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Neurocircuitry of Stress: Central Control of the Hypothalamo-Pituitary-Adrenocortical Axis
Abstract
Integration of the hypothalamo–pituitary–adrenal stress response occurs by way of interactions between stress-sensitive brain circuitry and neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN). Stressors involving an immediate physiologic threat (`systemic' stressors) are relayed directly to the PVN, probably via brainstem catecholaminergic projections. By contrast, stressors requiring interpretation by higher brain structures (`processive' stressors) appear to be channeled through limbic forebrain circuits. Forebrain limbic sites connect with the PVN via interactions with GABA-containing neurons in the bed nucleus of the stria terminalis, preoptic area and hypothalamus. Thus, final elaboration of processive stress responses is likely to involve modulation of PVN GABAergic tone. The functional and neuroanatomical data obtained suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways.
... The hippocampus has a high glucocorticoid receptor density (20)(21)(22)(23), making this region a target of investigations into stress-related brain changes. Having a three layered allocortex, the hippocampal formation consists of multiple subfields, or zones, starting at the subiculum (SUB) and moving inward to the hippocampus proper; the cornu ammonis (CA1-3), and dentate gyrus such as stress (23). ...
... In particular, we observed that increases in CA1-3 volume after Affect training corresponded to a decrease in total diurnal cortisol as well as hair cortisol output. These results can be interpreted in line with the mainly inhibitory role of the hippocampus in stress regulation (20)(21)(22)81). Specifically, the hippocampus is involved in the negative feedback inhibition of the HPA axis. ...
The hippocampus is a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3-months mental Training Modules geared towards nurturing a) attention-based mindfulness, b) socio-affective or c) socio-cognitive skills may impact hippocampal organization by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, by combining longitudinal structural and resting-state fMRI connectivity analysis in 332 healthy adults. We related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3-months compassion-based module targeting socio-affective skills ( Affect module), as compared to socio-cognitive skills ( Perspective module) or a waitlist cohort with no training intervention. Structural changes were paralleled by relative increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Furthermore, training-induced changes in CA1-3 structure and function consistently correlated with reductions in cortisol output. Notably, using a multivariate approach, we found that other subfields that did not show group-level changes also contributed to changes in cortisol levels, suggesting that circuit-level changes within the hippocampal formation are linked to diurnal stress markers. Overall, we provide a link between a socio-emotional behavioural intervention, changes in hippocampal subfield structure and function, and reductions in cortisol in healthy adults.
... The hippocampus has a high glucocorticoid receptor density (18)(19)(20)(21) making this region a target of investigations into stress-related brain changes. Being three layered allocortex, the hippocampal formation consists of multiple subfields, or zones, starting at the subiculum (SUB) and moving inward to the hippocampus proper; the cornu ammonis (CA1-3), and dentate gyrus (CA4/DG)(22-25). ...
... In particular, we observed that increases in CA1-3 volume after Affect training corresponded to a decrease in total diurnal cortisol as well as hair cortisol output. These results can be interpreted in line with the mainly inhibitory role of the hippocampus in stress regulation (18)(19)(20)77). Specifically, the hippocampus is involved in the negative feedback inhibition of the HPA axis. ...
The hippocampus forms a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3-months mental training modules geared towards nurturing a) attention-based mindfulness, b) socio-affective skills, or c) socio-cognitive abilities may impact hippocampal integrity by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, based on resting-state fMRI connectivity analysis in a group of healthy adults (N=332). We then related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3-months compassion-based module targeting socio-affective skills (Affect module), as compared to socio-cognitive skills (Perspective module) or a waitlist cohort that did not undergo an intervention. Structural changes were paralleled by increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Moreover, training-related changes in CA1-3 structure and function consistently correlated with reduction in cortisol output. In sum, we provide a link between socio-emotional behavioral intervention, CA1-3 structure and function, and cortisol reductions in healthy adults.
... The hippocampus has a high glucocorticoid receptor density (18)(19)(20)(21) making this region a target of investigations into stress-related brain changes. Being three layered allocortex, the hippocampal formation consists of multiple subfields, or zones, starting at the subiculum (SUB) and moving inward to the hippocampus proper; the cornu ammonis (CA1-3), and dentate gyrus (CA4/DG)(22-25). ...
... In particular, we observed that increases in CA1-3 volume after Affect training corresponded to a decrease in total diurnal cortisol as well as hair cortisol output. These results can be interpreted in line with the mainly inhibitory role of the hippocampus in stress regulation (18)(19)(20)77). Specifically, the hippocampus is involved in the negative feedback inhibition of the HPA axis. ...
The hippocampus forms a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3-months mental training modules geared towards nurturing a) attention-based mindfulness, b) socio-affective skills, or c) socio-cognitive abilities may impact hippocampal integrity by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, based on resting-state fMRI connectivity analysis in a group of healthy adults (N=332). We then related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3-months compassion-based module targeting socio-affective skills (Affect module), as compared to socio-cognitive skills (Perspective module) or a waitlist cohort that did not undergo an intervention. Structural changes were paralleled by increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Moreover, training-related changes in CA1-3 structure and function consistently correlated with reduction in cortisol output. In sum, we provide a link between socio-emotional behavioral intervention, CA1-3 structure and function, and cortisol reductions in healthy adults.
... The central nucleus of the amygdala (CeA) plays a major role in neuroendocrine, autonomic and behavioral responses to stress (Chaouloff, 1993;Gray, 1993;Herman and Cullinan, 1997;Ronan and Summers, 2011;Callahan et al., 2013;Gilpin et al., 2014;van den Burg and Stoop, 2019). Lesions of the CeA diminish hypothalamic-pituitary-adrenal (HPA) activation in response to immobilization stress (Beaulieu et al., 1987), and also produce deficits in the learning about stressors (Maren, 1998). ...
... Behavioral and clinical studies implicate central CRF and 5-HT in the pathophysiology of drug relapse, anxiety disorders, traumaand stressor-related disorders such as posttraumatic stress disorder (PTSD), depression, and other psychiatric disorders exacerbated by stress (Chalmers et al., 1996;Coplan et al., 1996;Deakin, 1998;Holsboer, 1999;Keck and Holsboer, 2001;Le et al., 2002;Waters et al., 2015). A common feature of these disorders is that previous stress experience may promote inappropriate stress responsiveness (Herman and Cullinan, 1997;Chaouloff et al., 1999;Kosten and Ambrosio, 2002). In rat models, the effects of prior stress on HPA axis and behavioral responses to subsequent stressors (Bhatnagar and Dallman, 1998;Chung et al., 2000) appear to be mediated through central CRF and 5-HT systems. ...
Corticotropin-releasing factor (CRF) is essential for coordinating endocrine and neural responses to stress, frequently facilitated by vasopressin (AVP). Previous work has linked CRF hypersecretion, binding site changes, and dysfunctional serotonergic transmission with anxiety and affective disorders, including clinical depression. Crucially, CRF can alter serotonergic activity. In the dorsal raphé nucleus and serotonin (5-HT) terminal regions, CRF effects can be stimulatory or inhibitory, depending on the dose, site, and receptor type activated. Prior stress alters CRF neurotransmission and CRF-mediated behaviors. Lateral, medial, and ventral subdivisions of the central nucleus of the amygdala (CeA) produce CRF and coordinate stress responsiveness. The purpose of these experiments was to determine the effect of intracerebroventricular (icv) administration of CRF and AVP on extracellular 5-HT as an index of 5-HT release in the CeA, using in vivo microdialysis in freely moving rats and high performance liquid chromatography (HPLC) analysis. We also examined the effect of prior stress (1 h restraint, 24 h prior) on CRF- and AVP-mediated release of 5-HT within the CeA. Our results show that icv CRF infusion in unstressed animals had no effect on 5-HT release in the CeA. Conversely, in rats with prior stress, CRF caused a profound dose-dependent decrease in 5-HT release within the CeA. This effect was long-lasting (240 min) and was mimicked by CRF plus AVP infusion without stress. Thus, prior stress and AVP functionally alter CRF-mediated neurotransmission and sensitize CRF-induced inhibition of 5-HT release, suggesting that this is a potential mechanism underlying stress-induced affective reactivity in humans.
... Often the psychological stress is not related to changes in metabolic demand such that the mobilised energy is not used but rather stored in visceral fat depots, leading to physiological disturbances involved in the metabolic syndrome and enhanced cardiometabolic risk factors in humans (Bjorntorp, 2001;Tsatsoulis & Fountoulakis, 2006;Vanitallie, 2002). Furthermore, chronic stress has deleterious effects on the brain, particularly impacting the hippocampal structure, an area that regulates the stress response (Herman & Cullinan, 1997), leading to cognitive and mood disturbances (Sapolsky, 2000). ...
... Favourable behaviour/temperament phenotypes may be more immediately desirable in the horse industry, since they can be observed by and responded to by handlers. However, an animal's exposure to persistent elevated cortisol (chronic stress) that may not be adequately managed may have a long-term negative effect on the health and welfare of the individual (Adell et al., 1988;Herman & Cullinan, 1997;McEwen, 2000;Monki et al., 2016;Sapolsky, 2000). It is not clear therefore, which of these phenotypes will be most relevant to the equine industries, and as such, our research was directed to understanding the molecular underpinnings of each phenotype separately. ...
Behavioural plasticity enables horses entering an exercise training programme to adapt with reduced stress. We characterised SNPs associated with behaviour in yearling Thoroughbred horses using genomics analyses for two phenotypes: (1) handler‐assessed coping with early training events [coping] (n = 96); and (2) variation in salivary cortisol concentration at the first backing event [cortisol] (n = 34). Using RNA‐seq derived gene expression data for amygdala and hippocampus tissues from n = 2 Thoroughbred stallions, we refined the SNPs to those with functional relevance to behaviour by cross‐referencing to the 500 most highly expressed genes in each tissue. The SNPs of high significance (q < 0.01) were in proximity to genes (coping – GABARAP, NDM, OAZ1, RPS15A, SPARCL1, VAMP2; cortisol – CEBPA, COA3, DUSP1, HNRNPH1, RACK1) with biological functions in social behaviour, autism spectrum disorder, suicide, stress‐induced anxiety and depression, Alzheimer's disease, neurodevelopmental disorders, neuroinflammatory disease, fear‐induced behaviours and alcohol and cocaine addiction. The strongest association (q = 0.0002) was with NDN, a gene previously associated with temperament in cattle. This approach highlights functionally relevant genes in the behavioural adaptation of Thoroughbred horses that will contribute to the development of genetic markers to improve racehorse welfare.
... In peripheral tissues, we focused on the pituitary where the mRNA signal of tiCRH, tiCRHR1b, tiCRHR2 and tiCRHBP1 were all detectable. The stimulation of CRH on ACTH secretion and synthesis from the pituitary has been extensively investigated (de Kloet et al., 2005;Herman and Cullinan, 1997;Juruena et al., 2004). On one hand, it elucidated the reason for the expression of receptors, as they could bind CRH and initiate ACTH synthesis in the pituitary gland. ...
... However, our MVPA analysis only revealed hypothalamic rather than amygdala spatial patterns predicted autistic traits. The hypothalamus, is involved in emotion processing [59][60][61][62], can function as a valence detector and modulator [60,63] and is highly connected with the hippocampus and amygdala [64][65][66]. Hypothalamic morpho-functional differences have also been reported in ASD [67]. ...
Autistic individuals generally demonstrate impaired emotion recognition but it is unclear whether effects are emotion-specific or influenced by oxytocin receptor (OXTR) genotype. Here we implemented a dimensional approach using an implicit emotion recognition task together with functional MRI in a large cohort of neurotypical adult participants (N = 255, male = 131, aged 17–29 years) to establish associations between autistic traits and neural and behavioral responses to specific face emotions, together with modulatory effects of OXTR genotype. A searchlight-based multivariate pattern analysis (MVPA) revealed an extensive network of frontal, basal ganglia, cingulate and limbic regions exhibiting significant predictability for autistic traits from patterns of responses to angry relative to neutral expression faces. Functional connectivity analyses revealed a genotype interaction (OXTR SNPs rs2254298, rs2268491) for coupling between the orbitofrontal cortex and mid-cingulate during angry expression processing, with a negative association between coupling and autistic traits in the risk-allele group and a positive one in the non-risk allele group. Overall, results indicate extensive emotion-specific associations primarily between patterns of neural responses to angry faces and autistic traits in regions processing motivation, reward and salience but not in early visual processing. Functional connections between these identified regions were not only associated with autistic traits but also influenced by OXTR genotype. Thus, altered patterns of neural responses to threatening faces may be a potential biomarker for autistic symptoms although modulatory influences of OXTR genotype need to be taken into account.
... Anxiety responses arising from exposure to contextual anxiogenic environments, as the EPM, have been found to involve the mediation of the BNST (Ventura- Silva et al., 2013), under the regulation of other regions, such as the hippocampus and the amygdala, particularly the BLA (Parfitt et al., 2017). The BNST is intrinsically involved in stress and in the HPA-axis modulation of emotional behaviors (Herman and Cullinan, 1997), particularly in anxiety-associated settings (Pêgo et al., 2008). SNX27 +/− mice that display an anxious-like phenotype on the EPM test, were shown to present more complex BNST neurons. ...
Sorting Nexin 27 (SNX27) is a brain-enriched endosome-associated cargo adaptor that shapes excitatory control, being relevant for cognitive and reward processing, and for several neurological conditions. Despite this, SNX27's role in the nervous system remains poorly explored. To further understand SNX27 function, we performed an extensive behavioral characterization comprising motor, cognitive and emotional dimensions of SNX27+/− mice. Furthermore, attending on the recently described association between SNX27 function and cellular stress signaling mechanisms in vitro, we explored SNX27-stress interplay using a Caenorhabditis elegans Δsnx-27 mutant and wild-type (WT) rodents after stress exposure.
SNX27+/− mice, as C. elegans Δsnx-27 mutants, present cognitive impairments, highlighting a conserved role for SNX27 in cognitive modulation across species. Interestingly, SNX27 downmodulation leads to anxiety-like behavior in mice evaluated in the Elevated Plus Maze (EPM). This anxious phenotype is associated with increased dendritic complexity of the bed nucleus of the stria terminalis (BNST) neurons, and increased complexity of the basolateral amygdala (BLA) pyramidal neurons. These findings highlight the still unknown role of SNX27 in anxiety regulation.
Moreover, we uncovered a direct link between SNX27 dysfunction and stress susceptibility in C. elegans and found that stress-exposed rodents display decreased SNX27 levels in stress-susceptible brain regions.
Altogether, we provided new insights on SNX27's relevance in anxiety-related behaviors and neuronal structure in stress-associated brain regions.
... Perturbations of the stress response are commonly observed in patients with mood and anxiety disorders (Nestler et al. 2002;Tafet and Nemeroff 2020). Recent work by our laboratory investigated whether somatomotor-sympathetic circuitry of the PVN, an key integrator of behavioral, endocrine, and autonomic responses to stress (Herman and Cullinan 1997), is altered in rodent models with emotional behavior dysregulation (Shupe et al. 2021). Our PRV-mediated neuroanatomical investigations in male Wistar-Kyoto (WKY) and selectively bred Low Novelty Responder (bLR) rats, two models featuring inborn differences in emotionality and stress reactivity (Stead et al. 2006;Stedenfeld et al. 2011;Nam et al. 2014;Burke et al. 2016;Prater et al. 2017), revealed that both strains display fewer descending somatomotor projections from the PVN, potentially contributing to the locomotor disturbances associated with their altered emotional states (Shupe et al. 2021). ...
Emotionally motivated behaviors rely on the coordinated activity of descending neural circuits involved in motor and autonomic functions. Using a pseudorabies (PRV) tract-tracing approach in typically behaving rats, our group previously identified descending premotor, presympathetic, and dual-labeled premotor-presympathetic populations throughout the central rostral-caudal axis. The premotor-presympathetic populations are thought to integrate somatomotor and sympathetic activity. To determine whether these circuits are dysregulated in subjects with altered emotional regulation, subsequent neuroanatomical analyses were performed in male subjects of two distinct genetic models relevant to clinical depression and anxiety: the Wistar Kyoto (WKY) rat and selectively bred Low Novelty Responder (bLR) rat. The present study explored alterations in premotor efferents from locus coeruleus (LC) and subdivisions of the periaqueductal grey (PAG), two areas involved in emotionally motivated behaviors. Compared to Sprague Dawley rats, WKY rats had significantly fewer premotor projections to hindlimb skeletal muscle from the LC and from the dorsomedial (DMPAG), lateral (LPAG), and ventrolateral (VLPAG) subdivisions of PAG. Relative to selectively bred High Novelty Responder (bHR) rats, bLR rats had significantly fewer premotor efferents from LC and dorsolateral PAG (DLPAG). Cumulatively, these results demonstrate that somatomotor circuitry in several brain areas involved in responses to stress and emotional stimuli are altered in rat models with depression-relevant phenotypes. These somatomotor circuit differences could be implicated in motor-related impairments in clinically depressed patients.
... The combined output of the sympathoadrenal and HPA systems culminates in a comprehensive and integrated stress response involving rapid physiological changes and sustained adjustments over time . Even though the specific nature of the interactions between the sympathoadrenal system and the HPA axis can vary in different stress-related circumstances (Herman and Cullinan, 1997;McEwen, 2007), cortisol modulates the release of epinephrine and norepinephrine (Wurtman, 2002) whereas catecholamines can stimulate the HPA axis (Lee et al., 2011;Lundberg, 2007) to release more cortisol (Goldstein and Kopin, 2008;Tsigos et al., 2000). Acute stress (seconds-minutes) primarily engages the sympathoadrenal system, while prolonged-(minutes-hours) or chronic stress is characterized in more complex interactions (Carrasco and Van de Kar, 2003;Godoy et al., 2018;Ulrich-Lai and Herman, 2009). ...
... The amygdala is an ideal potential biomarker for psychological threat to frequent stressors that plays crucial roles in danger stress reactivity, perception, and recall of negative information. [35,36,37]. It has implications for various anger, sleep, and depression-related diseases and is composed of about 13 subnuclei. ...
Stress is the body's response to any changes that might place it under mental, emotional, or physical strain and could either demand attention or prompt action. A stress reaction can be brought on by both internal and external factors. The conditions, demands, issues, and expectations you deal with every day are all regarded as external influences, as are your physical surroundings, your job, your contacts with others, your family, and all other related factors. The ability of your body to respond to and handle external stimuli depends on internal factors. Your ability to handle stress is influenced internally by your food habits, level of general health and fitness, mental health, and the amount of sleep and rest you get. Such demanding conditions could affect how certain stress hormone levels are regulated. Biomarkers such as mGlu2/3, 5-hydroxyindoleacetic acid (5-HIAA), serum alpha-amylase, amygdala reactivity, neuropeptide Y (NPY), heat shock proteins, cortisol, and catecholamines are used to assess the hormone imbalance. Disease prevention, early detection, and therapy are all possible uses for biomarkers. In this review, we looked at a wide range of stress-related biomarkers that might cause different psychiatric illnesses and how those conditions can, over time, alter a person's lifestyle.
... The sample size was based on previous studies using optogenetic stimulation to control PVN CRH neurons [19]. A total of 40 CRH-Cre and CRH-Cre::tdtomato mice were used in all experiments (8)(9)(10)(11)(12)(13) weeks old at the beginning of experimentation; 24 females and 16 males; 19 females and 9 males were used for Experiment 1; 5 females and 7 males were used for Experiment 2). An unequal number of male and female mice were used due to stock availability within the colony. ...
Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVNCRH synaptic projections to the LH.
... In response to an external stressor, interactions among cortico-limbic regions of the brain culminate in the release of cortisol, a glucocorticoid hormone, from the adrenal glands. The release of cortisol, via a cascade of biochemical interactions, activates the paraventricular nucleus, hippocampus, and medial prefrontal cortex, which in turn down-regulate activity in the HPA axis [51]. Together, these regions facilitate the integration of the physical and cognitive resources required to manage the environmental threat. ...
Social dysfunction plays a critical role in the development and maintenance of depression in both adolescents and adults. Interpersonal psychotherapy (IPT) and interpersonal psychotherapy for depressed adolescents (IPT-A) are effective, evidence-based, and time-limited treatments for depression that aim to mitigate depressive symptoms by strengthening an individual’s interpersonal relationships and skills. Though the efficacy of IPT/IPT-A has been well established, we are just beginning to know how biological systems are implicated in its success. In this scoping review, we examine the extant literature on biological mechanisms and predictors of IPT/IPT-A treatment efficacy. Overall, seven studies were identified that consider biological processes in the context of evaluating IPT/IPTA, and the studies that were conducted are typically preliminary in nature. Notably, there is some evidence showing that the hypothalamic–pituitary–adrenal axis, various frontal and limbic brain regions, and behavioral indexes that represent brain functioning are associated with changes in IPT/IPT-A or predictive of IPT/IPT-A outcomes. We also consider consequences for treatment and future research. The hope is that a better understanding of how and for whom IPT/IPT-A works can optimize the success of the treatment in reducing an individual’s depressive symptoms.
... Microdialysis performed on rats has shown that acute stress caused by incapacitation of an animal increases the extracellular concentration of Glu in the nuclei complexes of the basolateral (BLA) and central parts of the amygdala (37,38,43). Glu, in turn, stimulates the HPA axis (9,14). Glu release from the amygdala also occurs in other types of stress, and it is modulated by the fear response. ...
Glutamic acid (Glu), as the most stimulating neurotransmitter, occurs in almost all structures of the central
nervous system (CNS). Especially high concentrations are found in the structures of the motivational system
(hypothalamus, hippocampus, amygdala, prefrontal cortex – mPFC) and the motor system (striatum, caudate
nucleus, pallidum). Glu is also found in the autonomic nervous system (ANS), as well as in peripheral tissues
and organs (in the adrenal glands, especially important in stress; the hypothalamic-pituitary-adrenal axis
– HPA axis). Catecholamines (CA), including dopamine (DA), norepinephrine (NE), and/or epinephrine (E),
are major neurotransmitters that mediate various CNS functions, such as motor control, cognition, emotion,
memory processing, pain, stress, and endocrine modulation. The aim of the study was to investigate the in vitro
effect of different concentrations of Glu (5, 50, and 200 µM in a volume of 1 ml of Krebs medium) on CA release
from rabbit amygdala sections collected after decapitation of 12-week-old female rabbits. The same piece of
tissue was transferred every 30 minutes to successive incubation wells containing Glu in an appropriate dose.
The medium collected from the wells after 30, 60, and 90 minutes of incubation was frozen until DA, NE, and
E analyses were performed by the RIA method. The results showed that Glu differently affected CA release
from the amygdala. Generally, an inhibitory effect of Glu on CA release from the amygdala was observed.
It was surprising to find that the concentrations of E in the amygdala were higher than those of NE and DA.
... Second, we found that higher SER scores were associated with greater functional integration (higher participation coefficient) of the subcortical network implicated in motor planning, threat and safety learning, and emotion processing (68)(69)(70)(71). These findings converge with extensive evidence linking SER to structural, functional, and connectivity profiles of subcortical regions, such as the amygdala and hippocampus (72)(73)(74). ...
Socioeconomic resources (SER) calibrate the developing brain to the current context, which can confer or attenuate risk for psychopathology across the lifespan. Recent multivariate work indicates that SER levels powerfully influence intrinsic functional connectivity patterns across the entire brain. Nevertheless, the neurobiological meaning of these widespread alterations remains poorly understood, despite its translational promise for early risk identification, targeted intervention, and policy reform. In the present study, we leverage the resources of graph theory to precisely characterize multivariate and univariate associations between household SER and the functional integration and segregation (i.e., participation coefficient, within-module degree) of brain regions across major cognitive, affective, and sensorimotor systems during the resting state in 5,821 youth (ages 9-10 years) from the Adolescent Brain Cognitive Development (ABCD) Study. First, we establish that decomposing the brain into profiles of integration and segregation captures more than half of the multivariate association between SER and functional connectivity with greater parsimony (100-fold reduction in number of features) and interpretability. Second, we show that the topological effects of SER are not uniform across the brain; rather, higher SER levels are related to greater integration of somatomotor and subcortical systems, but greater segregation of default mode, orbitofrontal, and cerebellar systems. Finally, we demonstrate that the effects of SER are spatially patterned along the unimodal-transmodal gradient of brain organization. These findings provide critical interpretive context for the established and widespread effects of SER on brain organization, indicating that SER levels differentially configure the intrinsic functional architecture of developing unimodal and transmodal systems. This study highlights both sensorimotor and higher-order networks that may serve as neural markers of environmental stress and opportunity, and which may guide efforts to scaffold healthy neurobehavioral development among disadvantaged communities of youth.
... Temporomandibular disorders (TMDs) comprise a variety of conditions that affect the anatomy and functional characteristics of the temporomandibular joint (TMJ) [1]. The etiology of TMDs can be associated with acute or chronic inflammation to stress include activation of the autonomic nervous system (ANS), which results in the release of noradrenaline, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the secretion of catecholamines (adrenaline and noradrenaline) and the release of glucocorticoids by the adr7enal cortex [6,7]. ...
Stress substantially increases the risk of developing painful temporomandibular disorders (TMDs) by influencing the release of endogenous catecholamines. Propranolol, an antagonist of β‐adrenergic receptors, has shown potential in alleviating TMD‐associated pain, particularly when the level of catecholamines is elevated. The aim of this study was to explore whether intra‐articular propranolol administration is effective in diminishing temporomandibular joint (TMJ) pain during repeated stress situations. Additionally, we investigated the effect of repeated stress on the expression of genes encoding β‐adrenoceptors in the trigeminal ganglion. In the present study, rats were exposed to a stress protocol induced by sound, then to the administration of formalin in the TMJ (to elicit a nociceptive response), followed immediately afterward by different doses of propranolol, after which the analgesic response to propranolol was evaluated. We also assessed the levels of beta‐1 and beta‐2 adrenergic receptor mRNAs ( Adrb1 and Adrb2 , respectively) using reverse transcription–quantitative PCR (RT‐qPCR). Our findings revealed that propranolol administration reduces formalin‐induced TMJ nociception more effectively in stressed rats than in non‐stressed rats. Furthermore, repeated stress decreases the expression of the Adrb2 gene within the trigeminal ganglion. The findings of this study are noteworthy as they suggest that individuals with a chronic stress history might find potential benefits from β‐blockers in TMD treatment.
... The AMG is responsible for processing and encoding intense emotional information, positive and negative, especially that which is important for survival. The AMG is active when people experience threatening situations, and thus, it also activates processes involved in stress management (Herman & Cullinan, 1997). Therefore, the AMG is involved in emotional learning (Tottenham & Sheridan, 2010). ...
... among different brain areas, the hippocampus, especially the ca3 region and dentate gyrus (DG), are most sensitive areas that will undergo neurophysiological, structural, and molecular changes against harmful factors and stress situations [5]. One of the important effects of endurance activity in the hippocampus is the neurotrophic effects leading to neurogenesis and angiogenesis [15]. the ca3 region of the hippocampus is the major projection area from the DG. ...
Purpose:
Central fatigue plays an important role in reducing endurance exercise activity during brain development. c-Fos gene expression in the hippocampus was examined as an indicator of neuronal activation after exhaustion.
Methods:
Eighteen pre-pubertal male rats at four weeks old and 18 adult rats at eight weeks were randomly divided into three groups: Control (C), Constant time exercise (CTEx), Endurance Exercise until Exhaustion (ExhEx), which started at two minutes and ended in 20 min, the main swimming test was performed with a weight equal to 5% of the bodyweight attached to the rats' tail as a single session in experimental groups and was recorded at the end of their time, while to evaluate the force loss, the Grip strength was measured before and after the activity. The brain activation rate was examined by c-Fos gene expression and Nissl staining in CA3 and dentate gyrus (DG) in the hippocampus of all groups.
Results:
Power grip and Nissl positive neurons in CA3 and DG have been significantly higher in pre-pubertal rats than in adults, both in the CTEx group (p = 0.04) and in the ExhEx group (p < 0.001). Also, real-time exhaustion in the pre-pubertal group was significantly longer than in adults. c-Fos gene expression was significantly reduced in adults' hippocampus in comparison to preadolescence (p < 0.01) and control (p < 0.001).
Conclusion:
These findings clarified that increased strength and longer fatigue in pre-puberal rats may lead to c-Fos gene expression and decreased neurons in the hippocampus. Perhaps this is a protective effect to suppress stress hormones.
... PVN subnuclei differentially innervate brainstem and spinal preganglionic neurons, controlling both parasympathetic and sympathetic divisions of the autonomic nervous system, respectively (Luiten et al. 1985). The PVN is also the gateway to the hypothalamic-pituitary-adrenal (HPA) axis, containing the corticotropin-releasing hormone (CRH) neurons that ultimately elicit glucocorticoid secretion (Herman and Cullinan 1997), and is a node of glucocorticoid negative feedback regulation (Herman and Tasker 2016;Reul and Kloet 1985). Thus, the PVN is critical for the function and regulation of physiological outcomes associated with stress responses. ...
The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate–high inter-rater reliability [n = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate–high reliability between the probabilistic atlases and manual segmentations [n = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology.
... The HPA axis involves multiple systems, including the autonomic, neuroendocrine, metabolic, and immune systems, which work in tandem to help manage stress and maintain homeostasis. One of the key functions of the HPA axis is the release of glucocorticoids (i.e., cortisol) in response to potential threats or danger [88]. The ability to mount a stress response and return to baseline is essential for survival: the mature HPA axis ideally responds to stress with a peak in cortisol and a swift return to baseline [89]. ...
This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic–pituitary–adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children’s neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions.
... The activation of peripheral physiological processes to correct homeostasis can even occur independently of any affective processes when the organism encounters conditions requiring an immediate response (e.g. hypoxia or hypoglycaemia as opposed to restraint; Herman & Cullinan, 1997). However, similar issues may also apply for upstream physiological markers (e.g. ...
Affective states, such as emotions, are presumably widespread across the animal kingdom because of the adaptive advantages they are supposed to confer. However, the study of the affective states of animals has thus far been largely restricted to enhancing the welfare of animals managed by humans in non-natural contexts. Given the diversity of wild animals and the variable conditions they can experience, extending studies on animal affective states to the natural conditions that most animals experience will allow us to broaden and deepen our general understanding of animal welfare. Yet, this same diversity makes examining animal welfare in the wild highly challenging. There is therefore a need for unifying theoretical frameworks and methodological approaches that can guide researchers keen to engage in this promising research area. The aim of this article is to help advance this important research area by highlighting the central relationship between physiology and animal welfare and rectify its apparent oversight, as revealed by the current scientific literature on wild animals. Moreover, this article emphasises the advantages of including physiological markers to assess animal welfare in the wild (e.g. objectivity, comparability, condition range, temporality), as well as their concomitant limitations (e.g. only access to peripheral physiological markers with complex relationships with affective states). Best-practice recommendations (e.g. replication and multifactorial approaches) are also provided to allow physiological markers to be used most effectively and appropriately when assessing the welfare of animals in their natural habitat. This review seeks to provide the foundation for a new and distinct research area with a vast theoretical and applied potential: wild animal welfare physiology.
... Zatiaľ čo pri systemických stresoroch možno pozorovať priame projekcie z mozgového kmeňa k oblasti PVN v hypotalame (spúšťajúcej kaskádu HPA osi), pri spracovaných stresoroch zohráva rolu zapojenie limbických štruktúr (napr. amygdala, hippokampus) a prefrontálnych oblastí, ktoré vysielajú k PVN neurónom excitačné aj inhibičné projekcie (Herman & Cullinan, 1997;Herman et al., 2016). Tieto práce demonštrujú, že minimálne tieto dva typy stresorov spracované špecificky odlišným spôsobom a vedú k odlišnej reakcii. ...
... Most of the studies linking stress-induced changes in brain structure are focused on the hippocampus due to its particular sensitivity to chronic stress and glucocorticoids, its critical role in learning and memory, and also its participation in the negative feedback regulation of the HPA axis [54][55][56][57]. Other regions such as the mPFC and the amygdala have received attention due to their relevance in the stress response and their role in processing, acquisition, and extinction of fear memories [58]. ...
Exposure to acute and chronic stress has a broad range of structural effects on the brain. The brain areas commonly targeted in the stress response models include the hippocampus, the amygdala, and the prefrontal cortex. Studies in patients suffering from the so-called stress-related disorders -embracing post-traumatic stress, major depressive and anxiety disorders- have fairly replicated animal models of stress response -particularly the neuroendocrine and the inflammatory models- by finding alterations in different brain areas, even in the early neurodevelopment. Therefore, this narrative review aims to provide an overview of structural neuroimaging findings and to discuss how these studies have contributed to our knowledge of variability in response to stress and the ulterior development of stress-related disorders. There are a gross number of studies available but neuroimaging research of stress-related disorders as a single category is still in its infancy. Although the available studies point at particular brain circuitries involved in stress and emotion regulation, the pathophysiology of these abnormalities -involving genetics, epigenetics and molecular pathways-, their relation to intraindividual stress responses -including personality characteristics, self-perception of stress conditions…-, and their potential involvement as biomarkers in diagnosis, treatment prescription and prognosis are discussed.
... E-mail address: michael.winterdahl@clin.au.dk (M. Winterdahl). 1 ORCID: 0000-0002-8790-7574 users [21,27,31]. The HPA axis regulates stress responses by promoting the synthesis and release of glucocorticoids, via the central release of corticotropin-releasing factor, and adrenocorticotropic hormone (ACTH), using negative feedback loops to control this process [56]. ...
Introduction:
Oral contraceptives (OCs) are primarily known for their effects on the reproductive system, but they can also impact the hypothalamic-pituitary-adrenal (HPA) axis. The present study aimed to compare plasma adrenocorticotropic hormone (ACTH) responses to the anticipatory stress of participating in a scientific experiment and venepuncture in OC users versus naturally cycling (NC) women, with a focus on variations throughout the menstrual cycle.
Methods:
We recruited 131 young women (average age 20.5) and obtained blood samples to measure plasma ACTH concentrations immediately after venepuncture and again after 15minutes of group activities designed to facilitate interpersonal attachment and stress-buffering.
Results:
ACTH levels decreased in 70% of all participants throughout the group activities. A two-way repeated measures ANOVA highlighted a significant interaction between time and OC use, indicating differential changes in ACTH levels during social interaction between OC users and NC women. Further, the post-hoc analysis revealed that a period of stress-buffering group activities significantly decreased ACTH levels in NC women during menstrual and secretory phases, but not during the proliferative phase. In contrast, OC users did not display a decrease during group activities, regardless of the phase.
Conclusion:
This study underscores the influence of OC use on stress regulation, demonstrating that OCs not only modulate reproductive functions but also impact ACTH stress reactivity. Additionally, it emphasizes the importance of considering hormonal contraceptive use and menstrual cycle phases when assessing female stress responses.
... Sonuç olarak insan vücudu stresli olaylara abartılı yanıtlar verebilir içerisinde yer aldığı bir takım özel beyin bölgeleri aracılığıyla düzenlenir. Yapılan çalışmalar sonucunda HPA eksenin negatif ve pozitif geri bildirim mekanizmasında hipokampüsun öncelikli rolü olduğu ifade edilmiştir(Herman ve Cullinan, 1997). ...
The main purpose of this study is to examine the relationship between psychophysiological stress, anxiety, and success during cross-country competitions in elite female athletes. Twelve female athletes competing in the senior category of the Turkcell Turkish Cross-Country Super League voluntarily participated in the study. The psychophysiological state of the athletes was determined by analyzing salivary cortisol (sCor) and alpha-amylase (sAA) during the two consecutive rounds (round I and final round) with different difficulty and importance. The anxiety instrument included the State and Trait Anxiety Inventory (STAI-I). Cortisol and alpha-amylase awakening responses (CAR, AAAR, respectively) were assessed on pre-competition and competition day. The official race scores were used to provide the competition performance of the athletes. Pearson correlation and paired-sample t-test analyzes were used to assess study hypotheses. Pre-competition day AAAR correlated with competition performance in round I (p<0.05), while no correlations were detected between stress and anxiety variables and competition performance in the final round (p>0.05). Competition day AAAR correlated with competition performance in the final round. Post-race sCor and sAA responses were greater than pre-race in round I (p<0.05) but, no significant change was found in the final round (p>0.05). Pre-competition day AAAR, competition day CAR, and pre-race sCor in the final round were greater compared to round I. The results indicated that lower AAAR appears to be a biomarker for competition performance in female cross-country athletes. The cross-country race has also been found to be a psychophysiological stressor. Further research using saliva analysis as a non-invasive tool is still needed for larger samples for more comprehensive data.
... Neurons in the NTS relay information to the hypothalamic paraventricular nucleus and sympathoexcitatory neurons in the RVLM (Herman & Cullinan, 1997;Sawchenko et al., 1996). A recent study reported that IH increases RVLM neuronal activity linked to presympathetic neurons (Karlen-Amarante et al., 2023). ...
Carotid bodies are the principal sensory organs for detecting changes in arterial blood oxygen concentration, and the carotid body chemoreflex is a major regulator of the sympathetic tone, blood pressure and breathing. Intermittent hypoxia is a hallmark manifestation of obstructive sleep apnoea (OSA), which is a widespread respiratory disorder. In the first part of this review, we discuss the role of carotid bodies in heightened sympathetic tone and hypertension in rodents treated with intermittent hypoxia, and the underlying cellular, molecular and epigenetic mechanisms. We also present evidence for hitherto‐uncharacterized role of carotid body afferents in triggering cellular and molecular changes induced by intermittent hypoxia. In the second part of the review, we present evidence for a contribution of a hypersensitive carotid body to OSA and potential therapeutic intervention to mitigate OSA in a murine model. image
... Acute stress responses are normally evolved processes that are protective whereas chronic over-activity of the stress system increases the risk of disease [6]. Chronic stimulation of the acute stress response (i.e., chronic stress) has deleterious effects on the brain, particularly impacting the hippocampus, an area that regulates the stress response [7], leading to cognitive and mood disturbances [8]. Behavioural plasticity enables a horse to experience new situations with reduced stimulation of the acute stress response. ...
Thoroughbred horses are bred for competitive racing and undergo intense training regimes. The maintenance of physical soundness and desirable behavioural characteristics are critical to the longevity of a racing career. Horses intended for Flat racing generally enter training as yearlings and undergo introductory training prior to exercise conditioning for racing. This period requires rapid adjustment to a novel environment. As a prey animal, a horse’s ‘fight-or-flight’ response is highly adapted, in which a well-understood component of this response, the hypothalamic-pituitary-axis, is activated in response to a stress stimulus, releasing cortisol. In the Thoroughbred, a significant difference in salivary cortisol concentrations between pre- and post-first time ridden (i.e., first backing) by a jockey have previously been identified. Here, to test the hypothesis that salivary cortisol concentrations may be used to objectively detect individual variations in the acute physiological stress response we investigate individual variation in cortisol response to training milestones. Saliva samples were collected from a cohort of n = 96 yearling Flat racehorses, at the same training yard, across three timepoints at rest: before entering the training yard (n = 66), within three days of entry to the training yard (n = 67) and following 2–3 weeks in the training yard (n = 50). Salivary cortisol concentration was measured using an ELISA. There was no significant difference in cortisol concentration (ANOVA, P > 0.05) across the samples collected at timepoints at rest. Samples were also collected before and 30 minutes after exposure to three novel training events: first time long-reined (n = 6), first time backed by a jockey (n = 34), and first time ridden on the gallops (n = 10). Mean salivary cortisol concentration after all three novel training events was significantly higher than prior to the training event (Paired t-test, P
... The link between stress and corticolimbic functioning is bidirectional, such that crucial corticolimbic brain regions (e.g. prefrontal cortex, hippocampus, and amygdala) not only are impaired by chronic stress but also play a crucial role in neuroendocrine and autonomic regulation and thus the acute stress response (Herman & Cullinan, 1997;Lupien et al., 2009). ...
Childhood adversity might impair corticolimbic brain regions, which play a crucial role in emotion processing and the acute stress response. The dimensional model of childhood adversity proposed that deprivation and threat dimensions might associated with individuals’ development through different mechanisms. However, few studies have explored the relationship between different dimensions of childhood stress, emotion processing, and acute stress reactivity despite the overlapping brain regions of the last two. With the aid of the event-related potentials technique, we explore whether negative emotion processing, which might be particularly relevant for adaptive stress responding among individuals with adverse childhood experience, mediates the relationship between dimensional childhood stress and acute stress response. Fifty-one young adults completed a free-viewing task to evaluate neural response to negative stimuli measured by late positive potential (LPP) of ERPs (Event-related potentials). On a separate day, heart rate and salivary cortisol were collected during a social-evaluative stress challenge (i.e. TSST, Trier Social Stress Test). After the TSST, the childhood trauma questionnaire was measured to indicate the level of abuse (as a proxy of threat) and neglect (as a proxy of deprivation) dimensions. Multiple linear regression and mediation analysis were used to explore the relationship among childhood stress, emotion processing, and acute stress response. Higher level of childhood abuse (but not neglect) was distinctly related to smaller LPP amplitudes to negative stimuli, as well as smaller heart rate reactivity to acute stress. For these participants, smaller LPP amplitudes were linked with smaller heart rate reactivity to acute stress. Furthermore, decreased LPP amplitudes to negative stimuli mediated the relationship between higher level of childhood abuse and blunted heart rate reactivity to stress. Consistent with the dimensional model of childhood stress, our study showed that childhood abuse is distinctly associated with neural as well as physiological response to threat. Furthermore, the blunted neural response to negative stimuli might be the underlying mechanism in which childhood abuse leads to the blunted acute stress response. Considering that all the participants are healthy in the present study, the blunted processing of negative stimuli might rather reflect adaptation instead of vulnerability, in order to prevent stress overshooting in the face of early-life threatening experiences.
Both obesity and high fat diets (HFD) have been associated with an increase in inflammatory gene expression within the brain. Microglia play an important role in early cortical development and may be responsive to HFD, particularly during sensitive windows, such as adolescence. We hypothesized that HFD during adolescence would increase proinflammatory gene expression in microglia at baseline and potentiate the microglial stress response. Two stressors were examined, a physiological stressor [lipopolysaccharide (LPS), IP] and a psychological stressor [15 min restraint (RST)]. From 3 to 7 weeks of age, male and female mice were fed standard control diet (SC, 20% energy from fat) or HFD (60% energy from fat). On P49, 1 h before sacrifice, mice were randomly assigned to either stressor exposure or control conditions. Microglia from the frontal cortex were enriched using a Percoll density gradient and isolated via fluorescence-activated cell sorting (FACS), followed by RNA expression analysis of 30 genes (27 target genes, three housekeeping genes) using Fluidigm, a medium throughput qPCR platform. We found that adolescent HFD induced sex-specific transcriptional response in cortical microglia, both at baseline and in response to a stressor. Contrary to our hypothesis, adolescent HFD did not potentiate the transcriptional response to stressors in males, but rather in some cases, resulted in a blunted or absent response to the stressor. This was most apparent in males treated with LPS. However, in females, potentiation of the LPS response was observed for select proinflammatory genes, including Tnfa and Socs3. Further, HFD increased the expression of Itgam, Ikbkb, and Apoe in cortical microglia of both sexes, while adrenergic receptor expression (Adrb1 and Adra2a) was changed in response to stressor exposure with no effect of diet. These data identify classes of genes that are uniquely affected by adolescent exposure to HFD and different stressor modalities in males and females.
Depression is a neurological disorder that profoundly affects human physical and mental health, resulting in various changes in the central nervous system. Despite several prominent hypotheses, such as the monoaminergic theory, hypothalamic-pituitary-adrenal (HPA) axis theory, neuroinflammation, and neuroplasticity, the current understanding of depression's pathogenesis remains incomplete. Importantly, depression is a gender-dimorphic disorder, with women exhibiting higher incidence rates than men. Given estrogen's pivotal role in the menstrual cycle, it is reasonable to postulate that its fluctuating levels could contribute to the pathogenesis of depression. Estrogen acts by binding to a diversity of receptors, which are widely distributed in the central nervous system. An abundance of research has established that estrogen and its receptors play a crucial role in depression, spanning pathogenesis and treatment. In this comprehensive review, we provide an in-depth analysis of the fundamental role of estrogen and its receptors in depression, with a focus on neuroinflammation, neuroendocrinology, and neuroplasticity. Furthermore, we discuss potential mechanisms underlying the therapeutic effects of estrogen in the treatment of depression, which may pave the way for new antidepressant drug development and alternative treatment options.
There is limited research investigating whether perceived discrimination influences brain structures that subserve episodic memory, namely the hippocampus and amygdala. Our rationale for examining these regions build on their known sensitivity to stress and functional differences along the long-axis of the hippocampus, with the anterior hippocampus and amygdala implicated in emotional and stress regulation. We defined perceived discrimination as the unfair treatment of one group by a dominant social group without the agency to respond to the event. A potential moderator of perceived discrimination is personal mastery, which we operationally defined as personal agency. Our primary goals were to determine whether perceived discrimination correlated with amygdala and anterior hippocampal volume, and if personal mastery moderated these relationships. Using FreeSurfer 7.1.0, we processed T1-weighted images to extract bilateral amygdala and hippocampal volumes. Discrimination and personal mastery were assessed via self-report (using the Experiences of Discrimination and Sense of Control questionnaires, respectively). Using multiple regression, greater perceived discrimination correlated with lower bilateral amygdala and anterior hippocampal volume, controlling for current stress, sex, education, age, and intracranial volume. Exploratory subfield analyses showed these associations were localized to the anterior hippocampal CA1 and subiculum. As predicted, using a moderation analysis, personal mastery attenuated the relationship between perceived discrimination and amygdala and anterior hippocampal volume. Here, we extend our knowledge on perceived discrimination as a salient psychosocial stressor with a neurobiological impact on brain systems implicated in stress, memory, and emotional regulation, and provide evidence for personal mastery as a moderating factor of these relationships.
Contemporary brain research has expanded its field of study from that of pathological processes in relation to nervous and endocrine functions involved, up to the study of the normal relations of these two systems and the behavior. From the psychological perspective, it is important to address the study of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is connected to the central nervous system (CNS) and the endocrine system (ES). The HPA axis is a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. The evidence also informs of the role of HPA axes in neurocognitive changes. The parts of the HPA axis include the hypothalamus, limbic system, the pituitary gland, and the adrenal glands. The two systems work together to adjust the balance of the hormones and the stress response. It is well documented that the disruption of the HPA axes and changes in the neurocognitive and psychological state of individuals produce high levels of stress. This chapter presents an overview of brain structures and neurohormonal agents involved in HPA axes: Limbic System, hypothalamus, regulation of pituitary secretion and relationship with, stress, mode, personality and neurocognition.
Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic–pituitary–adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer’s and Parkinson’s, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.
In this article the authors address how pathological anxiety may develop from adaptive fear states. Fear responses (e.g., freezing, startle, heart rate and blood pressure changes, and increased vigilance) are functionally adaptive behavioral and perceptual responses elicited during danger to facilitate appropriate defensive responses that can reduce danger or injury (e.g., escape and avoidance). Fear is a central motive state of action tendencies subserved by fear circuits, with the amygdala playing a central role. Pathological anxiety is conceptualized as an exaggerated fear state in which hyperexcitability of fear circuits that include the amygdala and extended amygdala (i.e., bed nucleus of the stria terminalis) is expressed as hypervigilance and increased behavioral responsivity to fearful stimuli. Reduced thresholds for activation and hyperexcitability in fear circuits develop through sensitization- or kindling-like processes that involve neuropeptides, hormones, and other proteins. Hyperexcitability in fear circuits is expressed as pathological anxiety that is manifested in the various anxiety disorders.
Autistic individuals generally demonstrate impaired emotion recognition but it is unclear whether effects are emotion-specific or influenced by oxytocin receptor (OXTR) genotype. Here we implemented a dimensional approach using an implicit emotion recognition task together with functional MRI in a large cohort of subjects (N = 255) to establish associations between autistic traits and neural and behavioral responses to specific face emotions, together with modulatory effects of OXTR genotype. A searchlight-based multivariate pattern analysis (MVPA) revealed an extensive network of frontal, basal ganglia, cingulate and limbic regions exhibiting significant predictability for autistic traits from patterns of responses to angry relative to neutral expression faces. Functional connectivity analyses revealed a genotype interaction (rs2254298, rs2268491) for coupling between the orbitofrontal cortex and mid-cingulate during angry expression processing, with a negative association between coupling and autistic traits in the risk-allele group and a positive one in the non-risk allele group. Overall, results indicate extensive emotion-specific associations primarily between patterns of neural responses to angry faces and autistic traits in regions processing motivation, reward and salience but not in early visual processing. Functional connections between these identified regions were not only associated with autistic traits but also influenced by OXTR genotype. Thus, altered neural responses to threatening faces may be a potential biomarker for autistic symptoms although modulatory influences of OXTR genotype need to be taken into account.
Stress has been studied since the pioneering work of Selye in the mid-twentieth century (Selye, The stress of life. McGraw Hill, 1976). Thus, numerous animal models have been developed by basic research scientists, and they can be applied in acute or chronic stress studies. In addition, some are readily translatable to humans. Here, rodent models are reviewed, and their characteristics described. The effects of stress on higher-order brain functions such as mood and cognitive function are also described. In addition, since recent studies show that responses to stress by females can be different than males, sex as a biological variable is discussed, especially in relation to treatment of stress-related disorders. Chronic stressors generally impair performance of male rodents on commonly used memory tasks including radial arm maze, water maze, and object placement. In contrast, female rodents are either unaffected or show enhanced performance on the same tasks following the same stress. Anxiety increases in both sexes following chronic stress. Depression increases in males following stress, but effects in females are unclear since little rodent research on this topic has included females, despite the fact that human females have higher rates of depression than males. Morphology of neurons and activity of neurotransmitters are altered following stress and, like the behaviors, the changes are sexually dimorphic. Information from most animal models is translatable to humans and can be utilized to develop novel/more effective therapies for disorders which are precipitated by or related to stress such as anxiety, depression, post-traumatic stress disorder, and cognitive loss. With the World Health Organization naming stress the health epidemic of the twenty-first century, it is even more imperative to understand the neural underpinnings of stress.
Type 2 diabetes mellitus (T2DM) and depression are significant public health and socioeconomic issues. They commonly co-occur, with T2DM occurring in 11.3% of the US population, while depression has a prevalence of about 9%, with higher rates among youths. Approximately 31% of patients with T2DM suffer from depressive symptoms, with 11.4% having major depressive disorders, which is twice as high as the prevalence of depression in patients without T2DM. Additionally, over 80% of people with T2DM are overweight or obese. This review describes how T2DM and depression can enhance one another, using the same molecular pathways, by synergistically altering the brain’s structure and function and reducing the reward obtained from eating. In this article, we reviewed the evidence that eating, especially high-caloric foods, stimulates the limbic system, initiating Reward Deficiency Syndrome. Analogous to other addictive behaviors, neurochemical changes in those with depression and/or T2DM are thought to cause individuals to increase their food intake to obtain the same reward leading to binge eating, weight gain and obesity. Treating the symptoms of T2DM, such as lowering HbA1c, without addressing the underlying pathways has little chance of eliminating the disease. Targeting the immune system, stress circuit, melatonin, and other alterations may be more effective.
Gonadal hormone actions in the brain can both worsen and alleviate symptoms of neurological disorders. Although neurological conditions and reproductive endocrine function are seemingly disparate, compelling evidence indicates that reciprocal interactions exist between certain disorders and hypothalamic-pituitary-gonadal (HPG) axis irregularities. Epilepsy is a neurological disorder that shows significant reproductive endocrine dysfunction (RED) in clinical populations. Seizures, particularly those arising from temporal lobe structures, can drive HPG axis alterations, and hormones produced in the HPG axis can reciprocally modulate seizure activity. Despite this relationship, mechanistic links between seizures and RED, and vice versa, are still largely unknown. Here, we review clinical evidence alongside recent investigations in preclinical animal models into the contributions of seizures to HPG axis malfunction, describe the effects of HPG axis hormonal feedback on seizure activity, and discuss how epilepsy research can offer insight into mechanisms linking neurological disorders to HPG axis dysfunction, an understudied area of neuroendocrinology.
Illness is often predicated long before the manifestation of its symptoms. Exposure to stressful experiences particularly during critical periods of development, such as puberty and adolescence, can induce various physical and mental illnesses. Puberty is a critical period of maturation for neuroendocrine systems, such as the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes. Exposure to adverse experiences during puberty can impede normal brain reorganizing and remodelling and result in enduring consequences on brain functioning and behaviour. Stress responsivity differs between the sexes during the pubertal period. This sex difference is partly due to differences in circulating sex hormones between males and females, impacting stress and immune responses differently. The effects of stress during puberty on physical and mental health remains under-examined. The purpose of this review is to summarize the most recent findings pertaining to age and sex differences in HPA axis, HPG axis, and immune system development, and describe how disruption in the functioning of these systems can propagate disease. Lastly, we delve into the notable neuroimmune contributions, sex differences, and the mediating role of the gut microbiome on stress and health outcomes. Understanding the enduring consequences of adverse experiences during puberty on physical and mental health will allow a greater proficiency in treating and preventing stress-related diseases early in development.
Stress reactivity can be defined as any physiological response to a perturbation to homeostasis and generally includes both the response and recovery to a stressor. More broadly, in addition to the physiological response, it can include behavioral, subjective, and cognitive responses to stress. The focus of this chapter is primarily on stress reactivity as it pertains to the cardiovascular and neuroendocrine response to acute mental laboratory challenges or acute exercise. Stress reactivity is affected by sex, menstrual cycle phase, aging, and exercise. The role of stress reactivity in health and disease is outlined with a specific emphasis on the effects of acute and regular exercise on stress resilience. While the chapter focuses primarily on studies on women, additional studies on men are included for reference in areas where data on women are limited.KeywordsCortisolEstrogenFitnessHPA axisCardiovascular response
Temporomandibular disorder (TMD) is a common painful condition of the temporomandibular joint (TMJ) and associated structures. Stress is a significant risk factor for developing this painful condition that predominantly affects women. This study aimed to test the hypothesis that stress increases the risk of developing TMJ pain by facilitating inflammatory mechanisms in female and male rats. To test this hypothesis, we evaluated TMJ carrageenan-induced expression of pro-inflammatory cytokines and migration of inflammatory cells and TMJ formalin-induced nociception in female and male rats submitted to a repeated stress protocol induced by sound. We found that sound-induced repeated stress facilitates TMJ inflammation and contributes to TMJ nociception development equally in females and males. We conclude that stress is a risk factor for developing painful TMJ conditions in males and females, at least in part, by favoring the inflammatory process similarly in both sexes.
Psychiatric disorders are mental illnesses involving changes in mood, cognition and behavior. Their prevalence has rapidly increased in the last decades. One of the most prevalent psychiatric disorders is major depressive disorder (MDD), a debilitating disease lacking efficient treatments. Increasing evidence shows that microbial and immunological changes contribute to the pathophysiology of depression and both are modulated by stress. This bidirectional relationship constitutes the brain-gut axis involving various neuroendocrine, immunological, neuroenterocrine and autonomic pathways. The present review covers the most recent findings on the relationships between stress, the gut microbiome and the inflammatory response and their contribution to depression.
Ageing is generally characterised by the declining ability to respond to stress, increasing homeostatic imbalance, and increased risk of ageing-associated diseases. Mechanistically, the lifelong accumulation of a wide range of molecular and cellular impairments leads to organismal senescence. The aging population poses a severe medical concern due to the burden it places on healthcare systems and the general public as well as the prevalence of diseases and impairments associated with old age. In this chapter, we discuss organ failure during ageing as well as ageing of the hypothalamic–pituitary–adrenal axis and drugs that can regulate it. A much-debated subject is about ageing and regeneration. With age, there is a gradual decline in the regenerative properties of most tissues. The goal of regenerative medicine is to restore cells, tissues, and structures that are lost or damaged after disease, injury, or ageing. The question arises as to whether this is due to the intrinsic ageing of stem cells or, rather, to the impairment of stem-cell function in the aged tissue environment. The risk of having a stroke event doubles each decade after the age of 55. Therefore, it is of great interest to develop neurorestorative therapies for stroke which occurs mostly in elderly people. Initial enthusiasm for stimulating restorative processes in the ischaemic brain with cell-based therapies has meanwhile converted into a more balanced view, recognising impediments related to survival, migration, differentiation, and integration of therapeutic cells in the hostile aged brain environment. Therefore, a current lack of understanding of the fate of transplanted cells means that the safety of cell therapy in stroke patients is still unproven. Another issue associated with ischaemic stroke is that patients at risk for these sequels of stroke are not duly diagnosed and treated due to the lack of reliable biomarkers. However, recently neurovascular unit-derived exosomes in response to Stroke and released into serum are new plasma genetic and proteomic biomarkers associated with ischaemic stroke. The second valid option, which is also more economical, is to invest in prevention.KeywordsAgeingObesityComorbiditiesDementiaStrokeGenomicsRehabilitation
Objective
The objective is to verify whether a genetic condition associated with bipolar disorder (BD) is frequent in old adults adapted to their environment, without BD, but with aptitudes for hyperactivity and novelty seeking (H/NS).
Methods
In this cross-sectional study, the study sample included healthy elderly people (40 participants, aged 60 or older) living in an urban area and recruited from a previous study on physical exercise and active aging, who were compared with 21 old adults with BD from the same area. The genetic methodology consisted of blood sampling, DNA extraction, real-time PCR jointly with FRET probes, and the SANGER sequencing method. The genetic variant RS1006737 of CACNA1C, found to be associated with bipolar disorder diagnosis, was investigated.
Results
The frequency of the RS1006737 genetic variant in the study group (H/NS) is not higher than in the BD group and is statistically significantly higher than in all the control groups found in the literature. However, the familiarity for BD is higher in old adults with BD than in the H/NS sample without BD. The risk of BD in the family (also considering those without BD but with family members with BD) is not associated with the presence of the genetic variant examined.
Conclusion
The study suggests that the gene examined is associated with characteristics of hyperactivity rather than just BD. Nevertheless, choosing to participate in an exercise program is an excessively general way to identify H/NS. The next step would be to identify the old adults with well-defined H/NS features with an adequate tool.
The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their underlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical surface. Based upon the connectivity between these portions of the prefrontal cortex and the amygdala and evidence that the amygdala is involved in emotional modulation, activity was measured in the left amygdala and found to be significantly increased in the depressed group. A separate group of subjects with FPDD who were currently asymptomatic were also imaged to determine whether these findings represented abnormalities associated with the depressed state, or with a trait difference that might underlie the tendency to become depressed. Only the depressed group had increased activity in the left prefrontal cortex, suggesting that this abnormality represents a state marker of FPDD. Both the depressed and the remitted groups demonstrated increased activity in the left amygdala, though this difference achieved significance only in the depressed group. This suggests that the abnormality involving the left amygdala may represent a trait marker of FPDD, though further assessment in a larger sample size is necessary to establish this. These data along with other evidence suggest that a circuit involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus is involved in the functional neuroanatomy of depression.
The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their un-derlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial
Inhibition of the adrenocortical axis by glucocorticoids (GCs) occurs at both hypothalamic and suprahypothalamic sites. In the rat, the hippocampus has been shown to be an essential suprahypothalamic site. The present study shows that the hippocampal system serves a similar role in the nonhuman primate. Bilateral lesions that included the hippocampal formation and the parahippocampal cortex; the hippocampal formation, parahippocampal cortex, and the amygdala; or the fornix all produced GC hypersecretion in cynomolgus monkeys. The hypersecretion occurred throughout the day. Moreover, these lesions were also associated with dexamethasone resistance (i.e., GC hypersecretion following administration of the synthetic GC dexamethasone). The hypersecretion could not be attributed to acute surgical trauma, because neither circumscribed lesions of the amygdala nor conjoint lesions of the perirhinal and parahippocampal cortex produced adrenocortical abnormalities. Finally, in agreement with data derived from the rat, the GC hypersecretion following hippocampal lesions was transient. Secretory activity returned to normal levels by 6-15 months in all operated groups. Thus, the primate hippocampal system appears to share some neuroendocrine functions with the rodent.
I. Introduction THE STABILITY of the “milieu interieur” was first recognized by Claude Bernard (1), and this concept was extended by Walter Cannon (2), who coined the term homeostasis to denote the condition of relative constancy of the internal environment. The hypothalamic-pituitary-adrenal axis (HPA) and the autonomic nervous system are recognized as primary effector systems which serve to minimize excursions from the homeostatic state and to restore a relative equilibrium in response to disturbances (3, 4). Many of the physiological adjustments accompanying sympathetic activation complement those brought about by glucocorticoid secretion. Indeed, the responsiveness and physiological consequences of activation of these two systems are so inter-twined as to have generated the hypothesis that activation of the HPA is evoked by sympathoadrenomedullary activation (5, 6). Thus an organism's response to an actual or perceived challenge (stressor) usually involves activation of both the HPA and the sympatheti...
Expression of mRNAs coding for the ACTH secretagogues corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) was examined in the hypothalamic paraventricular nucleus (PVN) of rats bearing hippocampal lesions. Either total hippocampectomy (HPX) or extirpation of the dorsal hippocampus (DHPX) precipitated a 4-fold increase in CRF mRNA expression relative to sham-operated controls (SHAM), as determined by semiquantitative in situ hybridization histochemistry. AVP mRNA was localized to individual parvocellular neurons of the medial parvocellular division of the PVN in only the HPX and DHPX groups, consistent with enhanced production of AVP message in this neuronal population subsequent to hippocampal damage. HPX did not affect AVP mRNA content in magnocellular divisions of PVN. Plasma beta-endorphin levels were significantly elevated in the HPX and DHPX groups relative to SHAM animals, indicating a chronic increase in release of proopiomelanocortin peptides from the anterior pituitary gland in response to hippocampal lesion. Circulating corticosterone levels were elevated in HPX rats as well. To control for effects of lesion size and location, additional animals received large ablations of cerebral cortex or cerebellum. In neither case was CRF or AVP mRNA significantly altered in the PVN. The results suggest that the hippocampus exercises a tonic inhibitory role on ACTH secretagogue production in neuroendocrine neurons promoting ACTH release.
The present experiment was designed to explore the stress-relatedness of activity in noradrenergic neurons of the locus coeruleus (LC) of behaving cats. A stressor was defined as a stimulus that elicited a significant sympathoadrenal activation as measured by plasma norepinephrine level and heart rate. According to this definition, exposure to 15 min of 100 dB white noise or 15 min of restraint was stressful in cats. In contrast, exposure to inaccessible rats for 15 min was behaviorally activating but nonstressful. The single-unit activity of noradrenergic neurons in the LC of behaving cats was examined under these conditions. The stressful stimuli elicited a significant increase in LC neuronal activity for the entire 15 min stressor duration, whereas the behaviorally activating but nonstressful stimulus elicited no significant change in the activity of these neurons. These results provide evidence that behavioral activation per se is not sufficient to evoke a tonic activation of these neurons. Rather, these data support the hypothesis that the LC is involved in the CNS response to stress and provide additional evidence that the activity of LC noradrenergic neurons increases in association with sympathoadrenal activation.
We have summarized here recent evidence that clarifies the cellular organization and connections of the paraventricular nucleus of the hypothalamus (PVH) in the rat. The nucleus consists of a magnocellular division, with three distinct parts, and a parvocellular division with five distinct parts. Most neurons in the magnocellular division contain either oxytocin or vasopressin, and project to the posterior lobe of the pituitary gland. Separate cell populations centered in the parvocellular division give rise to projections to the median eminence, or to the brain stem and spinal cord including the intermediolateral column; some cells project both to the dorsal vagal complex and to the spinal cord. Cells with long descending projections may contain either oxytocin, vasopressin, somatostatin, or dopamine, although the biochemical specificity of most such neurons has not been determined. Noradrenergic fibers are found preferentially within those parts of the magnocellular division that are predominantly vasopressinergic. The parvocellular division is innervated by adrenergic as well as noradrenergic fibers from the brain stem, and by fibers from the dorsal vagal complex and the parabrachial nucleus. The bed nucleus of the stria terminalis and adjacent parts of the hypothalamus also innervate the PVH. The evidence indicates that subpopulations of neurons in the PVH are directly related to autonomic and neuroendocrine effector mechanisms, and suggest that the nucleus plays an important role in the regulation of visceral responses in the periphery and in the CNS itself.
The hippocampus is the principal target site in the brain for adrenocortical steroids, as it has the highest concentration of receptor sites for glucocorticoids. The aged rat has a specific deficit in hippocampal glucocorticoid receptors, owing in large part to a loss of corticoid-sensitive neurons. This deficit may be the cause for the failure of aged rats to terminate corticosterone secretion at the end of stress, because extensive lesion and electrical stimulation studies have shown that the hippocampus exerts an inhibitory influence over adrenocortical activity and participates in glucocorticoid feedback. We have studied whether it is the loss of hippocampal neurons or of hippocampal glucocorticoid receptors in the aged rat that contributes most to this syndrome of corticosterone hypersecretion. To do this, we used two model systems for producing reversible glucocorticoid receptor depletion in the hippocampus, and we found that depletion of receptors without inducing cell loss results in corticosterone hypersecretion. Furthermore, correction of the receptor deficit results in normalization of corticosterone secretion. These results focus attention on the hippocampus as an important glucocorticoid sensor in relation to the stress response. They also provide important new physiological correlates for the remarkable plasticity of the hippocampal glucocorticoid receptor system, which is under independent control by corticosterone and by vasopressin.
We have each recently proposed models of hippocampal function. The central concept of Gray’s model is that the septohippocampal system, together with the Papez circuit, functions as a comparator detecting departures from expectation in respect to both stimulus—stimulus and response—stimulus relationships. Rawlins’s model, in contrast, treats the hippocampal formation as a high-capacity, intermediate-term memory buffer. The principal aim of this chapter is to consider ways in which the two models may perhaps be integrated. We shall first present brief summaries of the two models (fuller accounts, including reviews of the data on which the models are based, are available elsewhere: Gray, 1982a,b; Rawlins, 1985). Gray’s model is given a relatively more detailed treatment as it is the more far-ranging.
Objective:
This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses.Data Sources:
Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE.Data Extraction:
Independent extraction and cross-referencing by us.Data Synthesis:
Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful.Conclusions:
This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.(Arch Intern Med. 1993;153:2093-2101)
The effect of septal lesions on plasma catecholamine and corticosterone (B) levels has been studied in rats during single and 7 times repeated immobilization stress (IMO). Blood samples were obtained via a catheter in the tail artery or by decapitation. The increased circulating epinephrine (EPI) and norepinephrine (NE) levels observed in the initial phase of acute stress as well as the elevated baseline EPI level after six times repeated IMO are indicative of an enhanced response of the sympathetic adrenomedullary system after lesions of the septum. After decapitation of rats with septal lesions there was a significant increase in plasma NE one day after the sixth IMO and a block of EPI increase after the seventh IMO compared to sham-operated rats. The adrenocortical system was similarly found to be activated after septal lesions, exhibiting increased baseline plasma B levels. It has been suggested that the septal region affects the studied systems by exerting an inhibitory tonus. The removal of this inhibitory system results in an increase of adrenocortical and sympathetic-adrenomedullary activities.
Serotonin (5-HT) is generally considered to serve a facilitatory role in the regulation of adrenocortical secretion. Numerous studies have shown that administration of -HT1a receptor agonists increases plasma corticosterone (CS) concentrations in rats; however, the mechanism has not been established. Rats were prepared with a cannula implanted above the lateral cerebral ventricle, or bilateral cannulae above the hypothalamic paraventricular nuclei (PVN), the site of the perikarya of corticotropin-releasing factor (CRF)-secreting neurons regulating adrenocortical secretion. In sodium pen-tobarbital-anesthetized rats, intracerebroventricular and intra-PVN administration of 5-HT resulted in a multi-component dose-response curve in plasma CS, whereas administration of 5-HT in conscious animals resulted in low-dose inhibition and higher dose elevation of plasma CS levels. Under pentobarbital anesthesia, central administration of the selective 5-HT1a agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone decreased plasma CS levels, relative to saline-treated control rats, at all doses tested (0.001-20 nmol). In conscious rats, administration of 8-OH-DPAT decreased adrenocortical secretion at lower doses and significantly increased plasma CS concentrations at higher doses. Ipsapirone produced similar but less pronounced effects. In contrast, intraperitoneal injection of 8-OH-DPAT (2 μmol/kg) increased plasma CS concentrations, but this was not prevented by prior intracerebroventricular administration of the 5-HT1a antagonist, NAN-190 (5 nmol). Pentobarbital anesthesia completely blocked the plasma CS response to peripheral administration of 8-OH-DPAT. In view of the adrenocortical activating effects of hypotensive stimuli, we speculate that the well-documented hemodynamic changes following -HT1a receptor stimulation may be responsible for the adrenocortical responses observed. Our data demonstrate that low doses of 5-HT1a agonists delivered directly into the CNS decrease adrenocortical secretion. Since intra-PVN injections of 8-OH-DPAT to pentobarbital-anesthetized rats also decreased hypothalamo-pituitary-adrenocortical activity, it appears that a component of the inhibitory effect of -HT1a receptor activation is mediated by a direct effect at the level of the PVN, and presumably involves CRF-secreting neurons.Copyright © 1992 S. Karger AG, Basel
This chapter summarizes the anatomical and functional organization of neural systems involved in effecting integrated visceromotor responses to stress, with an emphasis on hypothalamic neuroendocrine mechanisms. Implications for the nature of the interaction with the neural mechanisms subserving aspects of emotional experience and expression are discussed. The advent of “functional mapping” based on the induced expression of c-fos and other transcription factors has provided an extraordinarily powerful tool with which to glean a high-resolution profile of individual neurons and extended systems that are responsive to significant or “stressful” environmental events. Owing to the fact that no cellular immediateearly gene (cIE) is a perfect marker of synaptic and/or transcriptional activity, and uncertainties as to the significance of cIE expression at a cellular/molecular level under most circumstances, this technology seems best suited for use as a starting point from which to formulate hypotheses concerning situation-specific functional relatedness, which can then be tested experimentally. Such an approach has been most forthcoming in providing an initial level of definition of stress-specific operational circuits in several paradigms.
The axonal projections of the ventral subiculum to the bed nucleus of the stria terminalis (BST) were examined in the rat with the anterograde neuronal tracer Phaseolus vulgaris- leucoagglutinin (PHA-L). Axons originating in the ventral subiculum coursed to the BST through either the fimbria-fornix, or a pathway involving the stria terminalis via the amygdala. Ventral subicular axons gave rise to dense terminal networks that were preferentially distributed in medial and ventral subregions of the BST. The distribution of subicular fibers and terminals was examined in relation to BST neurons that project to the hypothalamic paraventricular nucleus (PVN). In these cases, discrete iontophoretic injections of the retrograde tracer Fluoro-gold were made in the PVN, with PHA-L delivered to the ipsilateral ventral subiculum. An immunocytochemical double-labeling protocol was then employed for the simultaneous detection of PHA-L and Fluoro-gold, and provided light microscopic evidence for subicular input to PVN-projecting cells located within the BST.
In a second series of experiments, the γ-amino butyric acid (GABA)ergic nature of the BST was examined by in situ hybridization histochemistry for detection of transcripts encoding GAD67 mRNA. The studies revealed that a high proportion of BST neurons express GAD67 transcripts. Also, experiments combining Fluoro-gold tracing with GAD67in situ hybridization suggested that a proportion of PVN-projecting neurons in the BST are GABAergic. Taken together, the results of these sets of studies suggest that the inhibitory influences of the hippocampus on the PVN might be relayed through specific portions of the BST. These findings may have important implications for our understanding of the neural regulation of the hypothalamic-pituitary-adrenal axis.
Anatomical studies indicate that the ventral subiculum is in a prime position to mediate hippocampal inhibition of the hypothalamo-pituitary-adrenocortical (HPA) axis. The present study evaluated this hypothesis by assessing HPA function following ibotenic acid lesion of the ventral subiculum region. Rats with lesions of the ventral subiculum (vSUB) or ventral hippocampus (vHIPPO) did not show changes in basal corticosterone (CORT) secretion at either circadian peak or nadir time points when compared to sham-lesion rats (SHAM) or unoperated controls. However, rats with vSUB lesions exhibited a prolonged glucocorticoid stress response relative to all other groups. Baseline CRH mRNA levels were significantly increased in the medial parvocellular paraventricular nucleus (PVN) of the vSUB group relative to controls. CRH mRNA differences were particularly pronounced at caudal levels of the nucleus, suggesting topographic organization of vSUB interactions with PVN neurons. Notably, the vHIPPO group, which received large lesions of ventral CA1, CA3 and dentate gyrus without significant subicular damage, showed no change in stress-induced CORT secretion, suggesting that the ventral subiculum proper is principally responsible for ventral hippocampal actions on the HPA stress response. No differences in medial parvocellular PVN AVP mRNA expression were seen in either the vSUB or vHIPPO groups. The results indicate a specific inhibitory action of the ventral subiculum on HPA activation. The increase in CRH biosynthesis and stress-induced CORT secretion in the absence of changes in baseline CORT secretion or AVP mRNA expression suggests that the inhibitory actions of ventral subicular neurons affect the response capacity of the HPA axis.
Corticotropin-releasing hormone (CRH) has been considered a major coordinator of the overall physical and behavioral response to stress. Moreover, prolonged hypersecretion of CRH has been implicated in the pathogenesis of disorders characterized by anxiety and/or depression. Drugs acting through the gamma-aminobutyric acid/benzodiazepine (GABA/BZD) receptor system have anxiolytic and/or antidepressant properties whereas benzodiazepine inverse agonists cause anxiety and stimulate the pituitary-adrenal axis in vivo. To examine the involvement of the GABA/BZD system in the regulation of hypothalamic CRH secretion, we studied the effects of various agonists and antagonists of GABAA and GABAB receptors using a sensitive rat hypothalamic organ culture with radioimmunoassayable CRH (IR-rCRH) as endpoint. The GABAA and GABAB receptor agonist GABA inhibited serotonin (5-HT)-induced IR-rCRH secretion from 10(-9) to 10(-6) M, but failed to do so at 10(-5) M. The GABAA receptor agonist muscimol was a weak inhibitor of 5-HT-induced IR-rCRH secretion, being effective only at the concentration of 10(-6) M. In contrast, the specific GABAB receptor agonist baclofen was able to inhibit 5-HT-induced IR-rCRH secretion from 10(-7) to 10(-5) M. The rank of potency was thus, GABA much greater than baclofen greater than muscimol. Bicuculline, a GABAA receptor antagonist, partially reversed the inhibitory effects of GABA. Diazepam, a classic benzodiazepine which interacts with the benzodiazepine-site of the GABAA receptor complex, inhibited 5-HT-induced IR-rCRH secretion from 3.3 X 10(-9) to 10(-5) M, an effect that could be reversed by the BZD inactive ligand Ro15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)
The locus ceruleus-norepinephrine system is one of the principal effectors of the stress response. Acute stress induces norepinephrine synthesis and release, and noradrenergic cells compensate by increasing the activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Here we use in situ hybridization histochemistry to show the effects of acute and chronic intermittent stress on the expression of tyrosine hydroxylase mRNA in the rat locus ceruleus. Restraint stress increased tyrosine hydroxylase mRNA in the locus ceruleus but not in dopaminergic nuclei such as the substantia nigra or ventral tegmental area. One hour of footshock or restraint caused a rapid increase in locus ceruleus tyrosine hydroxylase mRNA which returned to basal levels within 24 h. Chronic intermittent stress (1 hour of restraint or footshock per day for 14 days) produced no change in tyrosine hydroxylase mRNA. Neither adrenalectomy nor dexamethasone replacement significantly affected mRNA expression. These findings indicate that acute stress can increase the expression of tyrosine hydroxylase mRNA in the locus ceruleus but that adaptation occurs to repeated stress, and that the expression of tyrosine hydroxylase mRNA in the locus ceruleus is independent of direct glucocorticoid modulation.
A three dimensional reconstruction of the central neural pathways that appear to mediate release of ACTH in response to hemodynamic change is illustrated in Figure 11. Fibers from receptors in the right atrium and the carotid arteries project to the lateral solitary nucleus and then to the medial and the lateral nucleus intercalatus. A pathway containing projections from these nuclei then converges dominantly in the locus subcoeruleus and locus coeruleus. Multiple pathways then diverge, to travel in part directly to the hypothalamus through dorsal pathways. One pathway inhibits and another facilitates the release of ACTH. Multiple pathways also diverge, to travel in part medially, and then to the hypothalamus through ventral pathways. Again, one pathway inhibits and another facilitates the release of ACTH. The dorsal and ventral inhibitory pathways appear to converge in a region extending from just caudal and ventral to the paraventicular nucleus to the posterior hypothalamic area. Thus, after the coalescences of the various pontine-hypothalamic pathways, three principal pathways remain. These include a posterior inhibitor path, an anterodorsal facilitatory path that terminates in the paraventricular nucleus and that may be mediated through release of vasopressin, and an anteroventral facilitatory path that terminates in the suprachiasmatic and ventromedial nuclei and that is probably mediated through release of corticotropin-releasing hormone. The mode of integration of these pathways has not been defined. The pathways described herein are oligosynaptic: a signal may travel from atrium to hypothalamus over three to seven neurons. The combination of control of input hemodynamic signals and of measurement of ACTH permits quantitation of both sensory and motor events, that inevitably must be embedded in the neuronal pathways described here. The analysis of the input-output relations and their correlation with internal neural events must form the basis of a description of the physiology of the physiology of the system whose central neural anatomy has been defined in part by these studies.
The role of the amygdaloid complexes in the compensatory hypersecretion of ACTH following adrenalectomy was studied in the adult male rat. Unilateral or bilateral radiofrequency or knife-cut lesions were placed in the amygdalae, their efferent pathways or the septal region. Three weeks following adrenalectomy resting plasma ACTH concentrations were measured by radioimmunoassay. Bilateral lesions of a direct medial-projecting portion of the ventral amygdalo-hypothalamic pathway blocked the compensatory hypersecretion of ACTH following adrenalectomy. A unilateral complete amygdalar lesion coupled with destruction of the same direct amygdalo-hypothalamic pathway on the opposite side had the same positive effect. In contrast, unilateral destruction of the direct amygdalo-hypothalamic projections, ablation of the septum, or bilateral destruction of the stria terminalis did not block hypersecretion of ACTH following adrenalectomy. These data suggest that the amygdalae and their direct hypothalamic projections, but not the stria terminalis or septum, are essential for the hypersecretion of ACTH following adrenalectomy. Furthermore, one amygdaloid complex appears sufficient for this effect. It is possible that the amygdalae act as a central nervous system 'glucocorticoid-sensor' in the modulation of ACTH secretion in the rat.
Corticotropin-releasing factor (CRF-41) and arginine vasopressin (AVP) are the two major factors that regulate adrenocorticotropic hormone (ACTH) secretion. The two neurohormones are co-localized in the parvocellular neurons of the paraventricular nuclei (PVN) of the hypothalamus and are capable of potentiating each others' action on freshly excised anterior pituitary fragments or cells in vitro. Transection of all axons entering the medial basal hypothalamus from anterior and lateral directions blocks ACTH release induced by either adrenalectomy or ether-surgery stress. Adrenalectomy-induced ACTH release is almost completely suppressed by a long-term lesion of the PVN. Stress-induced ACTH release is blocked for only a few days after PVN lesion and the pituitary-adrenal response to ether-surgery stress returns to a large extent by a few weeks after PVN lesioning. This remarkable plasticity can be observed also in the homozygous Brattleboro rat, therefore it is not dependent on mediation by AVP. When parvocellular CRF-41- and AVP-containing cells are present, and the anterior lobe ACTH cells are desensitized to the stimulating effects of AVP, the ACTH response to haemorrhage and immobilization is markedly decreased. This indicates that AVP may partially mediate ACTH release under normal conditions. The hypothalamic control of the pituitary-adrenocortical system has a remarkable degree of redundancy which may compensate, at least under stressful conditions, for disruption of the function of CRF-41-containing cells of the paraventricular nucleus, the major source of CRF-41 in the stalk-median eminence.
To study the neurochemical identity of axons in synaptic contact with identified hypothalamic neurosecretory neurons in rats, we combined retrograde axonal transport of a marker molecule with postembedding immunogold staining for amino acid neurotransmitters. After intravenous injections of horseradish peroxidase, neurosecretory neurons with axons in the median eminence or neurohypophysis transported the peroxidase retrogradely back to the cell body of origin. Serial ultrathin sections from the paraventricular and arcuate nuclei were immunostained with glutamate or GABA antisera. Peroxidase-labeled neurons and their dendrites received synaptic contact from colloidal gold-labeled axons immunoreactive for GABA or for glutamate. Axons which were highly immunoreactive for GABA and other axons immunoreactive for glutamate but not for GABA consistently made converging synaptic contact with the same peroxidase-labeled cell. Some of the peroxidase-labeled neurons from the arcuate nucleus which were postsynaptic to both GABA and glutamate axons were themselves identified as being GABA immunoreactive. Serial ultrathin sections revealed that multiple presynaptic axons immunoreactive for glutamate or GABA made repeated contacts with single neurons. These results suggest a widespread convergence of the major inhibitory and excitatory amino acid transmitter on the neurons which control both the anterior and posterior pituitary hormones.
To investigate the role of gonadal steroids in the hypothalamic-pituitary-adrenal (HPA) response to stress, we studied adrenocorticotrophin (ACTH) and corticosterone (B) responses to 20-min restraint stress in cycling female rats, and in ovariectomized (OVX) rats replaced with physiological levels of estradiol (E2) and progesterone (P). In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases. No differences were found in either basal ACTH and B levels across the cycle phases. In a separate study, OVX rats were maintained on low, physiological levels of E2 and P with silastic implants for 3 days, and injected either with oil (O'), 10 micrograms of E2 (E') 24 h before stress testing, or with E2 and 500 micrograms P 24 and 4 h, respectively, prior to stress (EP'). These treatments mimicked endogenous profiles of E2 and P occurring during diestrous, proestrous, and late proestrous-early estrous phases, respectively. In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity.
The purpose of this study was to examine the contribution of the central nucleus of the amygdala to the expression of stress-induced increase in corticosterone and renin secretion. Neurons in the central amygdaloid nucleus of male rats were destroyed by bilateral injections of ibotenic acid, a neurotoxin that destroys cells but leaves fibers of passage intact. Two weeks later, the rats were subjected to immobilization for 20 min or to a conditioned stress (conditioned emotional response) procedure. Central amygdala lesions inhibited the increases in plasma corticosterone after exposure to both conditioned stress and immobilization. Lesions in the lateral amygdala had no effect on the corticosterone response to either stressor. Lesions in the central amygdala attenuated the renin response to conditioned stress but not to immobilization. In contrast, lateral amygdala lesions potentiated the renin response to immobilization but did not affect the renin response to conditioned stress. The results confirm previous studies that demonstrate the importance of the central amygdaloid nucleus in the expression of corticosterone to immobilization stress. In addition, the results show that neurons within the central amygdaloid nucleus are necessary for the full expression of conditioned stress-induced increase in corticosterone and renin secretion. The results are discussed with respect to the potential pathways that mediate stress-induced increases in corticosterone and renin secretion.
Infusion of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (2.5-20 micrograms in 1 microliter during 15 min), into the paraventricular nucleus of the hypothalamus (PVN) in the rat dose dependently increased plasma adrenaline and corticosterone concentrations, without affecting plasma noradrenaline concentrations. The highest dose also increased plasma glucose levels significantly. The results suggest that both the sympathoadrenomedullary system and the hypothalamo-pituitary-adrenocortical axis are activated after stimulation of 5-HT1A receptors in the PVN.
There is considerable, although not entirely consistent, evidence that the hippocampus inhibits most aspects of HPA activity, including basal (circadian nadir) and circadian peak secretion as well as the onset and termination of responses to stress. Although much of the evidence for these effects rests only on the measurement of corticosteroids, recent lesion and implant studies indicate that the hippocampus regulates adrenocortical activity at the hypothalamic level, via the expression and secretion of ACTH secretagogues. Such inhibition results largely from the mediation of corticosteroid feedback, although more work is required to determine whether the hippocampus supplies a tonic inhibitory input in the absence of corticosteroids. It must be noted that the hippocampus is not the only feedback site in the adrenocortical system, since removal of its input only reduces, but does not abolish, the efficacy of corticosteroid inhibition, and since other elements of the axis appear eventually to compensate for deficits in feedback regulation. The importance of other feedback sites is further suggested not only by the presence of corticosteroid receptors in other parts of the brain and pituitary, but also by the improved prediction of CRF levels by combined hypothalamic and hippocampal receptor occupancy. The likelihood of feedback mediated by nonhippocampal sites underscores the need for future work to characterize hippocampal influence on HPA activity in the absence of changes in corticosteroid secretion. However, despite the fact that the hippocampus is not the only feedback site, it is distinguished from most potential feedback sites, including the hypothalamus and pituitary, by its high content of both type I and II corticosteroid receptors. The hippocampus is therefore capable of mediating inhibition over a wide range of steroid levels. The low end of this range is represented by corticosteroid inhibition of basal (circadian nadir) HPA activity. The apparent type I receptor specificity of this inhibition and the elevation of trough corticosteroid levels after hippocampal damage support a role for hippocampal type I receptors in regulating basal HPA activity. It is possible that basal activity is controlled in part through hippocampal inhibition of vasopressin, since the inhibition of portal blood vasopressin correlates with lower levels of hippocampal receptor occupancy, and the expression of vasopressin by some CRF neurons is sensitive to very low corticosteroid levels. At the high end of the physiological range, stress-induced or circadian peak corticosteroid secretion correlates strongly with occupancy of the lower affinity hippocampal type II receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
To study the organization and distribution of the inhibitory amino acid neurotransmitter GABA in the medial hypothalamus, we used a postembedding immunocytochemical approach with colloidal gold. Quantitative analysis showed that half (49%) of all synapsing boutons studied were immunoreactive for GABA, based on immunogold staining of the suprachiasmatic, arcuate, supraoptic, and paraventricular nuclei. This was corroborated with pre‐embedding peroxidase immunostaining with antisera against glutamate decarboxylase, the GABA synthetic enzyme. These data suggest that GABA is the numerically dominant neurotransmitter in the hypothalamus, and emphasize the importance of inhibitory circuits in the hypothalamus.
Serial ultrathin sections were used to reconstruct GABA immunoreactive boutons and axons in three dimensions. With this type of analysis we found less morphological heterogeneity between GABA immunoreactive boutons than with single ultrathin sections. Single sections sometimes showed boutons containing only small clear vesicles, and others with both clear vesicles and small dense core vesicles. However, with serial sections through individual boutons, dense core vesicles were consistently found at the periphery of the pre‐synaptic GABA immunoreactive boutons, suggesting probable co‐localization of GABA with unidentified peptides in most if not all boutons throughout the hypothalamus.
A positive correlation was found between the density of small clear vesicles and the intensity of immunostaining with colloidal gold particles. GABA immunoreactive axons generally made symmetrical type synaptic specializations, although a small percentage made strongly asymmetrical synaptic specializations. Vesicles in GABA immunoreactive boutons were slightly smaller than those in non‐reactive boutons.
Synaptic efficacy is related to the position of the synapse on the post‐synaptic neuron. While the majority of GABA immunoreactive axons made synaptic contact with dendrites, the distribution of GABA immunoreactive synapses on somata and dendrites was the same as would be expected from a random distribution of all boutons. No preferential innervation of cell bodies by GABA immunoreactive terminals was found. Serial ultrathin sections showed that a GABA immunoreactive axon would sometimes make repeated synaptic contacts with a single postsynaptic neuron, indicating a high degree of direct control by the presynaptic GABAergic cell. Other immunoreactive axons made synaptic contact with a number of adjacent dendrites and cells, suggesting a role for GABA in synchronizing the activity of hypothalamic neurons. Based on the density of immunogold particles per unit area, varying concentrations of immunoreactive GABA were found in different presynaptic boutons in the hypothalamus.
Previous deafferentation studies have suggested that most hypothalamic GABAergic innervation originates from neurons within the hypothalamus. We have investigated the distribution of GABAergic cell groups in the rat hypothalamus by means of the in situ hybridization technique, using a cDNA probe for messenger RNA encoding glutamate decarboxylase. Several major GABAergic cell groups were demonstrated, including cells of the tuberomammillary nucleus, arcuate nucleus, suprachiasmatic nucleus, medial preoptic area, anterior hypothalamic area, the dorsomedial hypothalamic nucleus, perifornical area, and lateral hypothalamic area. The most prominent glutamate decarboxylase mRNA-containing cell groups were located in the medial preoptic area, anterior hypothalamic area and dorsomedial hypothalamic nucleus, and were composed of small- to medium-sized neurons. Compared to previously well-characterized GABAergic cell groups in the tuberomammillary nucleus, reticular thalamic nucleus, and non-pyramidal cells of cerebral cortex, the cells of these GABAergic groups demonstrated only weak cDNA labelling, indicating that they contain lower levels of glutamate decarboxylase mRNA. Several types of control experiments supported the specificity of this cDNA labelling, and the GABAergic nature of these cell populations was further supported by detection of glutamate decarboxylase and GABA immunoreactivity. Abundance of GABAergic cells in many hypothalamic nuclei indicates that GABA represents quantitatively the most important transmitter of hypothalamic neurons, and may be involved in neuroendocrine and autonomic regulatory functions.
There exists considerable evidence to suggest that CRH and arginine vasopressin (AVP)-secreting parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) are central integrators of negative feedback effects evoked by circulating glucocorticoid hormones. Most evidence suggests that these neurons may be receptive to circulating glucocorticoid levels, either via glucocorticoid receptors indigenous to these cells and/or via extrahypothalamic glucocorticoid-receptive neurons interacting with the PVN secretory cell. In an effort to address this issue, we performed anterior (ANT), posterior (POST) and total (TOT) deafferentations of the PVN region in male Sprague-Dawley rats using microknives fashioned from narrow-gauge spinal needles. Effective knife cuts were verified immunohistochemically, and deemed acceptable only if they avoided damage to the PVN proper and fibers of CRH and AVP-containing neurons coursing through the hypothalamus en route to the median eminence, while effectively eliminating neuronal input into the PVN region. Subsequent to surgery, levels of mRNA encoding for CRH and AVP in the parvocellular and magnocellular PVN were assayed via semiquantitative in situ hybridization histochemistry. Results indicate that TOT deafferentations resulted in significant increases in CRH mRNA expression in the PVN, and a slight but noticeable induction of AVP mRNA in the medial parvocellular but not posterior magnocellular divisions of the PVN. ANT lesions also produced an up-regulation of CRH and AVP mRNA relative to operated control rats. POST lesions did not produce a clear induction in either CRH or AVP mRNA. The data indicate that in the absence of neuronal input coming from anterior structures, CRH mRNA expression is up-regulated, suggesting that local effects of glucocorticoids on the PVN neuron are ineffective in maintaining normal CRH mRNA expression. These results support a role for neuronal feedback in regulation of the CRH neuron. The limited up-regulation (compared with adrenalectomized rats) of AVP mRNA in the TOT group suggests that while neuronal input may have some control of AVP mRNA expression, local glucocorticoid feedback is clearly able to restrict AVP message to levels considerably less than those seen in steroid-deficient animals. Analysis of knife-cut effects on plasma corticosterone and ACTH levels reveals that POST and TOT, but not ANT, deafferentations prohibit the secretory activity of the hypothalamo-pituitary-adrenocortical (HPA) axis seen pursuant to the anesthesia/thoracotomy in lesion and operated control groups.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetylcholine (ACh) plays a major role in central autonomic regulation, including the control of arterial blood pressure (AP). Previously unknown neuroanatomic substrates of cholinergic - autonomic control were mapped in this study. Cholinergic perikarya and bouton-like varicosities were localized by an immunocytochemical method empolying a monoclonal antiserum against choline acetyltransferase (ChAT), the enzyme synthesizing ACh.
In the forebrain, bouton-like varicosities and/or perikarya were detected in the septum, bed nucleus of the stria terminalis, amygdala (in particular, autonomic projection areas AP1 and AP2 bordering the central subnucleus, hypothalamus rostrolateral/innominata transitional area, perifornical, dorsal, incertal, caudolateral, posterior [PHN], subparafascicular, supramammillary and mammillary nuclei. Few or no punctate varicosities were labeled in the paraventricular (PVN) or supraoptic (SON) hypothalamic nuclei.
In the mid and hindbrain, immunoreactive cells and processes were present in the nucleus of Edinger-Westphal, periaqueductal gray, parabrachial complex (PBC), a periceruleal zone avoiding the locus ceruleus (LC), pontine micturition field, pontomedullary raphe, paramedian reticular formation and periventricular gray, A5 area, lateral tegmental field, nucleus tractus solitarii (NTS), nucleus commissuralis, nucleus reticularis rostroventrolateralis (RVL), and the ventral medullary surface (VMS).
In the PBC, immunoreactive varicosities identified areas previously unexplored for cholinergic autonomic responsivity superior, internal, dorsal, and central division of the lateral subnucleus, nucleus of Koelliker-Fuse and the medial subnucleus. In the NTS, previously undescribed ChAT-immunolabeled cells and processes were concentrated at intermediate and subpostermal levels and distributed viscerotopically in areas receiving primary cardiopulmonary afferents. In the nucleus RVL, cholinergic perikarya were in proximity to the VMS and medial to adrenergic cell bodies of the C1 area. Punctate varicosities of unknown origin and dendrites extending ventrally from the nucleus ambiguus overlapped the C1 area and immediate surround of RVL.
In conclusion: 1) Cholinergic perikarya and putative terminal fields, overlap structures that are rich in cholinoreceptors and express autonomic, neuroendocrine, or behavioral responsivity to central cholinergic stimulation (PHN, NTS, RVL). The role of ACh in most immunolabeled areas, however, has yet to be determined. Overall, these data support the concept that cholinergic agents act at multiple sites in the CNS and with topographic specificity. (2) The absence of immunoreactive elements in the LC, PVN, and SON was unexpected and suggests that cholinergic processing attributed to these nuclei is mediated polysynaptically or by synapses on processes extending into adjacent cholinoreceptor fields. (3) Putative cholinergic terminals overlapping sites that relay primary (NTS) or higher-order visceral afferents suggest anatomical substrates for cholinergic regulation of autonomic reflexes. (4) ChAT-immunoreactive terminals in areas where cells project to the IML support the view that central cholinergic stimulation provoking sympathoexcitation may be mediated by bulbospinal neurons. A rich plexus of varicose fibers overlapping the C7 area of RVL, which provides the excitatory drive for tonic sympathetic discharge, may form the anatomical basis for the increases in sympathetic nerve activity provoked by systemic or central administration of cholinergic agents.
Anterograde transport, retrograde transport, and immunohistochemical techniques were used to characterize the organization of neural inputs to the paraventricular (PVH) and supraoptic (SO) nuclei from the C1, C2, and C3 adrenergic cell groups in the rostral medulla. The results are as follows: 1) Phenylethanolamine-N-methyltransferase-immunoreactive (PNMT-IR) fibers and terminals were distributed to all parts of the parvicellular division of the PVH; the dorsal and dorsal medial subdivisions received the most prominent inputs, the lateral and ventral medial parts the least. Sparse terminal fields were found consistently in the magnocellular division of the PVH and in the SO. 2) A combined retrograde transport-immunohistochemical method was used to estimate the number and proportion of cells in the regions of the C1, C2, and C3 cell groups that contribute to the PNMT-IR innervation of the PVH. On average, 232 +/- 37 retrogradely labeled cells in the C1 cell group, 73 +/- 32 in the C2 cell group, and 96 +/- 26 in the C3 group stained positively for PNMT-IR. These values comprised 70%, 84%, and 89%, respectively, of all retrogradely labeled neurons in these regions. 3) Fibers and terminals arising from the regions of each of the three adrenergic cell groups were labeled by local injections of the anterogradely transported plant lectin PHA-L. Each component projection was found to distribute in a very similar fashion and to mimic the overall distribution of PNMT-IR; differential projection patterns within the PVH or SO were not seen consistently following deposits in any of the individual adrenergic cell groups or at different rostrocaudal levels of any individual cell group. 4) A dual anterograde tracing (PHA-L)-immunohistochemical (PNMT) labeling method revealed an appreciable number of varicosities arising from the regions of C1, C2, and C3 cell groups to contain PNMT-IR. These results suggest that adrenergic inputs to the PVH and SO, while arising from distinct medullary cell groups and presumably relaying different types of sensory information, are in a position to influence similar groups of parvicellular neurosecretory and/or autonomic-related projection neurons.
The distribution of neural inputs to the paraventricular (PVH) and supraoptic (SO) nuclei from the regions of the A1, the A2, and the A6 (locus coeruleus) noradrenergic cell groups was investigated by using a plant lectin, Phaseolus vulgaris leucoagglutinin (PHA-L), as an anterogradely transported tracer. An immunofluorescence double-labeling procedure was used to determine the extent to which individual anterogradely labeled fibers and terminals in the PVH and the SO also displayed immunoreactive dopamine-beta-hydroxylase (DBH), a marker for catecholaminergic neurons. The results may be summarized as follows: (1) Projections from the A1 region were found primarily, and in some experiments almost exclusively, in those parts of the magnocellular division of the PVH and the SO known to contain vasopressinergic neurons. (2) Projections from the A2 region were distributed primarily throughout the parvicellular division of the PVH and were most dense in the dorsal medial part, a region known to contain a prominent population of corticotropin-releasing factor (CRF)-immunoreactive neurons. In addition, a less-dense projection to the magnocellular division of the PVH and to the SO was consistently found. (3) Fibers originating from the locus coeruleus were distributed almost exclusively to the parvicellular division of the PVH, with the most prominent input localized to the periventricular zone, a part of the PVH known to contain dopamine-, somatostatin-, and thyrotropin-releasing-hormone-containing neurons. We found no evidence for a projection from A6 to the SO. (4) The majority of fibers originating from the A1, the A2 or the A6 regions contained DBH immunoreactivity, although an appreciable number did not. These results suggest that each of the three brainstem noradrenergic cell groups that contribute to the innervation of the PVH and/or the SO is in a position to modulate the activity of anatomically and chemically distinct groups of neurosecretory neurons.
The bed nucleus of the stria terminalis (BST) sends a dense projection to the parabrachial nucleus (PB) in the pons. The BST contains many different types of neuropeptidelike immunoreactive cells and fibers, each of which exhibits its own characteristic distribution within cytoarchitecturally distinct BST subnuclei. Corticotropin releasing factor (CRF)-, neurotensin (NT)-, somatostatin (SS)-, and enkephalin (ENK)-like immunoreactive (ir) neurons are particularly numerous within areas of the BST that project to the PB. In this study, we use the combined retrograde fluorescence-immunofluorescence method to determine whether neurons in the BST that project to the PB contain these immunoreactivities. After Fast Blue injections into PB, retrogradely labeled neurons were numerous throughout the lateral part of the BST, particularly in the dorsal lateral (DL) and posterior lateral subnuclei. Retrogradely labeled neurons were also present in the preoptic, ventral lateral, and supracapsular BST subnuclei and in the parastrial nucleus. Many of the CRF-ir, NT-ir, and SS-ir neurons in DL were retrogradely labeled. A few double-labeled cells of each type were also found in the posterior lateral, ventral lateral and supracapsular BST subnuclei ENK-ir neurons were never retrogradely labeled. Our results show that BST neurons that project to the PB stain for the same neuropeptides as those in the central nucleus of the amygdala (CeA) that project to the PB, demonstrating further the close anatomical relations between these two structures.
Previous studies using the isolated rat hypothalamus in vitro have shown that both acetylcholine and 5-hydroxytryptamine (5-HT) stimulate the secretion of bioactive corticotrophin-releasing factor (CRF). However, the CRF complex consists of a number of bioactive substances, and in this study we examined the effect of acetylcholine and 5-HT on the release of immunoreactive (ir)-CRF-41 and ir-arginine vasopressin (AVP) in vitro . Acetylcholine caused a dose-dependent (10 pmol–10 nmol/l) release of both neuropeptides, and the effect was partially antagonized by both atropine and hexamethonium. Nicotine (0·1–10 μmol/l) also stimulated the release of both peptides, whereas bethanacol had no effect on AVP release, but had a variable action on CRF-41 release. 5-HT caused a dose-dependent (10 pmol–1 nmol/l) stimulation of CRF-41 release without any effect on AVP release, and this effect was antagonized by cyproheptadine, suggesting the participation of specific 5-HT receptors.
Journal of Endocrinology (1989) 122, 713–718
Four hypotheses have been proposed to explain why nonsuppression on the dexamethasone suppression test occurs in patients with major depression. These include 1) increased metabolism of dexamethasone, 2) decreased sensitivity of pituitary glucocorticoid receptors to dexamethasone, 3) hyperresponsivity of the adrenal gland to ACTH stimulation, and 4) increased central drive of the pituitary from hypothalamic/limbic structures that overrides the action of the dexamethasone. A critical review of the literature suggests that the last hypothesis is most closely supported by the data. Despite this conclusion, factors other than depression may be involved in hypothalamic-pituitary-adrenal axis dysfunction.
Much controversy exists concerning the role of catecholamines in the control of ACTH secretion. In this study, noradrenaline (0·1 nmol–0·1 μmol/l) stimulated the release of both immunoreactive corticotrophin-releasing factor-41 (ir-CRF-41) and ir-arginine vasopressin (ir-AVP) from the rat hypothalamus in vitro . The stimulatory effect of noradrenaline on CRF-41 release was blocked by propranolol, whilst that on AVP release was blocked by phentolamine. γ-Aminobutyric acid (GABA; 10 nmol/l) inhibited the acetylcholine-induced release of both AVP and CRF-41 in vitro , and the effect was blocked by picrotoxin (0·1 μmol/l). Neither substance had any effect on the basal secretion of either neuropeptide. The results indicate that noradrenaline stimulates and GABA inhibits the release of both peptides from the rat hypothalamus in vitro .
Journal of Endocrinology (1989) 122, 719–723
We previously reported that adrenalectomized rats given constant corticosterone via a sc pellet (B-PELLET) hypersecrete ACTH in response to stress. Although lacking a feedback signal, B-PELLET rats do not secrete ACTH indefinitely after stress; plasma ACTH levels in these animals returned to those in sham-operated (SHAM) rats within 1-4 h after 2-min restraint. To distinguish between the requirement for circadian or stress-induced increases in corticosterone, we compared changes in ACTH and corticosterone levels after stress in SHAM and B-PELLET rats with those in cyanoketone-treated rats (CK) and adrenalectomized rats given corticosterone in their drinking fluid (B-WATER). B-WATER rats exhibited sustained increases in plasma corticosterone after lights-off, correlating with the nocturnal feeding period. Morning plasma corticosterone levels in B-WATER rats were constant and even lower than those in B-PELLET rats; however, B-WATER rats did not differ from SHAM rats in their ACTH response to ip injection. CK rats, which have an approximately normal circadian corticosterone rhythm but do not have significant corticosterone responses to acute stimuli, also exhibited plasma ACTH levels similar to those of SHAM rats at all times after 5-min restraint. Compared with SHAM and B-WATER rats in the same experiment, B-PELLET rats tended to hypersecrete ACTH 60 min after 5 min of restraint, but only had significantly elevated plasma ACTH relative to both groups 45 min after 10 min of restraint. We conclude that circadian, rather than stress-induced, increases in corticosterone may be sufficient for normal termination of ACTH responses to stress.
Many parvocellular neurons in the paraventricular nucleus of the hypothalamus express high levels of corticotropin releasing factor (CRF) or vasopressin following adrenalectomy. To determine whether glucocorticoids feed back directly on these neurons, a mouse monoclonal antibody directed against the rat liver glucocorticoid receptor was used in combination with polyclonal antisera directed against either vasopressin or CRF to permit simultaneous visualization of either peptide with glucocorticoid receptor-like immunoreactivity (IR). Rats were adrenalectomized (ADX) for 2 weeks to optimize numbers of vasopressin - and CRF-IR neurons. Six hours prior to sacrifice, a separate group of adrenalectomized rats was treated with corticosterone (40 mg/kg). This short-term replacement resulted in nuclear localization of glucocorticoid receptor-like-IR but did not attenuate the increased numbers of CRF- and vasopressin-IR neurons observed after adrenalectomy. It was therefore possible to visualize vasopressin- or CFR-IR and nuclear glucocorticoid receptor-like-IR simultaneously. Cell counts of double-labeled neurons in the paraventricular nucleus of the hypothalamus (PVH) demonstrated that glucocorticoid receptor-like-IR is colocalized in virtually all the CRF and vasopressin immunoreactive parvocellular neurons studied, which respond to adrenalectomy by increased peptide expression. These data suggest that a major feedback effect of glucocorticoids on the hypothalamic-pituitary-adrenal axis is exerted directly within nuclei of CRF and vasopressin neurons.
The purpose of this study was to further elucidate the role of serotonin (5-HT) in adrenocortical regulation. The effects of stimulating the frontal cortex and extrahypothalamic limbic structures, on plasma corticosterone (CS) responses, were studied in rats with vehicle or 5,7-dihydroxytryptamine (5,7-DHT) injection into the midbrain raphe nuclei. In another group of rats the neurotoxin was injected locally into the paraventricular nucleus (PVN) in view of its importance in adrenocortical regulation, and the effects of photic and dorsal hippocampal stimulation on plasma CS were studied. 5,7-DHT caused a significant depletion of hypothalamic 5-HT and blocked the rise in plasma CS following the stimulation of the above neural modalities. These studies suggest that the PVN 5-HT mediates the adrenocortical responses following afferent neural stimuli.
The effect of ventral septal stimulation on pituitary-adrenal function was assessed by evaluating plasma corticosterone obtained prior to and following sham or electrical stimulation of the bed nucleus of the stria terminalis (BNST) of female rats anesthetized with urethane (1.3 g X kg-1). Hippocampal EEG, ECG, heart rate, blood pressure and respiration were routinely monitored; timed blood samples (0.2 ml) for determining plasma corticosterone (RIA) were obtained from a catheterized tail artery. Samples were taken at 0.5 min prior to and at 5, 10, 15 and 30 min after initiation of stimulation. Whereas increased plasma corticosterone levels followed stimulation of the medial aspect of the BNST, lateral stimulation resulted in decreased plasma corticosterone levels. The overall increase in plasma corticosterone following medial stimulation was 24%; the overall decrease was 13%. The largest increase in plasma corticosterone (36%) occurred at 30 min poststimulation; the largest decrease (22%) occurred at 15 min. Stimulation of the most rostral aspect of the BNST produced plasma corticosterone responses similar to that observed following medial stimulation. In contrast, no changes in corticosterone levels were observed following either sham stimulation or stimulation of the corpus callosum, fornix or anterior commissure.
To pursue the possibility that subdivisions within the amygdaloid complex are differentially involved in adrenocortical function, plasma samples obtained prior to and following electrical stimulation of the amygdala of urethane (1.30 g/kg) anesthetized female rats were assessed for corticosterone concentration. Hippocampal EEG, ECG, heart rate, mean arterial pressure, and respiration routinely were monitored, and timed blood samples (0.2 ml) were obtained from a catheterized artery. Blood samples were taken 0.5 min prior to and at 5, 10, 15, and 30 min after initiation of stimulation. Whereas stimulation of the central and lateral nuclei produced a decrease (p less than 0.05) in plasma corticosterone, stimulation of the basomedial, medial and posterior corticomedial nuclei resulted in increased plasma corticosterone levels (p less than 0.05). In contrast, no change in corticosterone levels were observed following sham stimulation or stimulation of several nonamygdaloid sites. Collectively, these data support the hypothesis that subdivisions within the amygdaloid complex are differentially involved in adrenocortical function.
Corticotrophin (ACTH) release has been studied in rats given intraventricular gamma-aminobutyric acid (GABA) infusions or injections of picrotoxin and bicuculline. As an index of ACTH release the corticosterone level of blood or plasma was determined. GABA (1 M/liter), infused at a rate of 1 μl/min into the 3rd ventricle, inhibited the rise in plasma corticosterone normally produced by surgical trauma. 60 min after surgical trauma the rats given GABA infusions had lower blood corticosterone levels than the control rats given infusions of 1 M/liter of proline, 1 M/liter of glycine, or 0.15 M/liter of sodium chloride. Picrotoxin, an antagonist of GABA, is a potent stimulus of ACTH release. In sub-convulsive intraperitoneal doses it produced a significant rise in plasma corticosterone in conscious rats with complete hypothalamic deafferentation. Under pentobarbital anesthesia 12.5 μg of picrotoxin injected into the 3rd ventricle produced a small but significant rise in plasma corticosterone in rats with hypothalamic deafferentation. After intraventricular injections of bicuculline methiodide a significant rise in plasma corticosterone occurred in rats with hypothalamic deafferentation; the ACTH releasing effect of 2.5 μg of bicuculline methiodide was strongly inhibited by a simultaneous infusion of 0.15 M/liter of GABA. On the basis of this pharmacological evidence, we suggest that GABA may be an inhibitory neurotransmitter of hypothalamic interneurons and/or afferent pathways involved in the regulation of ACTH release.Copyright © 1974 S. Karger AG, Basel
The participation of the amygdaloid complexes in the stress-induced release of ACTH was studied in the adult male rat. Unilateral and/or bilateral radiofrequency lesions were placed in the amygdalae or their efferent pathways. Plasma corticosterone concentrations were measured after either a leg break, tourniquet, or ether stress. Unilateral amygdaloid lesions did not block the effect of a contralaterally-applied tourniquet or leg break. Bilateral paired amygdaloid lesions blocked the effect of the leg break but not of ether or tourniquet. Bilateral paired lesions between the lateral hypothalamic area and the amygdalae also blocked the effect of the leg break but not ether or tourniquet, whereas bilateral lesions in the anterior portion of the striae terminali did not block the leg-break effect. These data suggest that the amygdalae facilitate rather than directly transmit neurogenic stress-induced signals (leg break) but not signals from systemic stresses (ether). Furthermore, one amygdaloid complex appears to be sufficient for achieving this effect. The pathway from the amygdalae to the hypothalamus involved in the facilitatory effect is probably a direct medial projection to the hypothalamus.Copyright © 1974 S. Karger AG, Basel
The intra-axonal transport of horseradish peroxidase (HRP) has been used to trace the nodose ganglion and brain stem projections of a physiologically distinct nerve — the aortic depressor nerve — following electrophysiological identification. Tetramethyl benzidine (TMB) has been used as the substrate for demonstrating the centrally transported HRP15,16. This sensitive method for horseradish peroxidase histochemistry has permitted the visualization of the central projections of aortic nerve afferents and has also provided information regarding the anatomical localization of cell bodies of these sensory nerve fibers within the nodose ganglion. This study demonstrates the usefulness of using TMB as a substrate for HRP histochemistry in anatomical studies where the detection of anterogradely transported HRP is an essential prerequisite. The uptake of HRP from the cut central ends of sensory nerve fibers and the transport of this enzyme to the sensory ganglion and subsequently into the central processes of these sensory neurons have made possible this study of the central projections of a functionally distinct peripheral nerve. Information has been provided by this study that cell bodies of aortic nerve afferent fibers are localized in the rostrolateral pole of the nodose ganglion. Dense central projections of sensory terminals of aortic afferents have been found in the dorsolateral and medial subdivisions of the nucleus of the tractus solitarius. These central projections of aortic afferents extend for 6 mm rostrocaudally in the medulla with the densest projection being found at the level of the obex. These projections are bilateral at all rostrocaudal levels. This anatomical demonstration of the dorsolateral and medial subdivision of the nucleus of the tractus solitarius confirms earlier reports based on electrophysiological studies 5–8,14.
Corticosteroid feedback inhibits the brain-hypothalamo-pituitary units of the adrenocortical system. Naturally occurring corticosteroids may have their primary actions in vivo at brain and hypothalamic sites of feedback, whereas synthetic glucocorticoids that do not bind to transcortin may act primarily on corticotropes and regions of brain outside the blood-brain barrier. There appear to be three major time frames of corticosteroid action: fast, intermediate and slow. These time frames probably are the consequence of three separate mechanisms of corticosteroid action at feedback-sensitive sites. The rapidity of occurrence of fast feedback is not compatible with a nuclear site of corticosteroid action, and protein synthesis is not required. The action of CRF on ACTH release may be inhibited by a rapid effect of corticosteroids at the cell membrane. Since stimulated, but not basal, ACTH and CRF release are inhibited in vitro, the corticosteroids may inhibit some event in stimulus-secretion coupling (e.g., cAMP production). Intermediate feedback also decreases ACTH release in response to stimulation of the corticotrope, but does not affect ACTH synthesis; CRF synthesis and release both appear to be affected by the intermediate corticosteroid action. The mechanism of intermediate feedback requires the presence of a protein whose synthesis is corticosteroid-dependent; however, the role of this protein is unknown. Intermediate feedback, like fast feedback, apparently does not involve inhibition of total ACTH stores or the releasable pool of ACTH since basal secretion of ACTH is also not inhibited in vitro within this time domain. On the other hand, slow feedback apparently involves the classical genomic steroid mechanism of action; slow feedback reduces pituitary ACTH content by decreasing levels of mRNA encoding for POMC, the ACTH precursor molecule. Slow feedback, therefore, inhibits basal as well as stimulus induced ACTH secretion. Corticosteroid-induced inhibition of basal ACTH secretion has been shown to occur within 2 h in vivo but not in vitro. The time course and sensitivity of this feedback effect is different than that demonstrated for stimulus induced secretion. This difference suggests that basal secretion is activated by different pathways to (CRF and) ACTH secretion. There is some evidence that suggests that whereas comparator elements are not reset during stress, a comparator element is reset during the course of the circadian rhythm so that different basal levels of steroid are achieved.(ABSTRACT TRUNCATED AT 400 WORDS)
The distribution of serotonin-immunoreactive varicosities in the paraventricular (PVH) and supraoptic (SO) nuclei was charted in normal immunohistochemical material and the probable cells of origin of these projections were identified using a combined retrograde transport-immunohistochemical method. The density of serotonergic fibers in the PVH and the SO is quite low relative to that in the immediately surrounding neuropil, in striking contrast to noradrenergic inputs to the nuclei. Immunoreactive fibers are concentrated in specific parts of the parvocellular division of the PVH, whereas in the magnocellular division of the nucleus, and in the SO, they are found mostly in regions where oxytocinergic cells predominate. These projections appear to arise from 3 distinct serotonergic cell groups (B7, B8 and B9) in the midbrain.