BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus

Abstract

Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.knockout | cAMP response-element binding protein | CRTC2 | transcription T he hypothalamic-pituitary-adrenal axis (HPA) axis is regulated by the corticotrophin-releasing hormone (CRH), which controls the secretion of adrenocorticotropin (ACTH) from the anterior pituitary and glucocorticoids from the adrenal gland (1). Stress or threats activate the HPA axis via polysynaptic circuits that converge on the hypothalamic paraventricular nucleus (PVN) to activate CRH-producing neurons (2). Classically, endocrine feedback control is characterized by the down-regulation of CRH and ACTH by glucocorticoids to prevent the escalation of glucocorticoids to toxic levels (1, 3). Maintenance of the HPA axis, therefore, involves a homeostatic equilibrium between the activation and inhibitory feedback. Disruption of normal HPA axis is a major risk factor of neuropsychiatric disorders (4, 5). Elevated CRH levels have been documented in the cerebrospinal fluid of depressed individuals exhibiting hypercortisolism, indicating a close relationship between the production of glucocorticoids and CRH (4). Both activation and feedback regulation require the glucocorticoid receptor (GR), which occurs in brain structures that control HPA axis reactivity (2, 6).We find that genetic disruption of GR in the PVN disinhibited both the HPA axis and the expression of hypothalamic BDNF. Neurotrophic factors, such as BDNF, are involved in regulating many functions carried out by the HPA axis (7). BDNF and its receptor, TrkB, are both expressed in the PVN (8, 9) and many other brain regions, and display dramatic effects upon neuroprotection and synaptic plasticity (10, 11). Despite studies that indicate that BDN...

Nerve Growth Factor(s) Mediated Hypothalamic Pituitary Axis Activation Model in Stress Induced Genesis of Psychiatric Disorders

“…A study by Lambert et al has shown in primary rat cortical neurons that BDNF induces structural change at GR gene (phosphorylation at serine 155 and 287) and causes significant change in its transcriptome (125). Similar evidence for essential glucocorticoid-BDNF interaction for stress response have also been noted in hypothalamus controlling CRH synthesis at PVN (114). A schematic depiction of NGFs mediated hippocampal-HPA axis regulation in normal health and chronic restraint stress is presented in Fig.…”

“…NGFs show activity and stress based synthesis in various brain regions involved in stress response regulation (1,105,114) and the involved brain regions are known to differentially regulate HPA axis. For example, prefrontal cortex and hippocampus are known to inhibit but amygdala excites it (115).…”

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

“…Experiments on GR knockout mice revealed that neurosecretory CRH synthesis is tonically repressed by glucocorticoids even under basal (no stress) conditions (Kretz et al 1999). To further support the direct inhibitory effect on CRH gene, it has been recently shown that targeted disruption of GR signaling within the PVH results in upregulation of CRH mRNA levels (Jeanneteau et al 2012).…”

Expression of NGF, BDNF and their receptors in subcutaneous adipose tissue of lactating cows

“…2). The BDNF can modulate the hypothalamic-pituitaryadrenal axis (HPA) activity, leading to an alteration of energy metabolism, eating behavior and obesity (Jeanneteau et al, 2012). Furthermore, the corticotrophin-releasing hormone (CRH) is positively regulated by BDNF through its receptor TrkB via cAMP response element-binding protein (CREB) signaling (Jeanneteau et al, 2012;Fargali et al, 2012).…”

“…The BDNF can modulate the hypothalamic-pituitaryadrenal axis (HPA) activity, leading to an alteration of energy metabolism, eating behavior and obesity (Jeanneteau et al, 2012). Furthermore, the corticotrophin-releasing hormone (CRH) is positively regulated by BDNF through its receptor TrkB via cAMP response element-binding protein (CREB) signaling (Jeanneteau et al, 2012;Fargali et al, 2012). These actions are possible because BDNF and its receptor are expressed in the hypothalamic paraventricular nucleus (PVN) as well as in other hypothalamic areas such as ventromedial hypothalamic nucleus (VMN), the dorsomedial hypothalamic nucleus (DMN), and the lateral hypothalamic area (LH) (Conner et al, 1997).…”