Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction

Abstract

Background Multiple neuropsychiatric disorders, e.g., depression, are linked to imbalances in excitatory and inhibitory neurotransmission and prefrontal cortical dysfunction, and are concomitant with chronic stress. Methods We used electrophysiologic (n = 5–6 animals, 21–25 cells/group), neuroanatomic (n = 6–8/group), and behavioral (n = 12/group) techniques to test the hypothesis that chronic stress increases inhibition of medial prefrontal cortex (mPFC) glutamatergic output neurons. Results Using patch clamp recordings from infralimbic mPFC pyramidal neurons, we found that chronic stress selectively increases the frequency of miniature inhibitory postsynaptic currents with no effect on amplitude, which suggests that chronic stress increases presynaptic gamma-aminobutyric acid release. Elevated gamma-aminobutyric acid release under chronic stress is accompanied by increased inhibitory appositions and terminals onto glutamatergic cells, as assessed by both immunohistochemistry and electron microscopy. Furthermore, chronic stress decreases glucocorticoid receptor immunoreactivity specifically in a subset of inhibitory neurons, which suggests that increased inhibitory tone in the mPFC after chronic stress may be caused by loss of a glucocorticoid receptor–mediated brake on interneuron activity. These neuroanatomic and functional changes are associated with impairment of a prefrontal-mediated behavior. During chronic stress, rats initially make significantly more errors in the delayed spatial win-shift task, an mPFC-mediated behavior, which suggests a diminished impact of the mPFC on decision making. Conclusions Taken together, the data suggest that chronic stress increases synaptic inhibition onto prefrontal glutamatergic output neurons, limiting the influence of the prefrontal cortex in control of stress reactivity and behavior. Thus, these data provide a mechanistic link among chronic stress, prefrontal cortical hypofunction, and behavioral dysfunction.

Neuroticism Traits Selectively Impact Long Term Illness Course and Cognitive Decline in Late-Life Depression

“…In children, neuroendocrine markers of stress and adversity at baseline (i.e., high cortisol) are predictive of smaller amygdala and hippocampal volumes and cognitive functioning (31, 32). The neurological sequelae of chronic stress is considered diffuse (33), consistent with the present and prior findings where high VS resulted in greater decline in global cognitive functioning and more than doubled the risk of clinical and neuropathological confirmed dementia (34). There may also be a threshold to which VS must cross to influence cognitive decline in LLD.…”

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors

“…mPFC GR suppression was also reported following non-alcohol-related chronic stress (McKlveen et al, 2016), suggesting that the mPFC GR suppression reported herein may be a manifestation of chronic HPA-axis activation, perhaps engaging opponent (e.g., desensitization, tolerance) mechanisms in the mPFC. Mifepristone, a GR antagonist, may inhibit the effects of chronically elevated CORT on such compensatory processes in the mPFC, leading to a relative increase in GR expression and function compared to placebo groups.…”

“…These mismatches suggests that the GR-mediated effects on ethanol self-administration (also) involve regions other than the mPFC, perhaps the nucleus accumbens and ventral tegmental area (Repunte-Canonigo et al, 2015). Instead, mPFC GR changes may contribute to other stress-related behaviors (McKlveen et al, 2016; Myers et al, 2014). Our study also shows similar changes in plasma peak CORT levels in CIE-ED and ED rats.…”

“…Glutamatergic inputs from the mPFC dampen amygdala output (Likhtik et al, 2005), and deficient GR responses in the mPFC could contribute to amplified stress responses (McEwen, 2012). Furthermore, chronic stress increases local GABA release in mPFC and inhibits glutamatergic projections from mPFC (McKlveen et al, 2016). Therefore, chronic alcohol intake-mediated HPA dysregulation (and perhaps the associated elevated CORT) may disinhibit the regions regulated by mPFC and thereby exacerbate stress-related behavior.…”

Paraventricular Hypothalamic Mechanisms of Chronic Stress Adaptation

“…Lentiviral knockdown of GR in the IL (but not prelimbic cortex) produces a marked potentiation of HPA axis and PVN Fos induction to a novel stress in animals exposed to CVS (91), a phenomenon linked to interneuron-mediated decreases in IL output (92). Implants of the GR antagonist mifepristone in the NTS inhibit PVN excitability following chronic stress, suggesting that the glucocorticoids may play a role in inhibiting the NTS drive to the PVN (93).…”