptin. Prenatal LPS exposure induced social deficits and communicational abnormalities in juvenile rat offspring as well as elevated plasma IL-6 levels. Daily postnatal pioglitazone treatment blocked the impairments found in terms of the time spent on social interaction, the number of vocalizations (i.e., autistic-like behaviors) and the elevated plasma IL-6 levels. Thus, pioglitazone appears to be a relevant candidate for the treatment of autism. The present findings may contribute to a better understanding and treatment of autism and associated diseases.
... The striatum, which is part of the neurocircuitry of sexual motivation [24], was dissected, weighed, and stored at − 80°C until further analysis. Striatal dopamine and its metabolites (3,4-dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) were measured by high-performance liquid chromatography as previously described [25,26]. The data are expressed as ng/mg of tissue. ...
Prenatal undernutrition impairs copulatory behavior and increases the tendency to become obese/overweight, which also reduces sexual behavior. Re-feeding rats prenatally undernourished with a normocaloric diet can restore their physiological conditions and copulatory behavior. Thus, the present study investigated whether a hypercaloric diet that is administered in rats during the juvenile period prevents sexual impairments that are caused by maternal food restriction and the tendency to become overweight/obese. Female rats were prenatally fed a 40% restricted diet from gestational day 2 to 18. The pups received a hypercaloric diet from postnatal day (PND) 23 to PND65 (food restricted hypercaloric [FRH] group) or laboratory chow (food restricted control [FRC] group). Pups from non-food-restricted dams received laboratory chow during the entire experiment (non-food-restricted [NFR] group). During the juvenile period and adulthood, body weight gain was evaluated weekly. The day of balanopreputial separation, sexual behavior, sexual organ weight, hypodermal adiposity, striatal dopamine and serotonin, serum testosterone, and tumor necrosis factor α (TNF-α) were evaluated. The FRH group exhibited an increase in body weight on PND58 and PND65. The FRC group exhibited an increase in the latency to the first mount and intromission and an increase in serum TNF-α levels but a reduction of dopaminergic activity. The hypercaloric diet reversed all of these effects but increased adiposity. We concluded that the hypercaloric diet administered during the juvenile period attenuated reproductive impairments that were induced by maternal food restriction through increases in the energy expenditure but not the tendency to become overweight/obese.
... Consistent with changes in brain morphology (Li et al., 2009, Cui et al., 2009, Graciarena et al., 2010, alterations in neurotransmitter transmission (Boksa, 2010) have been reported as well as alterations in cell migration and synapse maturation (Cui et al., 2009). For example, maternal immune activation early during gestation (GD 9.5) led to reductions in dopamine and dopamine metabolite levels in the striatum (Soto et al., 2013, Kirsten et al., 2012, Kirsten et al., 2010 as well as to abnormalities in dopamine and serotonin activity in the substantia nigra (SN) (Wang et al., 2009). These early alterations may affect adult brain functioning leading to abnormalities in dopamine signaling (Eyles et al., 2012). ...
Rationale:
Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. High smoking incidence in these individuals in adulthood might be, at least in part, due to nicotine's cognitive enhancing effects.
Objectives:
Utilize prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) treatment at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments.
Materials and methods:
Pregnant rats were treated subcutaneously (sc) with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods (gestation days, GD 10/11, 15/16, 18/19). Cognitive assessment in male offspring commenced in early adulthood (postnatal day, PND, 60) and included: prepulse inhibition (PPI), latent inhibition (LI), and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, sc) were administered and animals were re-tested in the same tasks (PND 110).
Results:
Only maternal LPS exposure early during fetal neurodevelopment (GD 10/11) showed deficits in all tests compared to animals prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance.
Conclusion:
Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI).
... Maternal behavior: Eight pups were removed at 7 AM and placed in another cage away from their mothers, as previously described (Soto et al., 2013). ...
... We report that amphetamine-induced locomotion was significantly lower in LPS females at P60, while in male rats no difference during 60 min of recording was observed at either of ages tested. The reduced exploratory activity, as well as reactivity of adult LPS females to amphetamine, may be connected with the observed reduction of striatal levels of dopamine in Wistar females prenatally exposed to LPS [26]. Taking apart prenatal treatment effects, the more pronounced female response to amphetamine at P60 corroborates the findings that after injection of amphetamine adult female rats ambulate more than adolescent females [27] or adult male rats [28]. ...
Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100μg/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-α and IL-6 in dam blood withdrawn 2h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.
... LPS also affects CNS activity, leading to sickness behaviour in many species (Dantzer et al. 1998;Costa-Pinto et al. 2009), generally accompanied by a decrease in exploratory activity, a decrease in social and sexual behaviour, anhedonia, poor learning and a decrease in cognitive function Kirsten et al. 2010Kirsten et al. , 2012Pimentel et al. 2013;Soto et al. 2013;Penteado et al. 2014). As expected, LPS administration induced sickness behaviour in the NDLPS group, in which both total and peripheral locomotion decreased compared with the NDS group. ...
The effects of a maternal hypercaloric diet (HD) during puberty and early adulthood on neuroimmune aspects in offspring were investigated. In female rats of the F0 generation and male rats of the F1 generation, bodyweight (BW) gain, retroperitoneal fat (RPF) weight, the number of hypodermic adipocytes (HAs) and expression of glial fibrillary acidic protein (GFAP) were measured in hypothalamic astrocytes. On Postnatal Day 50, the F1 pups were challenged with lipopolysaccharide (LPS, 100 µg kg-1, s.c.) or an equal volume of saline (S), and behaviour in the open field test was evaluated, as were plasma neuropeptide and cytokine concentrations. The maternal HD caused the female F0 rats to become overweight. The F1 offspring of dams fed the HD and challenged with saline (HDS group) exhibited increases in BW gain, RPF weight and in the number of large HAs and a decrease in GFAP immunoreactivity. F1 offspring of dams fed the HD and challenged with LPS (HDLPS group) exhibited decreases in BW gain, RPF weight and GFAP immunoreactivity, but no differences were observed in the number of larger and small HAs. Plasma tumour necrosis factor-α concentrations were high in the HDS and HDLPS groups. Thus, the maternal HD during puberty and early adulthood caused the F1 generation to become overweight despite the fact that they received a normocaloric diet. These results indicate a transgenerational effect of the HD that may occur, in part, through permanent changes in immune system programming. The attenuation of neuroinflammation biomarkers after LPS administration may have resulted in a decrease in the number of adipocytes, which, in turn, reduced cytokine, adipokine and chemokine levels, which are able to recruit inflammatory cells in adipose tissue.
... The striatum was dissected, weighed, and stored at −80°C until further analysis. Striatal dopamine and its metabolites (3,4-dihydroxyphenylacetic acid [DOPAC]) and homovanillic acid ([HVA]), norepinephrine (NE) and its metabolite (vanillylmandelic acid [VMA]), and serotonin (5-hydroxytryptamine [5-HT]) and its metabolite (5-hydroxyindolacetic acid [5-HIAA]) were measured as previously described (Soto et al., 2013;Felicio et al., 1996). The data are expressed as pg/mg of tissue. ...
Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is use in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5 mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased anxiety-like behavior in adulthood.
Copyright © 2015. Published by Elsevier Inc.
Objective
The aim of this study was to investigate the effects of pre-pregnancy chronic exposure to Porphyromonas gingivalis LPS (Pg LPS) on the learning, memory, and seizure susceptibility of the offspring.
Design
To achieve periodontitis, Pg LPS (5 µg/kg) was injected into the gingival of five female rats every 48 hours for three weeks. Five control female rats received saline (0.9%) and five female were kept intact. The concentrations of TNF-α and IL-6 were measured in the blood samples. One week after the final injection, females were mated with intact males. Following birth and weaning, two male and two female offspring were randomly selected from each mother, and new groups of male and female offspring were defined for behavioral assessments. Morris water maze was used to evaluate spatial memory, shuttle box was used to investigate avoidance memory and a pentylenetetrazole-induced seizure was used to evaluate seizure susceptibility in the offspring.
Results
Spatial learning and avoidance memory significantly decreased in both male and female offspring of Pg LPS-exposed female rats, compared to the control offspring. Latency to reach seizure stages 1 and 2 significantly increased in the male offspring, but not the female offspring of Pg LPS-exposed female, compared to the control offspring. However, no significant difference was found in latency to reach stages 3-5.
Conclusion
Pre-pregnancy exposure to Pg LPS could affect some behavioral functions in both male and female offspring intergenerationally.
Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.
Aims: Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by Gram-negative bacteria, induced autistic-like behavior. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS because LPS induces hypozincaemia. Materials andmethods:We evaluated the effects of LPS and zinc on female reproductive performance. Communication, which is impaired in autism,was tested in pups by ultrasonic vocalizations. Plasma levels of brain-derived neurotrophic factor (BDNF) were determined because it has been considered an autism important biomarker. Key findings: Prenatal LPS exposure reduced offspring number and treatmentwith zinc prevented this reduction. Moreover, pups that were prenatally exposed to LPS spent longer periods without calling their mothers, and posttreatment with zinc prevented this impairment induced by LPS to the same levels as controls. Prenatal LPS also increased BDNF levels in adult offspring, and posttreatment with zinc reduced the elevation of BDNF to the same levels as controls. Significance: BDNF hyperactivity was also found in several studies of autistic patients. Togetherwith our previous studies, our model of prenatal LPS induced autistic-like behavioral, brain, and immune disturbances. This suggests that it is a valid rat model of autism. Prenatal zinc prevented reproductive, communication, and BDNF impairments. The present study revealed a potential beneficial effect of prenatal zinc administration for the prevention of autism with regard to the BDNF pathway.
The present study investigated whether late maternal inflammation disrupts the mother/pup interaction, resulting in long-lasting effects on pup behavior and alterations in biological pathways, thereby programming prepubertal behavior and the pups' inflammatory responses after bacterial endotoxin treatment. Female rats received 100 μg/kg lipopolysaccharide (LPS) or .9% saline solution on gestation day 18. Reproductive performance was observed at birth. On lactation days (LD) 5 and LD 6, respectively, maternal behavior and maternal aggressive behavior were assessed. In pups, maternal odor preference on LD 7, open field behavior on LD 21, and serum tumor necrosis factor α (TNF-α) levels after LPS challenge on LD 21 were investigated. The results showed that prenatal LPS exposure improved maternal care and reduced maternal aggressive behavior but did not alter maternal reproductive performance. Male offspring exhibited increased body weights at birth and reduced maternal odor preference. Lipopolysaccharide challenge increased the duration of immobility in the open field and induced a slight increase in serum TNF-α levels. Prenatal exposure to LPS during late pregnancy improved maternal care, reduced maternal olfactory preference, and induced TNF-α hyporesponsiveness to a single dose of LPS in pups.
Despite various suspected causes, ranging from endocrine and genetic to infectious and immunological aspects, the molecular mechanisms of miscarriage still remain enigmatic. This work provides evidence that downregulation of 11β-hydroxysteroid dehydrogenase (HSD) type 2, the key enzyme inactivating glucocorticoid activities, insults the pregnant inflammatory milieu by inhibiting the biosynthesis of lipoxin A4 (LXA4), a metabolite of arachidonic acid, leading to an early loss of the pregnancy. Both LXA4 and its biosynthetic enzymes were found to be decreased in women with spontaneous miscarriages and in the murine miscarriage model. Replenishing LXA4 reversed LPS-induced miscarriages in mouse models, whereas blocking LXA4 signaling resulted in miscarriages in the pregnant mice. The protective effect of LXA4 might be explained by LXA4's role in regulating uterine and placental inflammatory factors and mast cells. The underlying molecular mechanism involved miscarriage-inducing infections or stresses that downregulate the expression of 11β-HSD2, but not 11β-HSD1, resulting in increases in glucocorticoid activity and decreases in LXA4. Together, these findings suggest that the stress/glucocorticoid/LXA4 axis might be a common pathway through which miscarriages occur.
The brain is the central organ of the body's response to and perception of stress. Both the juvenile and the adult brain show a significant capacity for lasting physiological, structural and behavioral plasticity as a consequence of stress exposure. The hypothesis that epigenetic mechanisms might lie behind the lasting effects of stress upon the brain has proven a fruitful one. In this review, we examine the growing literature showing that stress has a direct impact on epigenetic marks at all life history stages thus far examined and how, in turn, epigenetic mechanisms play a role in altering stress responsiveness, anxiety and brain plasticity across the lifespan and beyond to succeeding generations. In addition, we will examine our own recent findings that stress interacts with the epigenome to regulate the expression of transposable elements in a regionally specific fashion, a finding with significant implications for a portion of the genome which is tenfold larger than that occupied by the genes themselves.
Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders.
Objective:
Our objective was to verify whether prenatal maternal periodontitis is a risk factor for the development of central nervous system disorders in rats.
Methods:
Periodontitis was induced by placing a ligature around the upper and lower first molars in 9 female Wistar rats (experimental group); 9 rats were left unligated (control group). The maternal general activity in an open field was observed on gestational day (GD) 0, GD 4, and GD 14, and the maternal performance was assessed on the second day after birth. The pups' play behavior was assessed on postnatal day 30. The relative level of reelin was measured in the frontal cortex by real-time PCR analysis.
Results:
The results showed that, compared with the control group, (1) the general activity in female rats with periodontitis was decreased, (2) the maternal performance of these rats was not modified by periodontitis, (3) the play behavior of pups from dams with periodontitis was decreased, and (4) there were no differences in the frontal cortex reelin levels of pups from dams with periodontitis.
Conclusions:
We conclude that pre- and postnatal periodontitis induces maternal sickness behavior and reduces the pups' play behavior without interference with frontal cortex reelin expression.
Predators are potent agents of natural selection in biological communities. Experimental studies have shown that the introduction of predators can cause rapid evolution of defensive morphologies and behaviours in prey(1-5) and chemical defences in plants(6,7). Such defences may be constitutively expressed (phenotypically fixed) or induced when predators initially attacks(8-10). Here we show that non-lethal exposure of an animal to carnivores, and a plant to a herbivore, not only induces a defence, but causes the attacked organisms to produce offspring that are better defended than offspring from unthreatened parents. This transgenerational effect, referred to as a maternally induced defence, is in contrast to the more common defences induced in single individuals within a generation. Transgenerational induction of defences is a new level of phenotypic plasticity across generations that may be an important component of predator-prey interactions.
The biological and medical importance of epigenetics is now taken for granted, but the significance of one aspect of it—epigenetic inheritance—is less widely recognized. New data suggest that not only is it ubiquitous, but both the generation and the transmission of epigenetic variations may be affected by developmental conditions. Population studies, formal models, and research on genomic and ecological stresses all suggest that epigenetic inheritance is important in both micro- and macroevolutionary change.Clinical Pharmacology & Therapeutics (2012); 92 6, 683-688. doi:10.1038/clpt.2012.158
Olanzapine is one of the most widely prescribed atypical antipsychotic drugs in the treatment of schizophrenia. Besides its well-known side effect on weight gain, it may also impair human parental behavior. In this study, we took a preclinical approach to examine the behavioral effects of olanzapine on rat maternal behavior and investigated the associated neural basis using the c-Fos immunohistochemistry. On postpartum days 6-8, Sprague-Dawley mother rats were given a single injection of sterile water or olanzapine (1.0, 3.0 or 5.0mg/kg, sc). Maternal behavior was tested 2h later, after which rats were sacrificed and brain tissues were collected. Ten brain regions that were either implicated in the action of antipsychotic drugs and/or in the regulation of maternal behavior were examined for c-Fos immunoreactivity. Acute olanzapine treatment dose-dependently disrupted various components of maternal behavior (e.g., pup retrieval, pup licking, nest building, crouching) and increased c-Fos immunoreactivity in the medial prefrontal cortex (mPFC), nucleus accumbens shell and core (NAs and NAc), dorsolateral striatum (DLSt), ventral lateral septum (LSv), central amygdala (CeA) and ventral tegmental area (VTA), important brain areas generally implicated in the incentive motivation and reward processing. In contrast, olanzapine treatment did not alter c-Fos in the medial preoptic nucleus (MPN), ventral bed nucleus of the stria terminalis (vBST) and medial amygdala (MeA), the core brain areas directly involved in the mediation of rat maternal behavior. These findings suggest that olanzapine disrupts rat maternal behavior primarily by suppressing incentive motivation and reward processing via its action on the mesocorticolimbic dopamine systems, other limbic and striatal areas, but not by disrupting the core processes involved in the mediation of maternal behavior in particular.
The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as 'Risk factors for schizophrenia--all roads lead to dopamine' or 'The dopamine hypothesis of schizophrenia--the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.
Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations in Nurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion of Nurr1 with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene-environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific gene-environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.
Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.
Immune challenge during pregnancy is associated with preterm birth and poor perinatal development. The mechanisms of these effects are not known. 5α-Pregnan-3α-ol-20-one (3α,5α-THP), the neuroactive metabolite of progesterone, is critical for neurodevelopment and stress responses, and can influence cognition and affective behaviours. To develop an immune challenge model of preterm birth, pregnant Long-Evans rat dams were administered lipopolysaccharide [LPS; 30 μg/kg/ml, intraperitoneal (IP)], interleukin-1β (IL-1β; 1 μg/rat, IP) or vehicle (0.9% saline, IP) daily on gestational days 17-21. Compared to control treatment, prenatal LPS or IL-1β reduced gestational length and the number of viable pups born. At 28-30 days of age, male and female offspring of mothers exposed to prenatal IL-1β had reduced cognitive performance in the object recognition task compared to controls. In females, but not males, prenatal IL-1β reduced anxiety-like behaviour, indicated by entries to the centre of an open field. In the hippocampus, progesterone turnover to its 5α-reduced metabolites was lower in prenatally exposed IL-1β female, but not in male offspring. IL-1β-exposed males and females had reduced oestradiol content in hippocampus, medial prefrontal cortex and diencephalon compared to controls. Thus, immune stress during late pregnancy reduced gestational length and negatively impacted birth outcomes, hippocampal function and central neurosteroid formation in the offspring.
Phasic activity of the mesolimbic dopamine pathway – burst-firing of dopamine neurons and the resulting dopamine release events at striatal targets – have been associated with a variety of motivational events, such as novelty, salient stimuli, social interaction, and reward prediction. Over the past decade, advances in electrochemical techniques have allowed measurement of naturally occurring dopamine release events, or dopamine transients, in awake animals during ongoing behavior. Thus, a growing body of studies has revealed dynamic dopamine input to ventral striatum during motivated behavior in a variety of experimental paradigms. We propose that dopamine transients may be important neural signals in pup-directed aspects of maternal behavior, as preliminary data suggest that dopamine transients in dams are associated with pup cues. Measurements of dopamine transients may be useful to investigate not only typical maternal behavior but also maternal inattention induced by drug exposure or stress.
The sexually active female rat solicits the male to approach for copulation, while the maternal dam displays aggression to expel him from the nest, suggesting that both behaviors are mutually exclusive. However, the rat has a postpartum estrus during which she is sexual and maternally motivated. Can she perceive the male as attractive and aversive, soliciting and attacking him at the same time? This study shows that postpartum estrous females exhibit a merge of sexual and maternal aggressive responses toward male intruders in the home cage. The concurrent expression of these behaviors did not affect their intensities, although the stimulation of maternal behavior increased maternal aggression without modifying sexual solicitation. These results indicate that the postpartum estrous rat can optimally express two opposite and independently regulated motivations, and that the male can be perceived as an ambivalent stimulus.
This study investigated the relationship between maternal sickness behavior during pregnancy and offspring development and behavior.
Pregnant Wistar rats were administered with lipopolysaccharide (LPS, 100 microg/kg, i.p.) on gestation day (GD) 9.5. Dams' sickness behavior was analyzed, and at birth, offspring number and weight were evaluated. Male offspring was evaluated through physical development, play behavior, adult social interaction, plus maze studies and morphological analysis of the brain.
Results, with respect to the control group, showed that: (1) LPS decreased general activity, food intake, and weight gain in dams, but no pyrexia was observed following treatment; (2) LPS reduced litter size, but no alterations in physical development were observed; (3) LPS reduced play behavior parameters in baby rats; (4) LPS decreased adult social interaction; (5) no alterations were observed between groups on plus maze studies; (6) no differences were observed between groups on morphological analyses of the brain.
These data reveal that LPS administered on GD 9.5 impaired male offspring's social behavior in infancy and adulthood. These results may be related to an alteration in motivational states or/and increased anxiety.
Even though the understanding of the cause of early pregnancy loss due to chromosomal abnormalities has improved, there is a dearth of knowledge of the causes of loss in euploid conceptuses. Maternal infections are a cause of abort in humans, but the mechanisms are not clear, so we have developed a murine model to study the mechanism of septic abortion by inducing embryonic resorption (ER) with lipopolysaccharide (LPS). We demonstrated that augmented production of nitric oxide (NO) and prostaglandins (PG) is involved in ER, and that inhibitors of their synthesis could prevent ER. Also, we observed an increase in the oxidative damage, evidenced by nitration of tyrosine proteins, due to the peroxynitrite anion. Since an association between chronic marijuana smoking and early miscarriage has been shown in women, we studied the participation of anandamide (AEA), the principal endocannabinoid, on the mechanism of action of LPS. We showed that LPS-induced NO synthesis and tissue damage were mediated by AEA, and that this endotoxin inhibited AEA degradation and increased its synthesis. These results suggest that several inflammatory molecules participate in the mechanism of early pregnancy loss and that their modulation could be useful tools to prevent it.
This study investigates the effects of prenatal lipopolysaccharide (LPS) exposure on the maternal behavior of pregnant rats and the physical development and sexual behavior of their male offspring in adulthood.
For two experiments, pregnant rats were injected with LPS (250 microg/kg, i.p.) on gestation day (GD) 21. In the first experiment, the maternal behavior (postnatal day, PND, 6) and the dam's open-field general activity (PND7) were evaluated. In the second experiment, the maternal pre- and postnatal parameters, the pup's development, the offspring's sexual behavior in adulthood, and the pup's organ weights were assessed.
Compared to the control group, the LPS-treated dams presented reduced maternal behavior, decreased general activity, a smaller body weight difference between GD21 and PND1, a greater number of perinatal deaths, and smaller litters. For the male pups, LPS treatment resulted in a decreased body weight on PND2, whereas the anogenital distance and the day of testis descent were not modified. The male sexual behavior was impaired by prenatal LPS. Particularly the number of ejaculating animals was reduced. The testis weight was also lower in the prenatally LPS-treated rats than in the control rats.
We propose that prenatal LPS exposure on GD21 acts as an imprinting factor that interferes with the programming of brain sexual determination in offspring.
INTRODUÇÃO: O brometo de etídio (BE) é reconhecido como um agente gliotóxico que causa desaparecimento focal astrocitário e oligodendroglial. OBJETIVO: Investigou-se a imunorreatividade astrocitária à proteína glial fibrilar ácida (GFAP) e à vimentina (VIM) após injeção do BE. MÉTODO: Ratos Wistar adultos foram tomados como controles histológicos (grupo H) ou injetados na cisterna basal com BE a 0,1% (grupo E) ou salina a 0,9% (grupo C). Fragmentos do tronco encefálico foram colhidos das 24 horas aos 31 dias pós-injeção para estudo imuno-histoquímico da GFAP e VIM pelo método da avidina-biotina. RESULTADOS: No grupo E, foram observadas extensas lesões na ponte e no mesencéfalo, com desaparecimento astrocitário da área central 24 horas pós-BE, bem como infiltração macrofágica e astrogliose periférica a partir do 3º dia. Os astrócitos marginais apresentaram imunorreatividade aumentada à GFAP e reexpressão de VIM, esta confinada às bordas imediatas do sítio lesional. No grupo C, foram visualizadas lesões pontinas discretas, com preservação astrocitária central e marcação menos intensa para GFAP nos bordos em relação ao grupo E. Nenhuma imunorreatividade para VIM foi notada em tais astrócitos. CONCLUSÃO: Os astrócitos das margens das lesões induzidas pelo BE apresentaram imunorreatividade aumentada para GFAP e reexpressão de VIM.
The double-hit hypothesis posits that an early life genetic or environmental insult sets up a neural predisposition to psychopathology, which may emerge in the presence of a subsequent insult, or 'second hit' in later life. The current study assessed the effect of neonatal lipopolysaccharide (LPS) exposure on anxiety-like behaviours in the adult Wistar rat. Rats were administered either LPS (Salmonella enterica, serotype enteritidis, 0.05 mg/kg, i.p.) or saline (equivolume) on days 3 and 5 of life (birth=day 1). In adulthood (85 days), subjects were allocated to either "stress" or "no stress" treatment groups. For the "stress" group, subjects were exposed to a three-day stress protocol consisting of a 30 min period of restraint and isolation. The "no stress" group was left unperturbed but were handled during this period to control for handling effects between adult "stress" and "no stress" conditions. All animals then underwent behavioural testing using standardised tests of anxiety-like behaviour, including either the Hide Box/Open Field, Elevated Plus Maze (EPM) or Acoustic Startle Response (ASR). Time and event measures for restraint and isolation, the Hide Box/Open Field and EPM were recorded using automated tracking software. Startle amplitude and habituation across time was measured in the ASR test. Prior to and following behavioural test sessions, peripheral blood was collected to assess serum corticosterone and ACTH levels. Data analysis indicated that LPS-treated animals exposed to stress in adulthood exhibited increased anxiety-like behaviour across all behavioural tests compared to controls. Sexually dimorphic effects were observed with males exhibiting increased anxiety-related behaviours compared to females (p<.05). Neonatal LPS exposure induced a significant increase in corticosterone compared to controls (p<.05), whereas corticosterone responses to stress in adulthood were associated with a significantly blunted HPA axis response (p<.05). No differences in ACTH were observed. These results lend support to the double-hit hypothesis of anxiety-related behaviour, demonstrating that neonatal immune activation produces an enhanced propensity toward anxiety-related behaviour following stress in adulthood, and that this susceptibility is associated with alterations to HPA axis ontogeny.
Maternal experience before and during pregnancy is known to play a key role in offspring development. However, the influence of social cues about disease in the maternal environment has not been explored. We indirectly exposed pregnant mice to infected neighbours by housing them next to non-contagious conspecifics infected with Babesia microti. We examined the effect of this indirect immunological exposure on both the females and their adult offspring. Exposed females had higher levels of serum corticosterone and increased kidney growth compared with those with uninfected neighbours. These exposed females subsequently produced offspring that as adults showed an accelerated immune response to B. microti and less aggression in social groups. We suggest that ambient information regarding disease is used adaptively to maximize offspring survival and reproductive success in a challenging environment. Our results shed light on the impact of social information and maternal effects on life histories, and have important consequences for our understanding of epidemiology and individual disease susceptibility in humans and other animals. They also lead us to question the suitability of some laboratory housing conditions during experimental procedures, which may impact negatively upon both animal welfare and the validity of animal science.
The term "maternal behavior," when applied to nonhuman mammals, includes the behaviors exhibited in preparation for the arrival of newborn, in the care and protection of the newly arrived young, and in the weaning of those young, and represents a complex predictable pattern that is often regarded as a single, comprehensive, species-specific phenomenon. Although the delivering first-time mammalian mother is immediately and appropriately maternal, a "virgin" with no prior exposure to young does not show immediate and appropriate behavior toward foster young. Nevertheless, the virgin female, and indeed the male, possess the neural circuitry that underlies the pattern referred to as maternal behavior, despite not exhibiting the pattern under normal circumstances. At parturition, or after extensive exposure to young, what emerges appears to be a single stereotyped maternal behavior pattern. However, it is actually a smoothly coordinated constellation of simpler actions with proximate causes that, when sequenced properly, have the appearance of a motivated, purposive, adaptive pattern of caretaking. Over the past 50 years, much research has focused on finding the principal external and internal factors that convert the nonmaternal behavior patterns of the nonpregnant nullipara, the virgin, to the almost immediate and intense maternal behavior characteristic of the puerpera, the mother. This review is an attempt to summarize the many comprehensive, even encyclopedic, reviews of these factors, with an emphasis on brain mechanisms, and to highlight the gaps that remain in understanding the processes involved in the almost immediate onset of maternal caretaking behaviors observed in mammals at delivery. Where possible, the reader is directed to some of those excellent reviews.
Although virgin females and males may be induced to display aspects of maternal behavior in Norway rats, only females of this species provide parental care in nature and the full repertoire requires that maternal behavior be integrated with the physiology of pregnancy, parturition, and lactation. This chapter focuses on the maternal behavior of postpartum rats. It gives an overview of somatosensation and maternal behavior: the major components of maternal care in rats; the neurobiology of the somatosensory system; the relationships between somatosensory reflexes, behavioral sequences, and motivated behavior; research strategies; and the role of physical interaction with pups on maternal behavior in rats. The chapter focuses on analysis of trigeminal and ventral trunk somatosensory contributions to the postpartum display of nurturant activities toward young and defense of the young. It concludes with discussions of neurobiological consequences and implications of the findings on somatosensory regulation of maternal behavior to date, including cortical plasticity, gene activation, and neural circuits.
IL-15 mediates LPS-induced abortion partially through its effects on NK cells.
The maternal immune response during pregnancy is critical for the survival of the fetus yet can be detrimental during infection and inflammation. Previously, IL-15 has been observed to mediate inflammation during LPS-induced sepsis. Therefore, we sought to determine whether IL-15 mediates the inflammatory process during LPS-induced abortion through the use of IL-15−/− and WT mice. Administration of 2.5 μg LPS i.p. on gd 7.5 drastically reduced fetal viability in WT mice, whereas it had a minimal effect on fetal survival in IL-15−/− mice. The uteroplacental sites of LPS-treated WT mice were characterized by vast structural degradation and inflammation compared with treated IL-15−/− and untreated controls. This suggests that IL-15 may mediate the inflammation responsible for LPS-induced resorption. As IL-15−/− mice are deficient in NK cells and resistant to LPS-induced abortion, these effects suggest that IL-15 may mediate abortion through their homeostatic and/or activation effects on NK cells. WT uteroplacental units exposed to LPS had an increase in the overall number and effector number of NK cells compared with their control counterparts. Furthermore, NK cell depletion before administration of LPS in WT mice partially restored fetal viability. Overall, this paper suggests that IL-15 mediates the inflammatory environment during LPS-induced fetal resorption, primarily through its effects on NK cells.
Plastic changes of neural circuits occur after spinal cord injury (SCI) at various level of the central nervous system. In this review we will focus on delineating the pathophysiological mechanisms of the brain plasticity changes following SCI, based on the existing neuroimaging and neurophysiological evidence in experimental models and humans. In animal experiments, reorganization of the sensory topography as well as of the topographical map of primary motor and premotor cortices have been reported in several studies. Brain imaging revealed that cortical representation in response to spared forelimb stimulation early enlarges and invades adjacent sensory-deprived hind limb territory. Electrophysiological studies demonstrated that the deafferentation due to SCI can immediately change the state of large cortical networks within 1hour, and that these changes play a critical role in the functional reorganization after SCI. In humans neuroimaging also showed shifts of functional motor and sensory cortical representations that relate to the severity of SCI. In patients with cervical SCI, cortical forearm motor representations, as assessed by means of transcranial magnetic stimulation, may reorganize towards the intrinsic hand motor representation to maximize output to muscles of the impaired forearm. Excessive or aberrant reorganisation of cerebral cortex may also have pathological consequences, such as phantom sensations or neuropathic pain. Integrated neuroimaging and neurophysiological approaches may also lead to the development of new therapeutic strategies, which have the potential of enhancing sensorimotor recovery in patients with SCI.
The aim of the present study was to evaluate the behavioral patterns associated with autism and the prevalence of these behaviors in males and females, to verify whether our model of lipopolysaccharide (LPS) administration represents an experimental model of autism. For this, we prenatally exposed Wistar rats to LPS (100 μg/kg, intraperitoneally, on gestational day 9.5), which mimics infection by gram-negative bacteria. Furthermore, because the exact mechanisms by which autism develops are still unknown, we investigated the neurological mechanisms that might underlie the behavioral alterations that were observed. Because we previously had demonstrated that prenatal LPS decreases striatal dopamine (DA) and metabolite levels, the striatal dopaminergic system (tyrosine hydroxylase [TH] and DA receptors D1a and D2) and glial cells (astrocytes and microglia) were analyzed by using immunohistochemistry, immunoblotting, and real-time PCR. Our results show that prenatal LPS exposure impaired communication (ultrasonic vocalizations) in male pups and learning and memory (T-maze spontaneous alternation) in male adults, as well as inducing repetitive/restricted behavior, but did not change social interactions in either infancy (play behavior) or adulthood in females. Moreover, although the expression of DA receptors was unchanged, the experimental animals exhibited reduced striatal TH levels, indicating that reduced DA synthesis impaired the striatal dopaminergic system. The expression of glial cell markers was not increased, which suggests that prenatal LPS did not induce permanent neuroinflammation in the striatum. Together with our previous finding of social impairments in males, the present findings demonstrate that prenatal LPS induced autism-like effects and also a hypoactivation of the dopaminergic system.
Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo models have been established in rats and mice in order to study this link on an experimental basis. These models provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, and to explore the critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. Here, we summarize the findings derived from numerous in-vivo models of prenatal infection and/or immune activation in rats and mice, including models of exposure to influenza virus, bacterial endotoxin, viral-like acute phase responses and specific pro-inflammatory cytokines. Furthermore, we discuss the methodological aspects of these models in relation to their practical implementation and their translatability to the human condition. We highlight that these models can successfully examine the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the contribution of gene–environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss that in-vivo models of prenatal immune activation offer a unique opportunity to establish and evaluate early preventive interventions aiming to reduce the risk of long-lasting brain dysfunctions following prenatal exposure to infection.
The effects of parity on the dopaminergic function of rats were studied. Striatal and hypothalamic levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) as well as serum prolactin (PRL) levels of 7-days primigravid and multigravid rats were compared. Brains and trunk blood were collected from 1200–1400 h on day 7 of pregnancy and assayed for monoamines and their metabolites, and prolactin, respectively. Multigravid rats showed a significant increase in striatal and hypothalamic dopamine levels. A tendency to increase in striatal DOPAC levels was also observed in multigravid rats. Levels of other neurotransmitters and metabolites were not statistically different. Haloperidol (1 mg/kg) treatment induced a significant increase in multigravid 5-HT striatal levels. There was no statistical difference among primigravid and multigravid serum PRL levels after either saline or haloperidol treatment. These data suggest that prior parity produces a shift in dopaminergic activity in multigravid rats.
Five experiments were conducted in order to examine the influence of some simple situational and experiential factors on the maternal aggression displayed by Rockland-Swiss (R-S) Albino mice toward adult male R-S intruders. The results of Experiment 1 showed that aggression is highest during the early lactation period (Postpartum Days 4 and 8) and is absent by the end of the lactation period (Postpartum Days 16 and 20). Experiment 2 showed that the aggression displayed by recently parturient (i.e., early lactating) females rapidly declines during a 10 minute test session with most attacks exhibited during the first 3 minutes of the encounter and few thereafter. The results of Experiment 3 showed that the behavior is significantly reduced when aggression testing takes place in a neutral cage as compared to testing in the homecage environment. The findings of Experiment 4 showed that young male and female intruders (25 and 45 days of age) are attacked as vigorously as adult (65 days of age) intruders of both sexes. The results of Experiment 5 showed that postweaning social deprivation (i.e., isolation) does not influence the development of aggression by lactating females. The significance of these findings for our understanding of the psychobiological basis of maternal aggression and other forms of agonistic behavior is discussed.
A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
Maternal behavior in female multiparous rats was investigated after ventral mesencephalic tegmentum (VMT) radiofrequency lesions. The lesioned rats (1) did not build nests before and after parturition, (2) cannibalized pups (100%) during or shortly after parturition, (3) did not spent time nursing their pups (0%). Fecundation and gestation were normal. The VMT region, limited dorsally by the nucleus ruber, ventrally by the interpeduncular nucleus, laterally by the substantia nigra, is an essential part of the Limbic Midbrain Area (LMA). These results which indicated a behavioral disorganization can be explain in terms of LMA-limbic forebrain relationships. The possible role of aminergic systems, as the dopaminergic A10 group, is discussed.
Bioanalytical method validation is the process used to establish that a quantitative analytical method is suitable for biomedical applications. Reassurances as to the quality of the method and its reliability come from adopting a minimum series of validation experiments and obtaining satisfactory results. Consistent evaluation of the key analytical parameters: recovery, response function, sensitivity, precision, accuracy, selectivity and stability, is discussed with a view to improving scientific standards in manuscripts submitted for publication.
The medial preoptic area (MPOA) and dopamine (DA) neural systems interact to regulate maternal behavior in rats. Two DA systems are involved: the mesolimbic DA system and the incerto-hypothalamic DA system. The hormonally primed MPOA regulates the appetitive aspects of maternal behavior by activating mesolimbic DA input to the shell region of the nucleus accumbens (NAs). DA action on MPOA via the incerto-hypothalamic system may interact with steroid and peptide hormone effects so that MPOA output to the mesolimbic DA system is facilitated. Neural oxytocin facilitates the onset of maternal behavior by actions at critical nodes in this circuitry. DA–D1 receptor agonist action on either the MPOA or NAs can substitute for the effects of estradiol in stimulating the onset of maternal behavior, suggesting an overlap in underlying cellular mechanisms between estradiol and DA. Maternal memory involves the neural plasticity effects of mesolimbic DA activity. Finally, early life stressors may affect the development of MPOA–DA interactions and maternal behavior.
The present review focuses on recent studies from our laboratory examining the neural circuitry subserving rat maternal motivation across postpartum. We employed a site-specific neural inactivation method by infusion of bupivacaine to map the maternal motivation circuitry using two complementary behavioural approaches: unconditioned maternal responsiveness and choice of pup- over cocaine-conditioned incentives in a concurrent pup/cocaine choice conditioned place preference task. Our findings revealed that, during the early postpartum period, distinct brain structures, including the medial preoptic area, ventral tegmental area and medial prefrontal cortex infralimbic and anterior cingulate subregions, contribute a pup-specific bias to the motivational circuitry. As the postpartum period progresses and the pups grow older, it is further revealed that maternal responsiveness becomes progressively less dependent on the medial preoptic area and medial prefrontal cortex infralimbic activity, and more distributed in the maternal circuitry, such that additional network components, including the medial prefrontal cortex prelimbic subregion, are recruited with maternal experience, and contribute to the expression of late postpartum maternal behaviour. Collectively, our findings provide strong evidence that the remarkable ability of postpartum females to successfully care for their developing infants is subserved by a distributed neural network that carries out efficient and dynamic processing of complex, constantly changing incoming environmental and pup-related stimuli, ultimately allowing the progression of appropriate expression and waning of maternal responsiveness across the postpartum period.
Emerging evidence indicates that schizophrenia is associated with activated peripheral and central inflammatory responses. Such inflammatory processes seem to be influenced by a number of environmental and genetic predisposition factors, and they may critically depend on and contribute to the progressive nature of schizophrenic disease. There is also appreciable evidence to suggest that activated inflammatory responses can undermine disease-relevant affective, emotional, social, and cognitive functions, so that inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Recent clinical trials of anti-inflammatory pharmacotherapy in this disorder provide promising results by showing superior beneficial treatment effects when standard antipsychotic drugs are co-administered with anti-inflammatory compounds, as compared with treatment outcomes using antipsychotic drugs alone. Given the limited efficacy of currently available antipsychotic drugs to ameliorate negative and cognitive symptoms, the further exploration of inflammatory mechanisms and anti-inflammatory strategies may open fruitful new avenues for improved treatment of symptoms undermining affective, emotional, social and cognitive functions pertinent to schizophrenic disease.
Unlabelled:
Brain plasticity refers to the capacity of the nervous system to change its structure and ultimately its function over a lifetime. There have been major advances in our understanding of the principles of brain plasticity and behavior in laboratory animals and humans. Over the past decade there have been advances in the application of these principles to brain-injured laboratory animals. To date, there have been few major applications of this knowledge to establish postinjury interventions in humans. A significant challenge for the next 20 years will be the translation of this work to improve the outcome from brain injury and disease in humans. The goal of this review is to synthesize the multidisciplinary laboratory work on brain plasticity and behavior in the injured brain to inform the development of rehabilitation programs.
Learning outcomes:
Readers will be able to: (a) identify principles of brain plasticity, (b) review the application of these principles to the treatment of brain-injured laboratory animals, and (c) consider the translation of the new treatments to brain-injured humans.
There has been emerging interest in the prenatal determinants of respiratory disease. In utero factors have been reported to play a role in airway development, inflammation, and remodeling. Specifically, prenatal exposure to endotoxins might regulate tolerance to allergens later in life. The present study investigated whether prenatal lipopolysaccharide (LPS) administration alters subsequent offspring allergen-induced inflammatory response in adult rats.
Pregnant Wistar rats were treated with LPS (100 μg/kg, i.p.) on gestation day 9.5 and their ovariectomized female offspring were sensitized and challenged with OVA later in adulthood. The bronchoalveolar lavage (BAL) fluid, peripheral blood, bone marrow leukocytes and passive cutaneous anaphylaxis were evaluated in these 75-day-old pups.
OVA sensitized pups of NaCl treated rats showed an increase of leucocytes in BAL after OVA challenge. This increase was attenuated, when mothers were exposed to a single LPS injection early in pregnancy. Thus, LPS prenatal treatment resulted in (1) lower increased total and differential (macrophages, neutrophils, eosinophils and lymphocytes) BAL cellularity count; (2) increased number of total, mononuclear and polymorphonuclear cells in the peripheral blood; and (3) no differences in bone marrow cellularity or passive cutaneous anaphylaxis.
In conclusion, female pups treated prenatally with LPS presented an attenuated response to experimentally-induced asthma. We observed reduced immune cell migration from peripheral blood to the lungs, with no effect on the production of bone marrow cells or antibodies. It was suggested that inflammatory events such as exposure to LPS in early fetal life can attenuate allergic inflammation in the lung, which is a common symptom in asthma.
Prenatal lipopolysaccharide (LPS) exposure causes reproductive, behavioral and neurochemical defects in both dams and pups. The present study evaluated male rats prenatally treated with LPS for behavioral and neurological effects related to the olfactory system, which is the main sensorial path in rodents. Pregnant Wistar rats received 100 μg/kg of LPS intraperitoneally (i.p.) on gestational day (GD) 9.5, and maternal behavior was evaluated. Pups were evaluated for (1) maternal odor preference, (2) aversion to cat odor, (3) monoamine levels and turnover in the olfactory bulb (OB) and (4) protein expression (via immunoblotting) within the OB dopaminergic system and glial cells. Results showed that prenatal LPS exposure impaired maternal preference and cat odor aversion and decreased dopamine (DA) levels in the OB. This dopaminergic impairment may have been due to defects in another brain area given that protein expression of the first enzyme in the DA biosynthetic pathway was unchanged in the OB. Moreover, there was no change in the protein expression of the DA receptors. The fact that the number of astrocytes and microglia was not increased suggests that prenatal LPS did not induce neuroinflammation in the OB. Furthermore, given that maternal care was not impaired, abnormalities in the offspring were not the result of reduced maternal care.
Exposure to prenatal inflammation is a known risk factor for long term neurobehavioral disorders including cerebral palsy, schizophrenia, and autism. Models of systemic inflammation during pregnancy have demonstrated an association with an immune response an adverse neurobehavioral outcomes for the exposed fetus. Yet, the most common route for an inflammatory exposure to a fetus is from intrauterine inflammation as occurs with chorioamnionitis. The aims of this study were to assess the effect of intrauterine inflammation on fetal and neonatal brain development and to determine if the gestational age of exposure altered the maternal or fetal response to inflammation.
CD‐1 timed pregnant mice on embryonic day 15 (E15) and E18.5 were utilized for this study. Dams were randomized to receive intrauterine infusion of lipopolysaccharide (LPS, 50 μg/dam) or normal saline. Different experimental groups were used to assess both acute and long‐term outcomes. For each gestational age and each treatment group, fetal brains, amniotic fluid, maternal serum and placentas were collected 6 h after intrauterine infusion. Rates of preterm birth, maternal morbidity and litter size were assessed. IL6 levels were assayed in maternal serum and amniotic fluid.
An immune response was determined in the fetal brains and placentas by QPCR. Cortical cultures were performed to assess for fetal neuronal injury. Gene expression changes in postnatal day 7 brains from exposed and unexposed pups were determined.
In the preterm period, low dose LPS resulted in a 30% preterm birth rate. Litter sizes were not different between the groups at either gestational age. IL6 levels were not significantly increased in maternal serum at either gestational time period. Low dose LPS increased IL6 levels in the amniotic fluid from exposed dams in the term but not preterm period. Regardless of gestational age of exposure, low dose intrauterine LPS activated an immune response in the placenta and fetal brain. Exposure to intrauterine LPS significantly decreased dendritic counts in cortical cultures from both the preterm and term period. Exposure to intrauterine inflammation altered gene expression patterns in the postnatal brain; this effect was dependent on gestational age of exposure.
In conclusion, intrauterine inflammation, even in the absence of preterm parturition, can evoke fetal brain injury as evidence by alterations in cytokine expression and neuronal injury. Despite an absent or limited maternal immune response in low dose intrauterine inflammation, the immune system in the placenta is activated which is likely sufficient to induce a fetal immune response and subsequent brain injury. Changes in the fetal brain lead to changes in gene expression patterns into the neonatal period. Subclinical intrauterine inflammation can lead to fetal brain injury and is likely to be mechanistically associated with long term adverse outcomes for exposed offspring.
In nonhuman primates and humans, similar to other mammals, hormones are not strictly necessary for the expression of maternal behavior, but nevertheless influence variation in maternal responsiveness and parental behavior both within and between individuals. A growing number of correlational and experimental studies have indicated that high circulating estrogen concentrations during pregnancy increase maternal motivation and responsiveness to infant stimuli, while effects of prepartum or postpartum estrogens and progestogens on maternal behavior are less clear. Prolactin is thought to play a role in promoting paternal and alloparental care in primates, but little is known about the relationship between this hormone and maternal behavior. High circulating cortisol levels appear to enhance arousal and responsiveness to infant stimuli in young, relatively inexperienced female primates, but interfere with the expression of maternal behavior in older and more experienced mothers. Among neuropeptides and neurotransmitters, preliminary evidence indicates that oxytocin and endogenous opioids affect maternal attachment to infants, including maintenance of contact, grooming, and responses to separation. Brain serotonin affects anxiety and impulsivity, which in turn may affect maternal behaviors such as infant retrieval or rejection of infants' attempts to make contact with the mother. Although our understanding of the neuroendocrine correlates of primate maternal behavior has grown substantially in the last two decades, very little is known about the mechanisms underlying these effects, e.g., the extent to which these mechanisms may involve changes in perception, emotion, or cognition.
Epidemiological studies with human populations indicate associations between maternal infection during pregnancy and increased risk in offspring for central nervous system (CNS) disorders including schizophrenia, autism and cerebral palsy. Since 2000, a large number of studies have used rodent models of systemic prenatal infection or prenatal immune activation to characterize changes in brain function and behavior caused by the prenatal insult. This review provides a comprehensive summary of these findings, and examines consistencies and trends across studies in an effort to provide a perspective on our current state of understanding from this body of work. Results from these animal modeling studies clearly indicate that prenatal immune activation can cause both acute and lasting changes in behavior and CNS structure and function in offspring. Across laboratories, studies vary with respect to the type, dose and timing of immunogen administration during gestation, species used, postnatal age examined and specific outcome measure quantified. This makes comparison across studies and assessment of replicability difficult. With regard to mechanisms, evidence for roles for several acute mediators of effects of prenatal immune activation has emerged, including circulating interleukin-6, increased placental cytokines and oxidative stress in the fetal brain. However, information required to describe the complete mechanistic pathway responsible for acute effects of prenatal immune activation on fetal brain is lacking, and no studies have yet addressed the issue of how acute prenatal exposure to an immunogen is transduced into a long-term CNS change in the postnatal animal. Directions for further research are discussed.
Prenatal lipopolysaccharide (LPS) exposure causes reproductive, behavioral and neurochemical injuries in both the mother and pups. Previous investigations by our group showed that prenatal LPS administration (100 microg/kg, i.p.) on gestational day 9.5 impaired the male offspring's social behavior in infancy and adulthood. In the present study, we investigated whether these social behavioral changes were associated with motor activity impairment. Male rat pups treated prenatally with LPS or not were tested for reflexological development and open field general activity during infancy. In adulthood, animals were tested for open field general activity, haloperidol-induced catalepsy and apomorphine-induced stereotypy; striatal dopamine levels and turnover were also measured. Moreover, LPS-treated or untreated control pups were challenged with LPS in adulthood and observed for general activity in the open field. In relation to the control group, the motor behavior of prenatally treated male pups was unaffected at basal levels, both in infancy and in adulthood, but decreased general activity was observed in adulthood after an immune challenge. Also, striatal dopamine and metabolite levels were decreased in adulthood. In conclusion, prenatal LPS exposure disrupted the dopaminergic system involved with motor function, but this neurochemical effect was not accompanied by behavioral impairment, probably due to adaptive plasticity processes. Notwithstanding, behavioral impairment was revealed when animals were challenged with LPS, resulting in enhanced sickness behavior.
Periventricular leukomalacia (PVL) is a major form of brain damage in premature infants. This study was to test whether IGF-1 can prevent PVL-like brain damage induced by lipopolysaccharide (LPS) in the neonatal rat. Intraventricular delivery of LPS resulted in an acute brain inflammatory response, i.e., rapid recruitment of polymorphonuclear leukocytes (PMNs), activation of microglia and astrocytes, and induction of IL-1beta (IL1beta) expression. Brain inflammation was associated with the loss of O4+ preoligodendrocytes (preOLs), a decrease of myelin basic protein (MBP) in the white matter and an increase of pyknotic cells in the cortex. IGF-1 at a low dose significantly prevented LPS-induced deleterious effects without alteration of IL-1beta expression and microglia/astrocytes activation. On the other hand, the low dose of IGF-1 enhanced LPS-induced PMNs recruitment and blood-brain barrier (BBB) permeability, and caused intracerebral hemorrhage. At higher doses, co-application of IGF-1 with LPS resulted in a high mortality rate. Brains from the surviving rats showed massive PMN infiltration and intracerebral hemorrhage. However, these adverse effects were not found in rats treated with IGF-1 alone. This study provides the alarming evidence that in an acute inflammatory condition, IGF-1 may have severe, harmful effects on the developing brain.
Cytokines are pleotrophic proteins that coordinate the host response to infection as well as mediate normal, ongoing signaling between cells of nonimmune tissues, including the nervous system. As a consequence of this dual role, cytokines induced in response to maternal infection or prenatal hypoxia can profoundly impact fetal neurodevelopment. The neurodevelopmental roles of individual cytokine signaling pathways are being elucidated through gain- and loss-of-function studies in cell culture and model organisms. We review this work with a particular emphasis on studies where cytokines, their receptors, or components of their signaling pathways have been altered in vivo. The extensive and diverse requirements for properly regulated cytokine signaling during normal nervous system development revealed by these studies sets the foundation for ongoing and future work aimed at understanding how cytokines induced normally and pathologically during critical stages of fetal development alter nervous system function and behavior later in life.
A body of evidence supports the idea that the mesolimbic dopamine (DA) system modulates the natural increase in responsiveness female rats show toward offspring (biological or foster) at birth. In the absence of the full hormonal changes associated with pregnancy and birth, female rats do not show immediate responsiveness toward foster offspring. Activation of the mesolimbic DA system can produce an immediate onset of maternal behavior in these females. For example, female rats that are hysterectomized and ovariectomized on day 15 of pregnancy (15HO) and presented with pups 48 hours later normally show maternal behavior after 2-3 days of pup exposure, but will show maternal behavior on day 0 of testing after microinjection of the DA D(1) receptor agonist, SKF 38393, into the nucleus accumbens (NA) at the time of pup presentation. DA D(1) receptor stimulation is known to activate cAMP intracellular signaling cascades via its stimulation of adenylyl cyclase (AC). However, some DA D(1) receptors are also linked to phospholipase C (PLC) and are capable of activating phosphatidylinositol signaling cascades. SKF 38393 stimulates both types of D(1) receptors. Here we provide evidence that the facilitatory effects of DA D(1) receptor stimulation in the NA on maternal behavior are mediated by AC-linked DA D(1) receptors. By examining the effects of intra-NA application of SKF 83822, a drug which selectively binds DA D(1)-AC receptors, or SKF 83959, a drug which selectively activates D(1)-PLC-linked receptors, we find that only SKF 83822 facilitates maternal behavior onset.
A decrease in specific [3H]spiroperidol binding to rat caudate tissue and a parallel decrease in sensitivity to apomorphine
in eliciting stereotyped behavior was observed in the offspring of rat mothers treated with either haloperidol or alpha-methyl-p-tyrosine-methyl
ester during pregnancy. In contrast, evidence of increased dopamine-receptor sensitivity was observed in the pups if haloperidol
was administered to their mothers postpartum during nursing rather than during pregnancy.
Juvenile rats were allowed short daily periods of social contact to see if this would reduce the known effects of isolation rearing upon habituation of locomotor activity and object contact in the open field. Animals totally deprived of social experience (ISOL) were slower to habituate than animals living in small social groups (SOC). Rats allowed 1 hr of social contact (partial isolates, PI), but living otherwise in isolation, were intermediate between ISOL and SOC animals. In further experiments the quality of social interactions in the daily period was altered by drugging one of the partners, either with amphetamine or with chlorpormazine. In later tests in the open field, the rats that had interacted with amphetamine-injected or chlorpromazine-injected partners differed from PI animals in the direction of resembling complete isolates (ISOL); this was particularly true of those paired with amphetamine animals. Observation revealed that injection of 1 of the partners considerably altered social interactions in the pair. A further test showed that 1 hr of contact a day considerably alleviated the deleterious effects of isolation rearing upon response reversal. We conclude that normal development in the rat may depend upon the flexibility of behavior encouraged by the early social situation.