Review
The molecular physiology of CRH neurons

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Abstract

Corticotropin releasing hormone (CRH) is essential for stress adaptation by mediating hypothalamic–pituitary–adrenal (HPA) axis, behavioral and autonomic responses to stress. Activation of CRH neurons depends on neural afferents from the brain stem and limbic system, leading to sequential CRH release and synthesis. CRH transcription is required to restore mRNA and peptide levels, but termination of the response is essential to prevent pathology associated with chronic elevations of CRH and HPA axis activity. Inhibitory feedback mediated by glucocorticoids and intracellular production of the repressor, Inducible Cyclic AMP Early Repressor (ICER), limit the magnitude and duration of CRH neuronal activation. Induction of CRH transcription is mediated by the cyclic AMP/protein kinase A/cyclic AMP responsive element binding protein (CREB)-dependent pathways, and requires cyclic AMP-dependent nuclear translocation of the CREB co-activator, Transducer of Regulated CREB activity (TORC). This article reviews current knowledge on the mechanisms regulating CRH neuron activity.

Highlights

► Activation of the CRH neuron by stress results in CRH release coupled to transient induction of transcription. ► All signaling pathways activated by stress in the CRH neuron phosphorylate CREB but only cyclic AMP induces CRH transcription. ► Phosphorylation of CREB and its binding to the CRH promoter CRE is not sufficient for initiation of CRH transcription. ► CRH transcription requires cyclic AMP-dependent activation and nuclear translocation of the CREB co-activator, TORC. ► Glucocorticoid feedback and intraneuronal autoregulatory mechanisms limit the duration of CRH transcriptional responses.

Introduction

Maintenance of homeostasis requires continuous adaptation to internal and external disturbances or stressors. Adaptive responses include activation of the autonomic nervous system, conducing to increase in cardiovascular and respiratory activity; behavioral changes leading to arousal, defense and escape reactions, and endocrine responses, of which the most important is activation of the hypothalamic–pituitary–adrenal (HPA) axis [115]. The later is mostly directed to increase energy availability. In addition, stress results in inhibition of non-essential functions such as gastrointestinal motility and reproduction. These stress responses are coordinated in the brain through neural pathways leading to the release of neurotransmitters and neuropeptides in the hypothalamus and limbic areas.

The 41-amino acid hypothalamic peptide, Corticotropin-releasing hormone (CRH), stimulates the secretion and synthesis of adrenocorticotropic hormone by the anterior pituitary and is the main regulator of HPA axis activity during stress. Soon after its isolation and characterization in 1981, it became clear from studies in experimental animals and in humans that in addition to stimulating ACTH secretion, CRH regulates autonomic and behavioral effects of stress, acting as an important integrator of stress responses [186], [51], [64], [127], [138]. The main source of CRH mediating HPA axis regulation is the hypothalamic paraventricular nucleus (PVN) but in addition the peptide is present at several extra-hypothalamic sites in the brain, most of them related to the limbic system and stress circuitry. This article will review current knowledge on the physiological regulation of the CRH neuron in the hypothalamic PVN, focusing on the molecular mechanisms for activation and termination of the response. While some of the mechanisms can also apply to extra-hypothalamic CRH in the brain, most studies to be discussed focus on the regulation of the hypothalamic CRH neuron.

Section snippets

The CRH neuron

The highest concentration of CRH neurons is found in the hypothalamic PVN [176]. As shown in Fig. 1 three major subdivisions have been described in the this nucleus [174]: (1) anterior and medial–dorsal parvocellular CRH neurons with axons projecting to hypophyseal portal capillaries in the external zone of the median eminence; CRH neurons also express small amounts of VP and release VP to the pituitary portal circulation in response to stress. These neurons are classified as parvocellular

Development of the hypothalamic CRH neuron

Studies in rats using in situ hybridization and immunohistochemistry have shown CRH mRNA expression in the PVN at embryonic day 17 (E17) [14], [53], and CRH peptide can be first detected at E18 [20], [34]. In the mouse, CRH is first detected in the PVN at E13.5 [73]. Several factors are necessary for the development and differentiation of hypothalamic neurons but the specific factors responsible for differentiation of the CRH neuron are unknown. The most important factor for hypothalamic

Regulation of the hypothalamic CRH neuron

Activity of the hypothalamic CRH neuron shows different patterns under resting and stress conditions. Activity is low in basal conditions but undergoes marked circadian variations, as judged by day/night changes in immunorective CRH and primary transcript. Circadian variations of CRH neuron activity are driven by the suprachiasmatic nucleus and likely mediate the characteristic circadian pattern of HPA axis activity [28], [132]. Studies in rats have shown that changes in CRH primary transcript

Signaling pathways regulating the CRH neuron

Afferent inputs to the PVN trigger the release of a number of neurotransmitters and neuropeptides such as noerepinephrine, glutamate, GABA, serotonin, angiotensin II, PACAP, CRH itself and other peptides (see Section 4.5). These factors interact with receptors in the CRH neuron triggering intracellular signal-transduction pathways (Fig. 4). The main neurotransmitters released in the PVN during stress are norepinephrine and glutamate [59], [142]. Norepinephrine acts on alpha adrenergic receptors

Regulation of CRH transcription

Activation of CRH neurons in the PVN during stress leads to rapid release of stored peptide (within seconds) an event which is usually followed by de novo synthesis of peptide in order to restore releasable pools in the nerve endings of the median eminence. Synthesis of the precursor involves activation of gene transcription with formation of primary transcript or heteronuclear RNA, within minutes, followed by splicing of the intron and formation of mature mRNA, which starts to increase within

Concluding remarks

Corticotropin releasing hormone (CRH) produced by parvocellular neurons of the hypothalamic PVN is the major regulator of hypothalamic–pituitary–adrenal (HPA) axis activity, as well as behavioral and autonomic responses to stress. Most evidence on the physiological actions and regulation of CRH comes from studies in rodents. However, information from clinical studies in conjunction with the high homology between rat, mouse and human CRH gene, and the similar distribution of CRH peptide and its

Acknowledgments

This work was supported by the Intramural Research Program, National Institute of Child Health and Human Development.

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