Epigenetic embedding of childhood adversity: mitochondrial metabolism and neurobiology of stress-related CNS diseases.

This invited article ad memoriam of Bruce McEwen discusses emerging epigenetic mechanisms underlying the long and winding road from adverse childhood experiences to adult physiology and brain functions. The conceptual framework that we pursue suggest multidimensional biological pathways for the rapid regulation of neuroplasticity that utilize rapid non-genomic mechanisms of epigenetic programming of gene expression and modulation of metabolic function via mitochondrial metabolism. The current article also highlights how applying computational tools can foster the translation of basic neuroscience discoveries for the development of novel treatment models for mental illnesses, such as depression to slow the clinical manifestation of Alzheimer's disease. Citing an expression that many of us heard from Bruce, while "It is not possible to roll back the clock," deeper understanding of the biological pathways and mechanisms through which stress produces a lifelong vulnerability to altered mitochondrial metabolism can provide a path for compensatory neuroplasticity. The newest findings emerging from this mechanistic framework are among the latest topics we had the good fortune to discuss with Bruce the day before his sudden illness when walking to a restaurant in a surprisingly warm evening that preluded the snowstorm on December 18th, 2019. With this article, we wish to celebrate Bruce's untouched love for Neuroscience.

Multidimensional predictors of antidepressant responses: Integrating mitochondrial, genetic, metabolic and environmental factors with clinical outcomes.

Major depressive disorder (MDD) is a primary psychiatric illness worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Although we continue to discover individual biological factors, a major challenge is the identification of integrated, multidimensional traits underlying the complex heterogeneity of depression and treatment outcomes. Here, we set out to ascertain the emergence of the novel mitochondrial mediator of epigenetic function acetyl-L-carnitine (LAC) in relation to previously described individual predictors of antidepressant responses to the insulin-sensitizing agent pioglitazone. Herein, we report that i) subjects with MDD and shorter leukocyte telomere length (LTL) show decreased levels of LAC, increased BMI, and a history of specific types of childhood trauma; and that ii) these multidimensional factors spanning mitochondrial metabolism, cellular aging, metabolic function, and childhood trauma provide more detailed signatures to predict longitudinal changes in depression severity in response to pioglitazone than individual factors. The findings of multidimensional signatures involved in the pathophysiology of depression and their role in predicting treatment outcomes provide a starting point for the development of a mechanistic framework linking biological networks and environmental factors to clinical outcomes in pursuit of personalized medicine strategies to effectively treat MDD.

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

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.