Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant

Abstract

The adult brain is capable of adapting to internal and external stressors by undergoing structural plasticity, and failure to be resilient and preserve normal structure and function is likely to contribute to depression and anxiety disorders. While the hippocampus has provided the gateway for understanding stress effects on the brain, less is known about the amygdala, a key brain area involved in the neural circuitry of fear and anxiety. Here, in mice more vulnerable to stressors, we demonstrate structural plasticity within the medial and basolateral regions of the amygdala in response to prolonged 21day chronic restraint stress (CRS). Three days before the end of CRS, treatment with the putative, rapidly acting antidepressant, acetyl-L-carnitine (LAC) in the drinking water opposed the direction of these changes. Behaviorally, the LAC treatment during the last part of CRS enhanced resilience, opposing the effects of CRS, as shown by an increased social interaction and reduced passive behavior in a forced swim test. Furthermore, CRS mice treated with LAC show resilience of the CRS-induced structural remodeling of medial amygdala (MeA) stellate neurons. Within the basolateral (BLA) amygdala, LAC did not reduce, but slightly enhanced, the CRS-increased length and number of intersections of pyramidal neurons. No structural changes were observed in MeA bipolar neurons, BLA stellate neurons, or in lateral amygdala (LA) stellate neurons. Our findings identify MeA stellate neurons as an important component in the responses to stress and LAC action and show that LAC can promote structural plasticity of the MeA. This may be useful as a model for increasing resilience to stressors in at risk populations.

Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance

“…Although stress is well recognized as a key factor in precipitating a variety of disorders (29), including depression, the role of stress in altering the responsiveness to antidepressants is less known. Recently, we showed that stress opens windows of epigenetic plasticity in atrisk individuals (22) and these temporary slots of plasticity can be manipulated by LAC pharmacological intervention to increase resilience, whereby structural plasticity of the medial amygdala stellate neurons plays an important role (30). Here, our findings in endogenously depressed FSL subjected to an acute stress during LAC treatment show that an individual responsiveness to stress needs to be factored in toward the development of better therapeutics.…”

Epigenetic mechanisms of major depression: Targeting neuronal plasticity

“…This is the first evidence for metabolic signaling to chromatin in the brain and indicates a critical role for this type of signaling in cognitive function. Molecules that affect energy homeostasis, such as the epigenetic molecule acetyl‐ l ‐carnitine that is produced during normal metabolism, affect and hence provide rapid antidepressant‐like activity . These results suggest that metabolic pathways are linked to epigenetic regulation of genes associated with depression.…”

Stress at work: Factors associated with cognitive disorganisation among private sector professionals

“…More recently, attention has been given to observing structural changes to the amygdala, the area of the brain involved in fear and anxiety, as a result of prolonged exposure to stress (Lau et al, 2017). This supports findings that stress leads to changes in the brain’s neurocircuitry, with particular regard to the amygdala and pre-frontal region (Mah et al, 2016).…”