Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress.

The hypothalamic-pituitary-adrenal axis is a pivotal component of an organism's response to stressful challenges, and dysfunction of this neuroendocrine axis is associated with a variety of physiological and psychological pathologies. We found that corticotropin-releasing factor type 1 receptor within the paraventricular nucleus of the hypothalamus is an important central component of hypothalamic-pituitary-adrenal axis regulation that prepares the organism for successive exposure to stressful stimuli.

CRFR1 in AgRP Neurons Modulates Sympathetic Nervous System Activity to Adapt to Cold Stress and Fasting.

Signaling by the corticotropin-releasing factor receptor type 1 (CRFR1) plays an important role in mediating the autonomic response to stressful challenges. Multiple hypothalamic nuclei regulate sympathetic outflow. Although CRFR1 is highly expressed in the arcuate nucleus (Arc) of the hypothalamus, the identity of these neurons and the role of CRFR1 here are presently unknown. Our studies show that nearly half of Arc-CRFR1 neurons coexpress agouti-related peptide (AgRP), half of which originate from POMC precursors. Arc-CRFR1 neurons are innervated by CRF neurons in the hypothalamic paraventricular nucleus, and CRF application decreases AgRP(+)CRFR1(+) neurons' excitability. Despite similar anatomy in both sexes, only female mice selectively lacking CRFR1 in AgRP neurons showed a maladaptive thermogenic response to cold and reduced hepatic glucose production during fasting. Thus, CRFR1, in a subset of AgRP neurons, plays a regulatory role that enables appropriate sympathetic nervous system activation and consequently protects the organism from hypothermia and hypoglycemia.