Brain mechanisms of HPA axis regulation: neurocircuitry and feedback in context Richard Kvetnansky lecture

Abstract

Regulation of stress reactivity is a fundamental priority of all organisms. Stress responses are critical for survival, yet can also cause physical and psychological damage. This review provides a synopsis of brain mechanisms designed to control physiological responses to stress, focusing primarily on glucocorticoid secretion via the hypothalamo-pituitary-adrenocortical (HPA) axis. The literature provides strong support for multi-faceted control of HPA axis responses, involving both direct and indirect actions at paraventricular nucleus (PVN) corticotropin releasing hormone neurons driving the secretory cascade. The PVN is directly excited by afferents from brainstem and hypothalamic circuits, likely relaying information on homeostatic challenge. Amygdala subnuclei drive HPA axis responses indirectly via disinhibition, mediated by GABAergic relays onto PVN-projecting neurons in the hypothalamus and bed nucleus of the stria terminalis (BST). Inhibition of stressor-evoked HPA axis responses is mediated by an elaborate network of glucocorticoid receptor (GR)-containing circuits, providing a distributed negative feedback signal that inhibits PVN neurons. Prefrontal and hippocampal neurons play a major role in HPA axis inhibition, again mediated by hypothalamic and BST GABAergic relays to the PVN. The complexity of the regulatory process suggests that information on stressors is integrated across functional disparate brain circuits prior to accessing the PVN, with regions such as the BST in prime position to relay contextual information provided by these sources into appropriate HPA activation. Dysregulation of the HPA in disease is likely a product of inappropriate checks and balances between excitatory and inhibitory inputs ultimately impacting PVN output.

Keywords: HPA Axis; amygdala; bed nucleus of the stria terminalis; glucocorticoids; hippocampus; prefrontal cortex.

Figure 1.

Neural mechanisms of acute stress inhibition. As noted, the CRH containing region of the medial parvocellular paraventricular nucleus (PVN) receives substantial inhibitory input from hypothalamic (medial preoptic nucleus (mPOA), dorsomedial nucleus (DMH), periPVN zone) and medial forebrain structures (bed nucleus of the stria terminalis (BST)). The regions receive excitatory inputs from forebrain structures such as the IL infralimbic (IL) and prelimbic (PL) cortices and the ventral subiculum (vSUB), which are thought to mediate trans-synaptic inhibition of HPA axis stress responses. Upstream limbic pathways may also limit drive of the PVN by way of local, intranuclear inhibition of HPA axis excitatory circuits, e.g., the nucleus of the solitary track (NTS) and/or posterior hypothalamus (PH). Open red circles and red lines: inhibitory (e.g., GABAergic) neurons/connections; closed green circles and green lines: excitatory (e.g., glutamatergic) neurons and connections. Figure modified from (Herman et al., 2005), with permission, and were constructed using Biorender software (www.biorender.com).

Figure 2.

Neural mechanisms of acute stress excitation. Data suggest PVN neurons can be driven by neurons communicating homeostatic challenge, including the nucleus of the solitary tract (NTS), among others. The PVN also has numerous connections with hypothalamic nuclei and subcortical telencephalic structures, including excitatory (PH, anterior BST) and inhibitory (POA, DMH, periPVN, anteroventral BST, posterior BST) inputs. Inhibitory input to the PVN provides a substantial inhibitory tone, which can be disrupted by inhibition from upstream sites such as the medial and central amygdaloid nuclei (MeA, CeA), providing a mechanism for trans-synaptic disinhibition from the limbic forebrain. There is also some evidence suggesting that some cortical regions, such as the infralimbic region (IL) of the medial prefrontal cortex, may also provide trans-synaptic excitation, perhaps via relays in the brainstem. There is less evidence for excitatory input from other forebrain stress circuits, such as the ventral subiculum (vSUB), prelimbic division of the mPFC or paraventricular thalamus. Input from limbic regions may also access the PVN by interaction with local interneurons in the PVN surround (periPVN). See Figure 1 legend for abbreviations and symbol definitions). Figure modified from (Herman et al., 2005), with permission, and were constructed using Biorender software (www.biorender.com).

Figure 3.

Neural mechanisms controlling chronic stress regulation of the HPA axis. Pathways responsible for drive of the HPA axis under chronic stress are not as well understood as those mediating acute response. There is strong evidence that the PVT, which is not involved in acute stress excitation or inhibition, is required for both stress habituation and stress facilitation, suggesting a role in communicating stress chronicity. Importantly, the PVT has extensive reciprocal projections to the IL, PL and vSUB, as well as projections to the area of the BST. Neuronal activation studies indicate the existence of a small network of structures that are differentially activated by chronic unpredictable stress (relative to restraint), including the IL, PL, PH and NTS. The NTS itself appears to contribute to chronic stress-related HPA drive via peptidergic neurons. Importantly, the PH and NTS are both connected with the IL, and both mediate acute stress excitation, suggesting a possible integrated circuit mediating chronic stress drive. Finally, chronic stress increases tone of CRH-expressing stress circuitry in the CeA, suggesting that CRH systems may be recruited by chronic stress and participate in HPA axis hyperdrive. See Figure 1 legend for abbreviations and symbol definitions). Figure modified from (Herman et al., 2005), with permission, and were constructed using Biorender software (www.biorender.com).