Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex

Abstract

Hindbrain neurons in the nucleus of the solitary tract (NTS) are critical for regulation of hypothalamo-pituitary-adrenocortical (HPA) responses to stress. It is well known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotropic corticotropin-releasing hormone (CRH) neurons and control activation of HPA axis responses to acute systemic (but not psychogenic) stressors. Norepinephrine (NE) signaling via alpha1 receptors is primarily excitatory, working either directly on CRH neurons or through presynaptic activation of glutamate release. However, there is also evidence for NE inhibition of CRH neurons (possibly via beta receptors), an effect that may occur at higher levels of stimulation, suggesting that NE effects on the HPA axis may be context-dependent. Lesions of ascending NE inputs to the paraventricular nucleus attenuate stress-induced ACTH but not corticosterone release after chronic stress, indicating reduction in central HPA drive and increased adrenal sensitivity. Non-catecholaminergic NTS glucagon-like peptide 1/glutamate neurons play a broader role in stress regulation, being important in HPA activation to both systemic and psychogenic stressors as well as HPA axis sensitization under conditions of chronic stress. Overall, the data highlight the importance of the NTS as a key regulatory node for coordination of acute and chronic stress.

Keywords: Corticotropin-releasing hormone; Glucagon-like peptide-1; Glucocorticoids; Norepinephrine; Paraventricular nucleus; Prolactin-releasing peptide.

Figure 1

Schematic of nucleus of the solitary tract (NTS) pathways regulating paraventricular nucleus (PVN) drive. Neurons in the PVN release CRH into blood vessels in the median eminence (ME), initiating the neuroendocrine cascade culminating in activation of HPA axis responses. Norepinephrine (NE) neurons in the NTS project to the PVN and act to excite HPA axis responses to systemic stressors. Under conditions of chronic stress, this projection appears to enhance stress reactivity by increasing adrenal sensitivity to ACTH, perhaps via effects on the sympathetic nervous system. A considerable population of NTS NE neurons co-express prolactin-releasing peptide, which may work in concert with NE to modulate PVN output. A separate population of NTS neurons express glucagon-like peptide 1 (GLP-1), along with glumate (Glu). These neurons play a broader role in integration of acute HPA axis responses, serving to drive both psychogenic and system responses. In addition, these neurons appear to directly modulate sensitization of PVN responses to chronic stress.