Genetic Dissection of the Neuroendocrine and Behavioral Responses to Stressful Challenges

Abstract

Dysregulation of the stress response is implicated in many psychopathologies. Data gathered over the past two decades have proposed a rather dualistic view of the central corticotropin-releasing factor (CRF)-urocortin system. Originally, it was thought that CRF/CRF receptor type 1 (CRFR1) signaling mediated stressinitiated effects and increased anxiety-like behavior, whereas activation of urocortins/CRFR2 ensured adequate recovery from stress and restoration of homeostasis. However, this view was based on data gained from genetically modified mouse models and pharmacological approaches; now, with the emergence of new and more specific biological tools, it has become clear that this is an over-simplistic proposal. It is becoming apparent that the function of the CRF-urocortin system's components relies profoundly on the spatial and temporal patterns of activity of the CRF family members. Here, we provide an overview of recent work that proposes a more dynamic, modulatory role for the CRF system's central pathways in the modulation of stress-linked behaviors. Recent findings suggest that the CRF system's actions are brain-region specific and dependent on the type of neuronal cell involved.In 1955, Hans Seyle recognized that the hypothalamic-pituitary-adrenal (HPA) axis orchestrates the stress response (Selye 1955). However, it took until 1981 for the structure of its principal regulatory peptide, corticotropin-releasing factor (CRF), to be characterized (Vale et al. 1981). Neurons in the paraventricular nucleus (PVN) of the hypothalamus secrete CRF, which binds to receptors in the pituitary, which, in turn, secretes adrenocorticotropic hormone (ACTH) into the circulation. The circulating ACTH binds at the adrenal cortex stimulating the synthesis and secretion of glucocorticoids: cortisol in humans and corticosterone in rodents. Glucocorticoids are the downstream biological effector of the neuroendocrine stress response and also provide negative feedback in the HPA axis.

Neuropeptidergic Control of an Internal Brain State Produced by Prolonged Social Isolation Stress

“…One interesting possibility would be that CRH controls the acute effects of stress, whereas Tac2 controls the more long-term effects of social isolation. This would be consistent with the prevailing view of CRH in controlling acute stress (Chen 2016), and it would also explain why CRH antagonists have failed at relieving the effects of long-term stress in clinical trials (Spierling and Zorrilla 2017).…”

“…One such candidate molecule is corticotropin releasing hormone (CRH). Given CRH's well-known role in mediating stress (Kormos and Gaszner 2013;Witkin et al 2014;Kash et al 2015;Chen 2016), it is natural to think that it too might underlie the effects of prolonged isolation stress.…”

A non-coding CRHR2 SNP rs255105, a cis-eQTL for a downstream lincRNA AC005154.6, is associated with heroin addiction

“…CRH has two receptors: CRHR1 and CRHR2 that share ~70% of their amino acid sequences, but differ in their localization and binding affinities. They modulate anxiety-like behavior in a brain region- and cell-type dependent manner [ 25 ]. There is limited data on CRFR2 signaling but its effects seem to be plastic and dependent on past experience and ligand quantity.…”

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

“…Following a ten-minute period of 8 performance of our models by creating a pair of "data similarity scores" quantifying model similarity to 143 data in terms of time-evolving dynamics and stimulus specificity (Fig 4i-k). 144 Persistent defensive states are typically attributed to neuroendocrine mechanisms, such as 145 activation of the HPA axis [7][8][9] . Here we provide the first evidence that persistent neural activity can 146 contribute causally to such persistent internal states.…”