Chronic Stress-Induced Alterations of Dendritic Spine Subtypes Predict Functional Decrements in an Hypothalamo–Pituitary–Adrenal-Inhibitory Prefrontal Circuit

Abstract

Activation of the hypothalamo-pituitary-adrenal (HPA) axis plays a vital role in promoting adaptation during acute stress, but adverse effects of chronic stress may result from overactivity of this system. Recent evidence highlights a subdivision of GABAergic neurons within anterior bed nuclei of the stria terminalis (aBST) that integrates and relays inhibitory influences to HPA-effector neurons in paraventricular hypothalamus during acute stress, notably from medial prefrontal [prelimbic (PL)] and hippocampal [ventral subiculum (vSUB)] cortical fields. Here we localize the site and candidate mechanism of neuroplasticity within upstream regions of this inhibitory network after chronic variable stress (CVS). Rats bearing retrograde tracer injections in aBST underwent CVS for 14 d. Retrogradely labeled and unlabeled neurons in vSUB and PL were selected for intracellular dye filling, followed by three-dimensional imaging and analysis of dendritic arborization and spine morphometry. Whereas PL neurons displayed decreases in dendritic branching and spine density after CVS, aBST-projecting cells showed a selective loss of mature mushroom-shaped spines. In a follow-up experiment, CVStreated and control rats were exposed to a novel restraint challenge for assay of HPA activation and engagement of aBST-projecting cortical regions. CVS animals showed enhanced HPA output and decreased Fos activation in aBST-projecting PL neurons compared with acutely stressed controls. In contrast, vSUB failed to show any significant differences in structural plasticity or functional activation patterns after CVS. These findings define a mechanism whereby synaptic destabilization in the PL 3 aBST pathway may dampen its ability to impart inhibitory control over the HPA axis after chronic stress exposure.

A Basal Forebrain Site Coordinates the Modulation of Endocrine and Behavioral Stress Responses via Divergent Neural Pathways

“…Rats were randomly assigned to groups receiving injections of AAV5 (University of North Carolina Vector Core) expressing enhanced yellow fluorescent protein (eYFP) alone (YFP control groups), ChannelRhodopsin2(E123A)-eYFP [ChR2(E123A)-eYFP; ChR2 groups), or enhanced archaerhodopsin 3.0-eYFP (eArch3.0-eYFP; Arch groups) under the control of a pan-neuronal promoter (human synapsin-1, hSyn). avBST microinjection placements were based on published stereotaxic coordinates from us and others and were laterally biased to avoid transduction of adjacent preoptic and parastrial regions (Radley et al, 2009, Radley and Sawchenko, 2011. After AAV injection, fiber optics [200 m diameter, 0.37 numerical aperture (NA); Thorlabs) housed in steel ferrules (Plastics One) were lowered into place immediately dorsal to avBST somata (AP: Ϫ0.10 mm; ML: 2.70 mm; DV: Ϫ6.95 mm; 10°), avBST terminal fields in PVH (AP: Ϫ1.55 mm; ML: 1.65 mm; DV: Ϫ7.00 mm; 10°), or avBST terminal fields in vlPAG (AP: Ϫ7.45 mm; ML: 1.75 mm; DV: Ϫ5.50 mm; 10°) and secured with dental cement and surgical screws.…”

“…Two days before acute stress exposure, rats were implanted with indwelling jugular catheters based upon previous studies (Ericsson et al, 1994;Radley et al, 2006). Briefly, indwelling jugular catheters (polyethylene PE 50) containing sterile heparin-saline (50 U/ml) were implanted under isoflurane anesthesia.…”

“…Conversely, dysregulation of neural systems that control stress-adaptive functions has been increasingly implicated in stress-related psychiatric illness (Sheline et al, 1996;Drevets et al, 1997;Videbech and Ravnkilde, 2004;MacQueen and Frodl, 2011;Price and Drevets, 2012). The bed nuclei of the stria terminalis (BST) and its subdivisions have been advanced as critically important nodal points in integrating stress-related signals from the limbic forebrain to HPA effector neurons within the paraventricular nucleus of the hypothalamus (PVH).…”

“…The bed nuclei of the stria terminalis (BST) and its subdivisions have been advanced as critically important nodal points in integrating stress-related signals from the limbic forebrain to HPA effector neurons within the paraventricular nucleus of the hypothalamus (PVH). However, the existing body of evidence has led to conflicting interpretations of the precise role of BST in modulating stress-induced HPA output (Dunn, 1987;Casada and Dafny, 1991;Herman et al, 1994;Spencer et al, 2005;Choi et al, 2007;Choi et al, 2008;Radley et al, 2009;Radley and Sawchenko, 2011), highlighting the need to use more sophisticated approaches to clarify circuit mechanisms underlying stress adaptation. Similarly, there is a long-standing literature highlighting the role of BST in modulating approach-avoidance (e.g., fear, anxiety-like) behaviors (Walker et al, 2003;Davis et al, 2010;Jennings et al, 2013;Kim et al, 2013), although little attention has been given to its capacity to modulate behavioral coping during inescapable challenges.…”

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

“…Thus, the amygdala is a key nucleus that can integrate both stress and pain signaling Greenwood-Van Meerveld, 2010, 2012). Chronic stress promotes an increase in dendritic arborization and axonal connections in amygdaloid neurons, while simultaneously pruning dendrites and axon connections within the hippocampus and PFC (Woolley et al, 1990;Vyas et al, 2002;Mitra and Sapolsky, 2008;Radley et al, 2013). The result of the neuronal remodeling is increased prostress/ pronociceptive activity from the amygdala concurrent with decreased antistress/antinociceptive activity from the hippocampus and PFC, leading to chronic facilitation of both the HPA axis and pain.…”