Figure 1.

The neuroendocrine (a), limbic (b), and brainstem (c) inter-related, stress-activated corticotropin releasing hormone (CRH) loops. (a) Stress-conveying signals rapidly activate immediate early genes in CRH-expressing neurons of the central nucleus of the amygdala (ACe). Rapid CRH release in the ACe is is thought to activate CRH expressing neurons in the hypothalamic paraventricular nucleus (PVN) to secrete CRH into the hypothalamo-pituitary portal system, inducing ACTH and glucocorticoid secretion from the pituitary and adrenal, respectively. In response to stress, CRH expression is also activated rapidly in these neurons. Glucocorticoids exert a negative feedback on PVN (directly and via hippocampus), yet activate CRH gene expression in the amygdala, potentially promoting further CRH release in this region. (b) Stressors involving ‘psychological’ or multi-modal elements activate the limbic circuit. This consists of ACe, which conveys information both to the hypothalamus and to the hippocampal formation via pathways that likely do not utilize CRH as a neurotransmitter. Within the hippocampus, CRH-expressing GABAergic interneurons (in purple) in the principal cell layers of the hippocampal CA1, CA3 and the dentate gyrus (DG) are positioned to control information flow in the major, tri-synaptic hippocampal pathway. (c) Sensory information regarding physical, somatic and visceral elements of stress is conveyed from sensory organs via a neuroanatomically defined brainstem pathway. Within this general circuit, a chemically defined loop, utilizing CRH (or a similar ligand) as a neurotransmitter which activates the CRF₂ receptor may be considered. This afferent pathway contributes to the integration of stress signals, resulting in behavioral and neuroendocrine responses. For panels (a) and (b), red and blue arrows denote established or putative potentiating and inhibitory actions, respectively. Thick arrows do not imply monosynaptic connections. For panel (c), blue frames indicate CRF₂ mRNA expression. Red shading over a region indicates the presence of CRH-expressing neurons. Red arrows denote established CRH-containing pathways. CEA = ACe-bed nucleus of the stria terminalis continuum; NTS = nucleus of the solitary tract; PBN = parabrachial nucleus; SCN = suprachiasmatic hypothalamic nucleus; PVT = thalamic paraventricular nucleus; VMH = ventromedial hypothalamic nucleus; MEA and BMA = medial and basomedial amygdalaoid nucleus, respectively. Panels (a) and (b) reprinted from Baram and Hatalski⁷⁹ with permission from Elsevier Science. Panel (c) reproduced from Eghbal-Ahmadi et al.⁴⁶ Copyright 1999 by the Society for Neuroscience.