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].

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