Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders

Abstract

To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress.

Figure 1

Expression of Corticotropin-releasing hormone (CRH), CRH-R1 and CRH-R2 mRNA in a normal mouse brain. CRH is synthesized in the PVN and shows high expression in the CeA, BnST and the hippocampus. CRH-R1 mRNA is highly expressed in the cortex, cerebellum, A Pit, hippocampus, BLA, MeA and the DMH. CRH-R2 displays high expression in the L Sep, SN, VMH, P Pit and the RN. Abundance of mRNA is shown as the density of representative symbols in an area. Abbreviations: Anterior pituitary, A Pit; Barrington’s nucleus, BAR; Basolateral nucleus of the amygdala, BLA; Bed nucleus of the stria terminalis, BnST; Central nucleus of the amygdala, CeA; Hippocampal areas, CA1, CA2, CA3; Cerebellum, Cereb; Cingulate cortex, Cing Ctx; Dentate gyrus, DG; Dorsomedial hypothalamus, DMH; Frontal cortex, Fr Ctx; Inferior colliculus, InfC; Inferior Olive, IO; Locus coeruleus, LC; Lateral dorsal tegmental nucleus, LDT; Medial nucleus of the amygdala, MeA; Medial septum, M Sep; Nucleus tractus solitarii, NTS; Occipital cortex, Occ Ctx; Olfactory bulb, OB; Posterior pituitary, P Pit; Periaqueductal gray, PAG; Parietal cortex, Par Ctx; Paraventricular hypothalamic nucleus, PVN; Raphe nucleus, RN; Supraoptic nucleus, SN; Superior colliculus, SupC; Thalamus, Thal; Ventromedial hypothalamus, VMH.