Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses

Abstract

In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nuclei also play an important role in neuroendocrine responses to psychogenic stressors mediated by the hypothalamic-pituitary-adrenocortical axis. Further, these nuclei integrate neuroendocrine responses with stress-related behaviors, significantly impacting mood and anxiety. The current review focuses on the prominent brainstem monosynaptic inputs to the endocrine paraventricular hypothalamic nucleus (PVN), including the periaqueductal gray, raphe nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract (NTS). The NTS is a particularly intriguing area, as the region contains multiple cell groups that provide neurochemically-distinct inputs to the PVN. Furthermore, the NTS, under regulatory control by glucocorticoid-mediated feedback, integrates affective processes with physiological status to regulate stress responding. Collectively, these brainstem circuits represent an important avenue for delineating interactions between stress and health.

Keywords: Glucocorticoid; Hypothalamic-pituitary-adrenocortical axis; Nucleus of the solitary tract; Paraventricular hypothalamic nucleus.

Figure 1. Anatomical diagram of PVN-projecting brainstem nuclei

Sagittal rat brain schematic adapted from Swanson 2004 indicating the relative location of major PVN-projecting brainstem regions. The top panel illustrates PVN (light brown), PAG (red), raphe nuclei (DR and MnR; light blue), PBN (orange), LC (cerulean blue), and NTS (green). Panel A depicts a coronal section through the midbrain as indicated by dashed line A. This coronal map adapted from Swanson 2004 indicates the location of the PAG, DR, and MnR relative to the aq. Panel B illustrates a coronal section corresponding to dashed line B and outlines the PBN and LC in relation to the 4v. Panel C is a schematic coronal section through the caudal medulla (dashed line C) depicting the location of the NTS relative to the cc. List of abbreviations aq: cerebral aqueduct, cc: central canal, DR: dorsal raphe, LC: locus coeruleus, MnR: median raphe, NTS: nucleus of the solitary tract, PAG: periaqueductal gray, PBN: parabrachial nuclei, PVN: paraventricular nucleus, 4v: fourth ventricle.

Figure 2. Summary of NTS as nexus for integrating descending limbic input with ascending interoceptive information to generate behavioral, neuroendocrine, and autonomic stress responses

Regions of the limbic forebrain including the PFC and amygdala, among others, project to the NTS. The NTS also expresses a high density of glucocorticoid receptors and receives ascending visceral signals related to physiological status. At the level of the NTS, this information is integrated and multiple output circuits including NE/Glu and GLP-1/Glu coordinate organismal adaptation to adversity. List of abbreviations GLP-1: glucagon-like peptide-1, Glu: glutamate, NE: norepinephrine, NTS: nucleus of the solitary tract, PFC: prefrontal cortex,