Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

Abstract

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety-and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxietyand depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety-and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.psychosocial stress | affective disorders D epression affects one in six individuals worldwide, resulting in a substantial personal and economic burden. Although the precise etiology of depression is not known, a constellation of findings suggests that predisposing factors, including individual genetic makeup, interacting with stressful life events, can precipitate depressive disorders. Currently available antidepressants are effective at treating both depression and anxiety, but the therapeutic response remains variable. Only 30% of patients achieve remission during the first line of treatment with a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine, and many patients show only limited improvements. Thus, it is critical to identify the neurobiological factors that predispose individuals to stress susceptibility and depression to understand the etiology and develop therapeutics for the disorder.A recent human imaging study has suggested that acetylcholine (ACh) levels are elevated in patients who are actively depressed, as measured by occupancy of nicotinic receptors throughout the brain, and remain high in patients who have a history of depression (1). In addition, de...

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…Contrary to what was observed when AChE was knocked down in the hippocampus (Mineur et al, 2013), knockdown in the amygdala had no effect on behavior in the tail suspension test (control vs AChE knockdown: 175 ± 24.75 vs 195 ± 25.24 s, Fo1), nor did it affect c-fos expression (control vs AChE knockdown: 110 ± 34.4 vs 87 ± 37.4 counted cells per section, Fo1). We then determined whether knockdown of the α7 or β2 nAChR subunit in the amygdala could reverse the effect of systemic antagonism of AChE activity by physostigmine.…”

“…Behavioral tests were conducted in sequence, with 24-48 h between each assay, as previously described (Mineur et al, 2013) and based on published recommendations. For local infusion experiments, only the tail suspension test was performed as the protruding cannula was incompatible with other behavioral tests.…”

“…CD1 mice were selected for aggressive behavior as described previously (Mineur et al, 2013(Mineur et al, , 2015. On the initial defeat day, each C57BL/6J mouse was placed into a CD1 aggressor mouse home cage.…”

“…Recent human SPECT imaging studies show that depressed unipolar and bipolar subjects have increased levels of ACh throughout the brain (Saricicek et al, 2012;Hannestad et al, 2013). In humans, blocking the degradation of ACh can induce depressive symptoms even in individuals with no history of illness (Janowsky et al, 1972;Risch et al, 1981), whereas in mice, blocking ACh breakdown in the hippocampus alone is sufficient to induce depression-and anxiety-like behaviors (Mineur et al, 2013). Finally, activity of the medial habenula-IPN pathway (a region rich in α3β4 nAChRs; Gotti et al, 2006) is also critical for the control of anxiety induced by nicotine withdrawal (Zhao-Shea et al, 2015) and contributes to the aversive properties of self-administered nicotine through nAChRs containing the α5 subunit (Fowler et al, 2011).…”

“…Acetylcholine signals through muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively) and many studies of depression have focused on mAChR signaling (Cannon et al, 2011;Riemann et al, 1994); however, blockade of either mAChRs or nAChRs can reverse the depression-like effects of increased cholinergic signaling in mice (Mineur et al, 2013) and it is likely that multiple receptors can mediate the effects of cholinergic signaling on depression (Drevets et al, 2013). The recent failure of a large clinical trial (Vieta et al, 2013) suggests that global antagonism of nAChRs will not be a viable strategy for antidepressant development; however, small human (Philip et al, 2009), and a number of rodent studies Rollema et al, 2009) suggest that targeting specific nAChR subtypes may be a potential strategy for treating depression.…”