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

Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less known. We found that an epigenetic and energetic agent, acetyl-l-carnitine (LAC, oral administration), rapidly rescued the depressive- and central and systemic metabolic-like phenotype of LAC-deficient Flinders Sensitive Line rats (FSL). After acute stress during LAC treatment, a subset of FSL continued to respond to LAC (rFSL), whereas the other subset did not (nrFSL). RNA sequencing of the ventral dentate gyrus, a mood-regulatory region, identified metabolic factors as key markers predisposing to depression (insulin receptors Insr, glucose transporters Glut-4 and Glut-12, and the regulator of appetite Cartpt) and to LAC responsiveness (leptin receptors Lepr, metabotropic glutamate receptors-2 mGlu2, neuropeptide-Y NPY, and mineralocorticoid receptors MR). Furthermore, we found that stress-induced treatment resistance in nrFSL shows a new gene profile, including the metabolic regulator factors elongation of long chain fatty acids 7 (Elovl7) and cytochrome B5 reductase 2 (Cyb5r2) and the synaptic regulator NPAS4. Finally, while improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrected a systemic hyperinsulinemia and hyperglicemia in rFSL and failed to do that in nrFSL. These findings establish CNS energy regulation as a factor to be considered for the development of better therapeutics. Agents such as LAC that regulate metabolic factors and reduce glutamate overflow could rapidly ameliorate depression and could also be considered for treatment of insulin resistance in depressed subjects. The approach here serves as a model for identifying markers and underlying mechanisms of predisposition to diseases and treatment responsiveness that may be useful in translation to human behavior and psychopathology.

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity.

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.

Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress.

BACKGROUND: Previous studies identified several separate risk factors for stress-induced disorders. However, an integrative model of susceptibility versus resilience to stress including measures from brain-body domains is likely to yield a range of multiple phenotypic information to promote successful adaptation to stress. METHODS: We used computational and molecular approaches to test whether 1) integrative brain-body behavioral, immunological, and structural domains characterized and predicted susceptibility or resilience to social defeat stress (SDS) in mice and 2) administration of acetyl-L-carnitine promoted resilience at the SDS paradigm. RESULTS: Our findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The copresence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, we provide initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience at the SDS paradigm. CONCLUSIONS: The current findings of multidimensional brain-body predictors of susceptibility versus resilience to stress provide a starting point for in vivo models of mechanisms predisposing apparently healthy individuals to develop the neurobiological and behavioral deficits resulting from stress exposure. This framework can lead to novel therapeutic strategies to promote resilience in susceptible phenotypes.

Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress.

We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP+-Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.