An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders

Advances in translational neuroscience are pointing to a new paradigm for conceptualizing diagnosis and treatment of major morbidities, such as major depressive disorders (MDD), diabetes, and dementia [1]. Here we explore the emerging framework that focuses on the epigenetic actions of metabolic mediators on regulation of gene expression in brain regions controlling cognition and emotion as an approach to examine the systemic, as well as neural bases, of stress-related CNS disorders.

Central to this epigenetic framework linking neural and systemic functions is the concept of allostasis (adaptation) and allostatic load (pathophysiology) [1]. This concept emphasizes that endogenous mediators for adaptation contribute to pathologies, including MDD, when activated persistently or dysregulated under circumstances of toxic stress and associated health-damaging behaviors [1]. There is an increasing scientific consensus to support a connection between systemic illness and MDD, a disorder still primarily seen as brain based. Recently, we reported decreased plasma levels of acetyl-L-carnitine (LAC) in two cohorts of patients suffering with MDD [2]. The LAC deficiency was greater with stronger severity, earlier disease onset and treatment-resistant-depression, which was associated with childhood trauma [2]. In rodent models, targeting the deficiency in LAC by supplementation of exogenous LAC leads to antidepressant-like responses after a few days of administration, while standard antidepressants require multiple weeks [3,4,5]. LAC is an endogenous molecule with a plethora of biological functions important for brain plasticity and systemic metabolism relevant to stress and pathophysiology of MDD [3]. In rodent models with sustained activation of neural mineralocorticoid receptors (MR), supplementation of LAC increased acetylation of histone markers of activate gene transcription leading to increased expression of an inhibitor of spontaneous glutamate release, mGluR2, and the neurotrophin, BDNF [3, 4]. Normalizing glutamate overflow and BDNF expression ameliorated decreased dendritic branching in  the hippocampus and connected brain areas important for the pathophysiology of depression [1, 3,4,5,6].

Within this framework, it is important to emphasize that, at least in rodent models, low LAC serves as a biomarker of insulin resistance (IR), which was also ameliorated by supplementation with LAC [4]. IR is a modifiable inflammatory state that is often observed in patients suffering from MDD [1].  Furthermore  biomarkers of allostatic load involving imbalance in systemic stress-related physiology, and also including heightened release of proinflammatory cytokines and hypercortisolemia [1], are inversely correlated with hippocampal volume in patients with affective dysregulation [1].

These studies provide a foundation for future research of the mechanisms of LAC action related to the pathophysiological role of systemic physiology in a variety of stress-related CNS disorders, including MDD and interrelated disorders, such as Alzheimer’s disease. This framework can lead to identify therapeutic targets for development of mechanism-based treatment strategies tailored to biologically defined patient populations [5].


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Authors acknowledge funding support from the American Foundation for Suicide Prevention (AFSP), the Robertson Foundation and the Hope for Depression Research Foundation (HDRF) (to C.N. and B.S.M.).

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Correspondence to Carla Nasca or Bruce McEwen.

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Nasca, C., Rasgon, N. & McEwen, B. An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders. Neuropsychopharmacol 44, 235–236 (2019).

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