Impact of Chronic Stress on the Spatial Learning and GR-PKAc-NF-κB Signaling in the Hippocampus and Cortex in Rats Following Cholinergic Depletion
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.
KeywordsCholinergic neuron Stress Glucocorticoid receptor Nuclear factor-kappa B Spatial memory
This study was funded by the National Research Foundation of Korea grants 2011-0015725 and 2015M3C7A1031395 to J.S.H.
S.Y.L. and J.S.H. designed the research; S.Y.L. and W.H.C. performed the research; S.Y.L. and J.S.H. analyzed the data; S.Y.L. and J.S.H. wrote the paper.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
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