CRH-deficient mice have a normal anorectic response to chronic stress.

Many studies have implicated corticotropin-releasing hormone (CRH) as a mediator of stress-induced decreases in food intake. However, urocortin, sauvagine, and urotensin, other members of the family of CRH-like molecules, have also been shown to be potent inhibitors of food intake. This raises the possibility that a CRH-related molecule might also be responsible for stress-induced anorexia. We therefore examined the effects of three chronic stressors, repetitive daily restraint, turpentine abscess, and surgical stress, upon food intake in wildtype and CRH-deficient mice created by targeted inactivation of the CRH gene. We have found that both genotypes have similar basal food intake which initially decreases to the same degree following initiation of each stress paradigm. Food intake also recovers following the same time course and to the same degree in both genotypes. Therefore, CRH is not necessary for decreases in food-intake induced by the chronic stressors examined in this study.     

A role for neuromedin U in stress response.

Neuromedin U (NMU) is a hypothalamic peptide that has been recently found to reduce food intake, but few is known about its other functions in the central nervous system. We here studied behavioral activities induced by an intracerebroventricular (ICV) administration of NMU in rats and mice. NMU increased gross locomotor activity, face washing behavior, and grooming. NMU-induced stress response was significantly abolished by pretreatment with an antagonist of corticotropin-releasing hormone (CRH), alpha-helical CRH (9-41) (alpha-hCRH), or anti-CRH IgG. NMU did not induce locomotor activity in CRH knockout mice. NMU that interacts anatomically and/or functionally with the CRH system is a novel physiological regulator of stress response.     

Corticotropin-releasing hormone contributes to the peripheral inflammatory response in experimental autoimmune encephalomyelitis

Peripheral corticotropin-releasing hormone (CRH) is thought to have proinflammatory effects. We used the model of experimental autoimmune encephalomyelitis (EAE) to study the role of CRH in an immune-mediated disease. We showed that CRH-deficient mice are resistant to EAE, with a decrease in clinical score as well as decreased cellular infiltration in the CNS. Furthermore, Ag-specific responses of primed T cells as well as anti-CD3/anti-CD28 TCR costimulation were decreased in crh(-/-) mice with decreased production of Th1 cytokines and increased production of Th2 cytokines. Wild-type mice treated in vivo with a CRH antagonist showed a decrease in IFN-gamma production by primed T cells in vitro. This effect of CRH is independent of its ability to increase corticosterone production, because adrenalectomized wild-type mice had similar disease course and severity as control mice. We found that IkappaBalpha phosphorylation induced by TCR cross-linking was decreased in crh(-/-) T cells. We conclude that peripheral CRH exerts a proinflammatory effect in EAE with a selective increase in Th1-type responses. These findings have implications for the treatment of Th1-mediated diseases such as multiple sclerosis.     

The role of CRH in behavioral responses to stress

Corticotropin-releasing hormone (CRH) and urocortin in the central nervous system affect behavior and can enhance behavioral responses to stressors. The action of CRH-related peptides is mediated through multiple receptors that differ markedly in their pharmacological profiles and anatomical distribution. Comparative pharmacology of CRH receptor agonists suggests that CRH, urocortin, sauvagine and urotensin consistently mimic, and CRH receptor antagonists consistently lessen, functional consequences of stressor exposure. Recently, important advances have been made in understanding the CRH system and its role in behavioral responses to stress by the development of specific CRH receptor antagonists, application of antisense oligonucleotides and development of transgenic mice lacking peptides and functional receptors. This review summarizes recent findings with respect to components of the CRH system and their role in stress-induced behavioral responses.     

Role of angiotensin II and corticotropin-releasing hormone in hemodynamic responses to cocaine and stress

Cocaine produces characteristic behavioral and autonomic responses due to its unique pharmacological properties. Many of the autonomic responses resemble those to acute behavioral stress. Both cocaine and behavioral stress have been shown to evoke an increase in sympathetic nerve activity that is primarily responsible for the peripheral cardiovascular responses. We noted varying hemodynamic and sympathetic response patterns to cocaine administration and to acute behavioral stress in rats that correlate with the predisposition to develop both a sustained increase in arterial pressure and cardiomyopathies. Several lines of evidence suggest that the autonomic response patterns are dependent on the actions of central peptides including angiotensin II (Ang II) and corticotropin-releasing hormone (CRH). This is based on observations demonstrating that intracerebroventricular (icv) administration of receptor antagonists for Ang II or CRH attenuated the decrease in cardiac output (CO) and increase in vascular resistance noted in some animals after cocaine administration or startle. In contrast, icv Ang II enhances the cardiodepression associated with cocaine administration or startle. Based on this and other evidence, we propose that the autonomic response patterns to startle and to cocaine are closely related and dependent on central Ang II and CRH. Furthermore, we suggest that these central peptides may be responsible for varying predisposition to cardiovascular disease.     

Corticotropin-releasing hormone: from endocrinology to psychobiology

Corticotropin-releasing hormone (CRH) is a brain neuropeptide which coordinates the endocrine, autonomic and behavioral responses to stress. We review the abnormal response to exogenous CRH in various psychiatric syndromes, including major depression and anorexia nervosa. We also contrast pituitary responses to CRH in patients with depression versus Cushing's disease. We hypothesize that CRH may play a role in the pathogenesis of various psychiatric syndromes which are characterized during their course by the symptom of depression.     

Corticotropin-releasing hormone in the regulation of adaptive behavior

Recent findings on the role of corticotropin-releasing hormone (CRH) in the regulation of stress and its consequences are summarized and analyzed in the review. Being involved in stress-activating system this neurohormone is referred to as a neurochemical factor triggering and integrating both endocrine and behavioral functions. The CRH distribution in hypothalamus and extrahypothalamic brain regions relevant to its involvement in the controlling of endocrine processes and behavior is viewed in details. Distinct behavioral outcomes of stress and the contribution of amygdalar, hippocampal, and striatal CRH-structures, implicated in general organism response to external influences, are widely discussed. From this viewpoint the mechanisms involved in the development of post-stress psychopathology, as well as drug addiction and alcoholism are treated.     

Effects of the corticoliberin on synaptic transmission in the rat olfactory cortex slices in water-immersion model depression

Corticoliberin (corticotrophin-releasing hormone, CRH) regulated of endocrine, autonomic and immune response to stress and is a mediator of anxiety in behavioral response. We studied the effect of corticoliberin on neuronal activity after microstimulation of olfactory cortex slices. Wistar rats strain were selected in T-maze labyrinth according to active and passive strategy of the adaptive behavior. The rats were exposed to water-immersions stress and after 10 days from their brain the olfactory cortex slices were prepared. The evoked focal potential were registered after perfusion with 0.1 mcM of CRH. It was revealed that in 60% of the slices of the active rats CRH induced the small decrease of excitatory amplitude but the increase amplitude inhibitory postsynaptic potential. In 40%, CRH induced the depression of synaptic transmission. Addition of CRH in incubation medium of the passive rat slices related, blockade the synaptic transmission.     

A genetic model of stress displays decreased lymphocytes and impaired antibody responses without altered susceptibility to Streptococcus pneumoniae.

Stress pathways affect immune function, the most notable of these pathways being activation of the hypothalamic-pituitary-adrenal (HPA) axis. Although HPA activation has generally been relegated to an immunosuppressive role, recent evidence suggests that stress and HPA activation can be immunoenhancing in certain situations. To investigate specific effects of stress on immune function, we used a genetic model of chronic stress wherein transgenic mice overexpress corticotropin-releasing hormone (CRH), a primary mediator of the stress response. In these mice, CRH is overproduced in the brain, leading to chronic activation of the HPA axis. We found that CRH-transgenic mice have decreased leukocyte numbers in lymphoid compartments, with preferential loss of B lymphocytes. They also exhibit decreased Ab production and impaired isotype switching in response to immunization with a thymus-dependent Ag, phosphocholine-keyhole limpet hemocyanin. Despite these deficits, immunization protected CRH-transgenic and wild-type mice equally well against lethal challenge with Streptococcus pneumoniae, an encapsulated Gram-positive bacterium known to require Ab-mediated opsonization for clearance. While IgG responses are severely depressed in these mice, IgM titers are only modestly decreased. This fairly robust IgM response may be sufficient to protect against S. pneumoniae. Additionally, while total leukocyte numbers are decreased in these mice, neutrophil numbers are increased. This increase in number of neutrophils may compensate for the depressed IgG response, allowing adequate host defense during chronic stress.     

Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats

Summary 1. The neuropeptide corticotropin-releasing hormone (CRH) is the main mediator of the neuroendocrine and behavioral response to stress. End-capped phosphorothioate antisense and sense oligodeoxynucleotides (ODN) corresponding to the start coding region of rat CRH mRNA were infused intracerebroventricularly (30 µg/3 l per injection) three times at 12 hr intervals. Six hours after the last injection rats were subjected to social defeat stress and subsequently tested on the elevated plus maze.2. Socially defeated CRH antisense-treated rats displayed markedly reduced anxiety-related behavior, as they spent significantly more time in the open arms of the plus maze compared to sense ODN- and vehicle-treated animals.3. In controls, social defeat evoked a stress-induced elevation of CRH mRNA and CRH in the hypothalamus and a significant increase in plasma corticotropin (ACTH) levels. These parameters were attenuated in antisense-injected rats.4. Our results suggest that CRH antisense treatment is effectively suppressing the neuroendocrine and behavioral effects of social defeat.     

Differences in basal and stress-induced HPA regulation of wild house mice selected for high and low aggression

Male wild house mice, selected for short (SAL) and long (LAL) attack latency, show distinctly different behavioral strategies in coping with environmental challenges. In this study, we tested the hypothesis that this difference in coping style is associated with a differential stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) system. SAL rather than LAL mice showed a clear fluctuation in circulating corticosterone concentrations around the circadian peak with significantly higher levels in the late light phase. LAL mice showed lower basal ACTH levels and higher thymic and spleen weights compared to SAL. Under basal conditions, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA in the hippocampus and corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus were not different between the two lines. Forced swimming for 5 min induced high immobility behavior in LAL mice which was associated with an enhanced and prolonged corticosterone response as compared to SAL, while absolute ACTH levels did not differ. In addition, LAL mice showed an increase in hippocampal MR mRNA (but not GR) and hypothalamic CRH mRNA at 24 h after forced swimming. In conclusion, a genetic trait in coping style of wild house mice is associated with an idiosyncratic pattern of HPA activity, and greater responsiveness of physiological and molecular stress markers in LAL mice. In view of the profound differences in behavioral traits and stress system reactivity, these mouse lines genetically selected for attack latency present an interesting model for studying the mechanism underlying individual variation in susceptibility to stress-related psychopathology.     

Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling

Recent evidence showed that the endocannabinoid system plays an important role in the behavioral adaptation of stress and fear responses. In this study, we chose a behavioral paradigm that includes criteria of both fear and stress responses to assess whether the involvement of endocannabinoids in these two processes rely on common mechanisms. To this end, we delivered a footshock and measured the fear response to a subsequently presented novel tone stimulus. First, we exposed different groups of cannabinoid receptor type 1 (CB₁)‐deficient mice (CB₁^?/?) and their wild‐type littermates (CB₁^+/+) to footshocks of different intensities. Only application of an intense footshock resulted in a sustained fear response to the tone in CB₁^?/?. Using the intense protocol, we next investigated whether endocannabinoids mediate their effects via an interplay with corticotropin‐releasing hormone (CRH) signaling. Pharmacological blockade of CB₁ receptors by rimonabant in mice deficient for the CRH receptor type 1 (CRHR1^?/?) or type 2 (CRHR2^?/?), and in respective wild‐type littermates, resulted in a sustained fear response in all genotypes. This suggests that CRH is not involved in the fear‐alleviating effects of CB₁. As CRHR1^?/? are known to be severely impaired in stress‐induced corticosterone secretion, our observation also implicates that corticosterone is dispensable for CB₁‐mediated acute fear adaptation. Instead, conditional mutants with a specific deletion of CB₁ in principal neurons of the forebrain (CaMK‐CB₁^?/?), or in cortical glutamatergic neurons (Glu‐CB₁^?/?), showed a similar phenotype as CB₁^?/?, thus indicating that endocannabinoid‐controlled glutamatergic transmission plays an essential role in acute fear adaptation.     

Behavioral and cardiac responses after intracerebroventricular corticotropin-releasing hormone (CRH) administration: role of adrenal cortical hormones.

Intracerebroventricularly (icv) administered corticotropin-releasing hormone (CRH) produces a dose-dependent increase in heart rate in association with behavioral activation. The present study was designed to investigate whether these CRH-induced responses are dependent on adrenal function. The effects of adrenalectomy (ADX) and subsequent corticosterone replacement were studied. Administration icv of 300 ng of CRH failed to produce behavioral activation and tachycardia in ADX rats. Corticosterone replacement restored the CRH-induced behavioral response to preoperative levels, whereas the CRH-induced tachycardia was partially restored. This latter result may be related to the fact that the baseline heart rate of ADX animals appeared to be significantly higher than that of corticosterone-treated ADX animals. It is concluded that circulating adrenal corticosterone in ADX rats is involved in the expression of the behavioral and cardiac effect of central CRH.     

Mice overexpressing CRH show reduced responsiveness in plasma corticosterone after a5-HT1A receptor challenge

Corticotropin-releasing hormone (CRH) overproduction and serotonergic dysfunction have both been implicated in a range of psychiatric disorders, such as anxiety and depression, and several studies have shown interactions between these two neurotransmitter systems. In this study, we investigated the effects of CRH challenge on hypothalamo-pituitary-adrenal (HPA) axis activity in female transgenic mice overproducing CRH. Furthermore, the effects of mild stress on HPA axis activity and body temperature were investigated in these mice. Pre- and post-synaptic 5-HT_1A receptor function were studied by monitoring body temperature and plasma corticosterone levels after challenge with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT). Hypothermia in response to 8-OH-DPAT treatment did not differ between transgenic and wild type mice, indicating unaltered somatodendritic 5-HT_1A autoreceptor function in mice overproducing CRH. In wild type mice 8-OH-DPAT increased plasma corticosterone levels, but not in transgenic animals. CRH injection, however, increased corticosterone levels in both groups. These data suggest desensitization of post-synaptic, but not pre-synaptic, 5-HT_1A receptors in mice overproducing CRH. These findings resemble those seen in depressed patients following 5-HT_1A challenge, which is in accord with the hypothesized role of CRH in the pathogenesis of depression.     

Prenatal Restraint Stress is Associated with Demethylation of Corticotrophin Releasing Hormone (CRH) Promoter and Enhances CRH Transcriptional Responses to Stress in Adolescent Rats

Maternal stress can disturb normal fetal neurodevelopmental progress, and lead to negative behavioral and neuroendocrine consequences for the offspring. These effects may be related to alterations in the hypothalamic–pituitary–adrenal (HPA) axis. Early life events disrupting the function of the HPA axis may be associated with epigenetic modification. This study investigated the effect of maternal stress on the methylation rate of the corticotrophin-releasing hormone (CRH) promoter and HPA axis response to acute stress in the adolescent offspring of Sprague–Dawley rats. Pregnant dams were randomly assigned to two groups: restraint stress group and normal control group. Adolescent male and female offspring were used from each group. The results showed that prenatal stress is associated with the demethylation of the CRH promoter, and leads to anxiety-like behaviors in adolescent life stages, as well as hyper-responsiveness of the HPA axis. Together, these results imply that prenatal stress alters the normal HPA function, which may be via the epigenetic mechanism.