Hypothalamic Corticotropin-releasing Hormone Neurons Research Articles

Glucocorticoid receptors regulate hypothalamic CRH neuron activity in primary hypertension

The hypothalamic-pituitary-adrenal axis is important in maintaining homeostasis in response to physical and psychological stressors. The corticotropin-releasing hormone (CRH) is a neuropeptide synthesized by CRH neurons in brain regions including paraventricular nucleus (PVN) of the hypothalamus. The glucocorticoids synthesized and released in adrenal gland act on hypothalamic CRH-expressing neurons inhibit the CRH production and maintain the level of glucocorticoids. The glucocorticoid receptor (GR) is critical for this negative feedback to regulate CRH synthesis and release. Hypertension is associated with high stress response and CRH mRNA levels. The number of CRH-expression neurons are significantly increased in PVN of the hypothalamus in primary hypertension patients. this study determined if the HPA axis negative feedback is altered and contribute to maintaining hypertension. We measured mRNA expression levels of GRs and MR in PVN tissue obtained from adult Wistar-Kyoto normotensive rats (WKYs) and spontaneously hypertensive rats (SHRs) and found that the GR mRNA expression level was significantly lower in SHRs that in WKY rats, while the MR gene expression did not differ between WKY rats and SHRs. Furthermore, we found that acute perfusion of dexamethasone (DEX), a synthetic glucocorticoid, significantly decreased frequency of spontaneous excitatory postsynaptic synaptic currents (EPSCs) in identified PVN-CRH expressing neurons in brain slices prepared from WKY and SHRs. DEX caused a greater reduction of frequency of EPSCs in SHRs was than in WKY rats. Acute perfusion of DEX significantly increased the firing rate of PVN-CRH neurons in WKY rats but did not change the firing rate in SHRs. In addition, incubation of brain slices with DEX for 1 hr significantly inhibited the firing activity of PVN-CRH neurons in WKY rats but did not change the firing activity of PVN CRH neurons in SHRs. These data suggested that the glucocorticoid excites PVN-CRH neurons in acute phase while inhibits these neurons in chronic phase in normotensive rat. In hypertension, downregulated GR may be responsible for impaired the HPA axis feedback and contribute to hypertension. HL139523, HL142133, and HL159157. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact and Role of Hypothalamic Corticotropin Releasing Hormone Neurons in Withdrawal from Chronic Alcohol Consumption in Female and Male Mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (World Health Organization, 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine and Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two-bottle choice alcohol consumption blunts the endocrine-mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. GABAergic synaptic transmission was unaffected by alcohol history. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disk test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress-responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol-mediated changes to PVNCRH neurons that alter stress response.SIGNIFICANCE STATEMENT Paraventricular nucleus of the hypothalamus neurons that release corticotropin releasing hormone (PVNCRH) are vital for stress response. These neurons have been understudied in relation to alcohol and withdrawal despite profound relations between stress, alcohol use disorders (AUD), and relapse. In this study, we use a variety of techniques to show that acute withdrawal from a history of alcohol impacts peripheral stress response, PVNCRH neurons, and behavior. Specifically, PVNCRH are in a hyperactive state during withdrawal, which drives an increase in active stress coping behaviors in female mice only. Understanding how alcohol use and withdrawal affects stress responding PVNCRH neurons may contribute to finding new potential targets for the treatment of alcohol use disorder.

Recruitment of Corticotropin-Releasing Hormone (CRH) Neurons in Categorically Distinct Stress Reactions in the Mouse Brain.

Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (PVH) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however its involvement in the organization of the stress response is not fully understood. In these experiments, we took advantage of recently available Crh-IRES-Cre;Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. A total of 95 brain regions in the adult male mouse brain have been identified as containing putative CRH neurons with significant expression of tdTomato marker gene. With comparison of CRH mRNA and tdTomato distribution, we found match and mismatch areas. Reporter mice were then exposed to restraint, ether, high salt, lipopolysaccharide and predator odor stress and neuronal activation was revealed by FOS immunocytochemistry. In addition to a core stress system, stressor-specific areas have been revealed to display activity marker FOS. Finally, activation of CRH neurons was detected by colocalization of FOS in tdTomato expressing cells. All stressors resulted in profound activation of CRH neurons in the hypothalamic paraventricular nucleus; however, a differential activation of pattern was observed in CRH neurons in extrahypothalamic regions. This comprehensive description of stress-related CRH neurons in the mouse brain provides a starting point for a systematic functional analysis of the brain stress system and its relation to stress-induced psychopathologies.

Hypothalamic PVN CRH Neurons Signal Through PVN GABA Neurons to Suppress GnRH Pulse Generator Frequency in Female Mice.

Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are central to the stress response. Chemogenetic activation of PVN CRH neurons decreases LH pulse frequency but the mechanism is unknown. In the present study, optogenetic stimulation of PVN CRH neurons suppressed LH pulse frequency in estradiol-replaced ovariectomized CRH-cre mice, and this effect was augmented or attenuated by intra-PVN GABAA or GABAB receptor antagonism, respectively. PVN CRH neurons signal to local GABA neurons, which may provide a possible indirect mechanism by which PVN CRH neurons suppress LH pulse frequency. Optogenetic stimulation of potential PVN GABAergic projection terminals in the hypothalamic arcuate nucleus in ovariectomized estradiol-replaced Vgat-cre-tdTomato mice via an optic fiber implanted in the arcuate nucleus suppressed LH pulse frequency. To further determine whether PVN CRH neurons signal through PVN GABA neurons to suppress LH pulsatility, we combined recombinase mice with intersectional vectors to selectively target these neurons. CRH-cre::Vgat-FlpO mice expressing the stimulatory opsin ChRmine in non-GABAergic CRH neurons alone or in combination with the inhibitory opsin NpHR3.3 in non-CRH-expressing GABA neurons in the PVN were used. Optogenetic stimulation of non-GABAergic CRH neurons suppressed pulsatile LH secretion; however, LH pulse frequency was not affected when CRH neurons were stimulated and PVN GABA neurons were simultaneously inhibited. Together, these studies demonstrate that suppression of LH pulse frequency in response to PVN CRH neuronal activation is mediated by GABAergic signalling intrinsic to the PVN and may incorporate PVN GABAergic projection to the hypothalamic GnRH pulse generator.

Deficiency in the cell-adhesion molecule dscaml1 impairs hypothalamic CRH neuron development and perturbs normal neuroendocrine stress axis function.

The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. In dscaml1 mutant animals, hypothalamic CRH neurons had higher crhb (the CRH homolog in zebrafish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically, dscaml1 mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of human DSCAML1-linked neuropsychiatric disorders.

Odor blocking of stress hormone responses

Scents have been employed for millennia to allay stress, but whether or how they might do so is largely unknown. Fear and stress induce increases in blood stress hormones controlled by hypothalamic corticotropin releasing hormone neurons (CRHNs). Here, we report that two common odorants block mouse stress hormone responses to three potent stressors: physical restraint, predator odor, and male–male social confrontation. One odorant inhibits restraint and predator odor activation of excitatory neurons upstream of CRHNs in the bed nucleus of the stria terminalis (BNSTa). In addition, both activate inhibitory neurons upstream of CRHNs in the hypothalamic ventromedial nucleus (VMH) and silencing of VMH inhibitory neurons hinders odor blocking of stress. Together, these findings indicate that odor blocking can occur via two mechanisms: (1) Inhibition of excitatory neurons that transmit stress signals to CRHNs and (2) activation of inhibitory neurons that act directly or indirectly to inhibit stressor activation of CRHNs.

Plasticity of intrinsic excitability across the estrous cycle in hypothalamic CRH neurons

Stress responses are highly plastic and vary across physiological states. The female estrous cycle is associated with a number of physiological changes including changes in stress responses, however, the mechanisms driving these changes are poorly understood. Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic–pituitary–adrenal (HPA) axis and stress-evoked corticosterone secretion. Here we show that CRH neuron intrinsic excitability is regulated over the estrous cycle with a peak in proestrus and a nadir in estrus. Fast inactivating voltage-gated potassium channel (IA) currents showed the opposite relationship, with current density being lowest in proestrus compared to other cycle stages. Blocking IA currents equalized excitability across cycle stages revealing a role for IA in mediating plasticity in stress circuit function over the female estrous cycle.

Disrupted hypothalamic CRH neuron responsiveness contributes to diet-induced obesity.

The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here, we found that HFD feeding blunted PVH CRH neuron response to nutritional challenges as well as stress stimuli and dexamethesone, which normally produce rapid activation and inhibition on these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which showed HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models developed rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rhythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity and may also contribute to stress-induced obesity.

Neuronal hypertrophy dampens neuronal intrinsic excitability and stress responsiveness during chronic stress.

The hypothalamic-pituitary-adrenal (HPA) axis habituates to repeated stress exposure. We studied hypothalamic corticotropin-releasing hormone (CRH) neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint. The intrinsic excitability of CRH neurons decreased after repeated stress in a time course that coincided with the development of HPA axis habituation. This intrinsic excitability plasticity co-developed with an expansion of surface membrane area, which increased a passive electric load and dampened membrane depolarization in response to the influx of positive charge. We report a novel structure-function relationship for intrinsic excitability plasticity as a neural correlate for HPA axis habituation. Encountering a stressor immediately activates the hypothalamic-pituitary-adrenal (HPA) axis, but this stereotypic stress response also undergoes experience-dependent adaptation. Despite the biological and clinical importance, how the brain adjusts stress responsiveness in the long term remains poorly understood. We studied hypothalamic corticotropin-releasing hormone neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint. Using patch-clamp electrophysiology in acute slices, we found that the intrinsic excitability of these neurons substantially decreased after daily repeated stress in a time course that coincided with their loss of stress responsiveness in vivo. This intrinsic excitability plasticity co-developed with an expansion of surface membrane area, which increased a passive electric load, and dampened membrane depolarization in response to the influx of positive charge. Multiphoton imaging and electron microscopy revealed that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that may efficiently accommodate the membrane area expansion. Overall, we report a novel structure-function relationship for intrinsic excitability plasticity as a neural correlate for adaptation of the neuroendocrine stress response.

Stress experience and hormone feedback tune distinct components of hypothalamic CRH neuron activity

Stress leaves a lasting impression on an organism and reshapes future responses. However, the influence of past experience and stress hormones on the activity of neural stress circuits remains unclear. Hypothalamic corticotropin-releasing hormone (CRH) neurons orchestrate behavioral and endocrine responses to stress and are themselves highly sensitive to corticosteroid (CORT) stress hormones. Here, using in vivo optical recordings, we find that CRH neurons are rapidly activated in response to stress. CRH neuron activity robustly habituates to repeated presentations of the same, but not novel stressors. CORT feedback has little effect on CRH neuron responses to acute stress, or on habituation to repeated stressors. Rather, CORT preferentially inhibits tonic CRH neuron activity in the absence of stress stimuli. These findings reveal how stress experience and stress hormones modulate distinct components of CRH neuronal activity to mediate stress-induced adaptations.

Corticosterone mediated functional and structural plasticity in corticotropin-releasing hormone neurons

Corticosteroid stress hormones drive a multitude of adaptations in the brain. Hypothalamic corticotropin-releasing hormone (CRH) neurons control the circulating levels of corticosteroid stress hormones in the body and are themselves highly sensitive to corticosteroids. CRH neurons have been shown to undergo various adaptions in response to acute stress hormone elevations. However, their structural and physiological changes under chronically elevated corticosterone are less clear. To address this, we determined the structural and functional changes in CRH neurons in the paraventricular nucleus of the hypothalamus following 14 days of corticosterone treatment. We find that prolonged corticosterone elevation reduces CRH neuron intrinsic excitability as measured by summation of subthreshold postsynaptic depolarisations and spiking output. We find that under normal conditions, CRH neurons have a relatively compact and simple dendritic arbor, with a low density of somatic and dendritic spines. Interestingly, the axon originated from a proximal dendrite close to the soma in approximately half of the CRH neurons reconstructed. While prolonged elevation in corticosterone levels did not result in any changes to gross dendritic morphology, it induced a significant reduction in both somatic and dendritic spine density. Together these data reveal the morphological features of hypothalamic CRH neurons and highlight their capacity to undergo functional and morphological plasticity in response to chronic corticosterone elevations.This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.

Balancing tonic and phasic inhibition in hypothalamic corticotropin-releasing hormone neurons.

GABA transporter (GAT) blockade recruits extrasynaptic GABAA receptors (GABAA Rs) and amplifies constitutive presynaptic GABAB R activity. Extrasynaptic GABAA Rs contribute to a tonic current. Corticosteroids increase the tonic current mediated by extrasynaptic GABAA Rs. Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling. We show that GABA transporters (GATs) limit constitutive activation of presynaptic GABAB receptors and ensure high release probability at GABA synapses. GATs in combination with GABAB receptors also curtail extrasynaptic GABAA R signalling. CORT has no effect on synaptic GABA signalling, but increases extrasynaptic GABA tone through upregulation of postsynaptic GABAA receptors. These data show that efficient GABA clearance and autoinhibition control the balance between synaptic (phasic) and extrasynaptic (tonic) inhibition in PVN CRH neurons. This balance is shifted towards increased extrasynaptic inhibition by CORT.

Molecular diversity of corticotropin-releasing hormone mRNA-containing neurons in the hypothalamus.

Hormonal responses to acute stress rely on the rapid induction of corticotropin-releasing hormone (CRH) production in the mammalian hypothalamus, with subsequent instructive steps culminating in corticosterone release at the periphery. Hypothalamic CRH neurons in the paraventricular nucleus of the hypothalamus are therefore considered as 'stress neurons'. However, significant morphological and functional diversity among neurons that can transiently produce CRH in other hypothalamic nuclei has been proposed, particularly as histochemical and molecular biology evidence associates CRH to both GABA and glutamate neurotransmission. Here, we review recent advances through single-cell RNA sequencing and circuit mapping to suggest that CRH production reflects a state switch in hypothalamic neurons and thus confers functional competence rather than being an identity mark of phenotypically segregated neurons. We show that CRH mRNA transcripts can therefore be seen in GABAergic, glutamatergic and dopaminergic neuronal contingents in the hypothalamus. We then distinguish 'stress neurons' of the paraventricular nucleus that constitutively express secretagogin, a Ca2+ sensor critical for the stimulus-driven assembly of the molecular machinery underpinning the fast regulated exocytosis of CRH at the median eminence. Cumulatively, we infer that CRH neurons are functionally and molecularly more diverse than previously thought.

The Severity of Acute Stress Is Represented by Increased Synchronous Activity and Recruitment of Hypothalamic CRH Neurons.

Stressors trigger adaptive responses in the body that are essential for survival. How the brain responds to acute stressors of varying intensity in an intact animal, however, is not well understood. We address this question using two-photon Ca(2+) imaging in larval zebrafish with transgenically labeled corticotropin-releasing hormone (CRH) cells, which represent a major regulator of the stress axis. We show that stressor strength-dependent responses of CRH neurons emerge via an intensity-dependent increase in the activity of individual CRH cells, and by an increase in the pool of responsive CRH cells at the population level. Furthermore, we report striking synchronicity among CRH neurons even across hemispheres, which suggests tight intrahypothalamic and interhypothalamic coordination. Thus, our work reveals how CRH neurons respond to different levels of acute stress in vivo.

An integrated map of corticotropin‐releasing hormone signaling pathway

An integrated map of corticotropin‐releasing hormone signaling pathway

Early-Life Experience Reduces Excitation to Stress-Responsive Hypothalamic Neurons and Reprograms the Expression of Corticotropin-Releasing Hormone

Increased sensory input from maternal care attenuates neuroendocrine and behavioral responses to stress long term and results in a lifelong phenotype of resilience to depression and improved cognitive function. Whereas the mechanisms of this clinically important effect remain unclear, the early, persistent suppression of the expression of the stress neurohormone corticotropin-releasing hormone (CRH) in hypothalamic neurons has been implicated as a key aspect of this experience-induced neuroplasticity. Here, we tested whether the innervation of hypothalamic CRH neurons of rat pups that received augmented maternal care was altered in a manner that might promote the suppression of CRH expression and studied the cellular mechanisms underlying this suppression. We found that the number of excitatory synapses and the frequency of miniature excitatory synaptic currents onto CRH neurons were reduced in "care-augmented" rats compared with controls, as were the levels of the glutamate vesicular transporter vGlut2. In contrast, analogous parameters of inhibitory synapses were unchanged. Levels of the transcriptional repressor neuron-restrictive silencer factor (NRSF), which negatively regulates Crh gene transcription, were markedly elevated in care-augmented rats, and chromatin immunoprecipitation demonstrated that this repressor was bound to a cognate element (neuron-restrictive silencing element) on the Crh gene. Whereas the reduced excitatory innervation of CRH-expressing neurons dissipated by adulthood, increased NRSF levels and repression of CRH expression persisted, suggesting that augmented early-life experience reprograms Crh gene expression via mechanisms involving transcriptional repression by NRSF.

Effects of spontaneous and forced running on activation of hypothalamic corticotropin-releasing hormone neurons in rats

Corticotropin-releasing hormone (CRH)-containing neurons in the hypothalamic paraventricular nucleus (PVN) are known to be activated during physical or psychological stress, and play an important role as one of the central activators of integrated stress response. Physical exercise has also been suggested as one of the stressors activating CRH neurons in the PVN. Spontaneous wheel running (SWR) has recently been reported to result in improved mental health or mood, unlike treadmill running that commonly forces the animal to run. Thus, forced running may strongly induce an activation of CRH neurons compared with spontaneous running, and spontaneous running may not represent a strong stressor. However, whether the effects of spontaneous running on activation of CRH neurons in the PVN differ from those of forced running is unknown. The present study examined the activity of CRH neurons in 1-h forced wheel running (FWR) and SWR using c-Fos/CRH immunohistochemistry in male Wistar rats. No significant differences in 1-h running distance were observed between FWR and SWR, indicating that amount of work was almost equal between exercises. Number of double-labeled neurons for c-Fos and CRH in the PVN was markedly higher in FWR than in SWR. In addition, no significant differences in Fos expression in the LC, which is related to various stress responses, were found between FWR and SWR. These results indicate that FWR strongly activates CRH neurons in the PVN compared with SWR, suggesting that spontaneous running is not an intense stressor even though running distance does not differ significantly from forced running.

Trimethylthiazoline supports conditioned flavor avoidance and activates viscerosensory, hypothalamic, and limbic circuits in rats

Interoceptive stimuli modulate stress responses and emotional state, in part, via ascending viscerosensory inputs to the hypothalamus and limbic forebrain. It is unclear whether similar viscerosensory pathways are recruited by emotionally salient exteroceptive stimuli, such as odors. To address this question, we investigated conditioned avoidance and central c-Fos activation patterns in rats exposed to synthetic trimethylthiazoline (TMT), an odiferous natural component of fox feces. Experiment 1 demonstrated that rats avoid consuming novel flavors that previously were paired with TMT exposure, evidence that TMT supports conditioned flavor avoidance. Experiment 2 examined central neural systems activated by TMT. Odor-naive rats were acutely exposed to low or high levels of TMT or a novel nonaversive control odor and were perfused with fixative 60-90 min later. A subset of rats received retrograde neural tracer injections into the central nucleus of the amygdala (CeA) 7-10 days before odor exposure and perfusion. Brain sections were processed for dual-immunocytochemical detection of c-Fos and other markers to identify noradrenergic (NA) neurons, corticotropin-releasing hormone (CRH) neurons, and retrogradely labeled neurons projecting to the CeA. Significantly greater proportions of medullary and pontine NA neurons, hypothalamic CRH neurons, and CeA-projecting neurons were activated in rats exposed to TMT compared with activation in rats exposed to the nonaversive control odor. Thus the ability of TMT to support conditioned avoidance behavior is correlated with significant odor-induced recruitment of hypothalamic CRH neurons and brain stem viscerosensory inputs to the CeA.

A single brain-derived neurotrophic factor injection modifies hypothalamo–pituitary–adrenocortical axis activity in adult male rats

Immobilization stress induces in adult male rats rapid activation of brain derived neurotrophic factor (BDNF) expression in the hypothalamic paraventricular nucleus (PVN) preceding the increases in corticotropin releasing hormone (CRH) and arginin-vasopressin (AVP) expression. The BDNF mRNA signal belatedly co-localizes with CRH and AVP mRNA signals in the PVN, as determined by in situ hybridization. Intracerebroventricular BDNF injections (5 microg/rat) in non-anesthetized adult male rats induce a gradual increase in the CRH mRNA signal whereas AVP mRNA signal progressively decreases in the parvocellular and magnocellular PVN portions. At the same time, the CRH hypothalamic content decreases while the AVP content increases. These variations are accompanied by increases in ACTH and corticosterone plasma concentrations. These results strongly suggest that BDNF could be a stress-responsive intercellular messenger since when it is exogenously administered acts as an important and early component in the activation and recruitment of hypothalamic CRH and AVP neurons.

Differential regulation of forebrain glutamic acid decarboxylase mRNA expression by aging and stress

In aging brain, degeneration or functional impairment of the hippocampus has been connected with stress dysregulation, serving to disinhibit stress responses and allow for glucocorticoid hypersecretion and its attendant pathophysiology. Hippocampal dysfunction appears to be communicated to paraventricular hypothalamic corticotropin-releasing hormone neurons by way of subcortical GABAergic neurons. As such, hippocampal–hypothalamic relays are likely to play an important role in age-related stress dysfunction. To test this hypothesis, regulation of glutamic acid decarboxylase isoform mRNA was studied in young (3 months), middle aged (15 months) and aged (30 months) Fischer 344/Brown Norway F1 hybrid rats. Basal expression of glutamic acid decarboxylase (GAD) 65 mRNA was increased in the medial preoptic area and posteromedial bed nucleus of the stria terminalis (BST) in aged rats relative to both middle-aged and young groups. Unlike young or middle-aged animals, exposure to chronic intermittent stress decreased GAD65 mRNA levels in the medial preoptic area and posteromedial BST of aged rats. Thus, while aged rats show evidence of elevated basal GABA synthesis, chronic stress causes differential loss of GAD in hippocampal–PVN relays, consistent with reduced PVN inhibition.