Stress – (self) eating: Epigenetic regulation of autophagy in response to psychological stress

Abstract

Autophagy is a constitutive and cytoprotective catabolic process. Aberrations in autophagy lead to a multitude of degenerative disorders, with neurodegeneration being one of the most widely studied autophagy‐related disorders. While the field has largely been focusing on the cytosolic constituents and processes of autophagy, recent studies are increasingly appreciating the role of chromatin modifications and epigenetic regulation in autophagy maintenance. Autophagy has been implicated in the regulation of neurogenesis, and disruption of neurogenesis in response to psychological stress is a proximal risk factor for development of neuropsychiatric disorders such as major depressive disorder (MDD). In this review, we will discuss the regulation of autophagy in normal neurogenesis as well as during chronic psychological stress, focusing on the epigenetic control of autophagy in these contexts, and also highlight the lacunae in our understanding of this process. The systematic study of these regulatory mechanisms will provide a novel therapeutic strategy, based on the use epigenetic regulators of autophagy to enhance neurogenesis and potentially alleviate stress‐related behavioral disorders.

Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

“…Alcohol withdrawal also increases the permeability of mitochondria to Ca+2 influx and increases the opening of the nonspecific permeability transition pore, which causes efflux of mitochondrial signals that induce neuron death (Rewal et al, 2005). At the same time, alcohol reduces the expression of inhibitory GABAA receptors, glutamic acid decarboxylase, which catalyzes the metabolism of glutamate to GABA (Proudfoot and Wilkins, 2017), and the protein that promotes GABA uptake into synaptic vesicles (Gruol et al, 2020), further pushing the signaling balance toward a hyperexcitatory state. Interestingly, the actions of alcohol that evoke glutamate excitotoxicity differentiate alcohol-induced cerebellar ataxia from many other forms, which have been shown to depend on glutamate excitotoxicity through a deficiency in the expression of glutamic acid decarboxylase, which catalyzes the metabolism of glutamate to GABA (Proudfoot and Wilkins, 2017).…”

“…Similarly, both psychosocial stress and direct application of cortisol increase the amyloid burden in a wide spectrum of animal models ( Justice, 2018 ). Chronic stress also reduces autophagy ( Puri and Subramanyam, 2019 ) and increases pro-inflammatory signaling ( Liu Y. Z. et al, 2017 ), affecting oxidative stress and mitochondrial function ( Jeanneteau et al, 2018 ; ( Liu Y.…”

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress

“…When dealing with the multiple effects of α1-ARs, we may summarize that LC-NE transmission increases VTA-DA neurons activity both directly and indirectly by acting on α1-ARs within i) VTA-DA neurons, ii) GABA and GLUT terminals within the VTA, iii) DA and GLUT terminals in the NAc and mPFC ( 36 – 63 ). A crucial role of α1-ARs stimulation in the VTA by LC-NE is documented for the neurochemical and reward processes of abused substances, which leads to an increase in DA release through LC projections to VTA and NAc shell ( 7 , 39 , 47 , 97 ).…”

“…BDNF and related autophagy ameliorate stress-induced behavioral and emotional alterations, suggesting that a direct association exists between autophagy impairment and BDNF deficiency ( 136 , 138 ). This is not surprising since autophagy has been implicated in the regulation of neurogenesis, which is altered by psychological stress and represents a risk factor for the development of mood/neuropsychiatric disorders ( 63 ). In line with this, the administration of either antidepressant drugs or the naturally occurring autophagy inducer resveratrol alleviates depressive-like behavior in mice models of CUMS or post-partum depression by increasing BDNF and autophagy-associated proteins ( 136 , 138 ).…”

“…This enlightens the mechanisms by which the functional balance of the nervous system and the related behavioral and cognitive capacities are guaranteed. A few studies directly explored the connection between stress and autophagy (62)(63)(64); most information can be drawn indirectly from psychostimulants research. In the present review we discuss the role of autophagy in brain catecholamine response to stress and those factors which may lead to dysregulation.…”