Impact of Chronic Stress on the Spatial Learning and GR-PKAc-NF-κB Signaling in the Hippocampus and Cortex in Rats Following Cholinergic Depletion

Abstract

Studies have shown that the removal of the cholinergic innervation to the hippocampus induces dysfunction of the hypothalamic-pituitary-adrenocortical axis and decreases the number of glucocorticoid receptors (GRs). Subsequent studies have revealed that the loss of cholinergic input to the hippocampus reduces the expression of GRs and activates nuclear factor-kappa B (NF-κB) signaling through interactions with the cytoplasmic catalytic subunit of protein kinase A (PKAc). We examined the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex. Male Sprague-Dawley rats received 192 IgG-saporin injections to selectively eliminate cholinergic neurons in their basal forebrain. Two weeks later, rats were subjected to 1 h of restraint stress per day for 14 days. Rats subjected to both chronic stress and cholinergic depletion showed more severe memory impairments compared to those that received either treatment alone. The reduction in nuclear GR levels induced by cholinergic depletion was unaffected by chronic stress. The activation of NF-κB signaling in the hippocampus and the cerebral cortex induced by cholinergic depletion was augmented by chronic stress, resulting in the increased expression of pro-inflammatory markers, such as inducible nitric oxide synthase and cyclooxygenase-2. The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer's disease to stress since activation of NF-κB is associated with stress.

Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors

“…Our results that chronic stress increases levels of ROS in the hippocampus are in agreement with previous studies. Studies have also shown that chronic stress enhances NF-κB signaling induced by cholinergic depletion in the hippocampus, thereby increasing the expression of pro-inflammatory factors (Lee et al, 2018). This is in line with our current finding that chronic stress induces NF-κB expression and promotes NF-κB translocation to the nucleus in the hippocampus.…”

Depressive Symptom Dimensions and Their Association with Hippocampal and Entorhinal Cortex Volumes in Community Dwelling Older Adults

“…Depression, as has largely been explained in terms of excess glucocorticoid production which proposes that depression is a type of stress response involving a chronic production of glucocorticoids which implicate the hypothalamic, pituitary, and limbic systems ( Sheline, 2011 ). Several studies have shown that cumulative exposure to glucocorticoids has been related to hippocampal (i.e., a core limbic structure) volume reduction and impairments in hippocampal-dependent cognitive tasks in rodents ( Woolley et al, 1990 ; Watanabe et al, 1992 ; Lee et al, 2017 ; Nguyen et al, 2018 ). Studies in humans have shown similar findings in healthy older adults who report high levels of stress concurrent with high levels of cumulative cortisol levels ( Newcomer et al, 1999 ; Gold, 2015 ; Radley et al, 2015 ).…”

Shenyu ningshen tablet reduced neuronal damage in the hippocampus of chronic restraint stress model rat by inhibiting A1-reactive astrocytes

“…In addition, the CRS model can also affect the immune system of animals, and studies have shown that chronic stress enhances NF-κB signaling in the hippocampus, thereby increasing the expression of pro-inflammatory factors [ 29 ]. Here, we found that the SYNS treatment groups improved the inflammatory response caused by the CRS model, and the differences between the model group and the medication groups were observed in the subsequent hippocampal pathomorphological observation, suggesting anti-inflammatory effect of SYNS to a certain degree.…”