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Identification of neural and epigenetic biomarkers for affective dysfunction following early adversity

Bowdoin CollegeProject Summary

An individual’s early life environment plays a central role in shaping developmental trajectories, and therefore confers substantial influence on later-life physical and mental health outcomes. As such, early life adversity (ELA), in the form of childhood abuse or maltreatment, can set the course – via aberrant brain maturation – for increased risk for mental illness, particularly those involving affective (emotional) dysfunction, such as anxiety, depression, schizophrenia, and posttraumatic stress disorder. While the field has made significant strides in our understanding of ELA-related emergence of psychopathology, much remains to be done in order to pinpoint the neural drivers of ELA-induced affective dysfunction (i.e., anxiety) and to determine predictive biomarkers capable of identifying individual risk. Of particular importance is the need for using translational model systems to systematically manipulate and characterize risk contributions across the lifespan so that we may isolate windows of opportunity for intervention and/or treatment. While we can probe anxiety and hypervigilance using the fearful face task (FFT) in humans, there exists no established analogue in rats. Here, we will leverage playback of aversive (22kHz) ultrasonic vocalizations (USVs), which we propose carry ethologically similar social and affective information to the receiving rat as does a fearful face in the FFT. The proposed aims seek to use a well-characterized model of ELA in rats (maternal separation) – as well as a novel USV playback assay – to identify putative neural and epigenetic biomarkers involved in risk for pathology defined by affective dysfunction (anxiety, hypervigilance). As anxiety and other affective disorders disproportionately impact females, the present aims will evaluate sex-specific effects of ELA on behavioral, neural, and epigenetic measures. It is believed that ELA and/or trauma can elicit changes to the epigenome, thereby altering neural expression/function. There is growing evidence for a role of parvalbumin- (PV) containing inhibitory neurons in the regulation of anxiety-like behaviors, as well as evidence of ELA-induced alterations in PV cell distribution and function in brain regions associated with anxiety (i.e., amygdala, prefrontal cortex). As such, it is likely that ELA-induced epigenetic changes, via aberrant DNA methylation, may contribute to PV dysfunction and, as a result, increased incidence of anxiety and hypervigilance due to changes in overall inhibition. To define relationships between ELA, sex, and development on anxiety-like behavioral, we will leverage within-subjects behavioral, immunohistochemical, neuroanatomical, and epigenetic (DNA methylation) approaches in a translational rat model to identify biomarkers and neural correlates of ELA risk/resilience.

Relevance

Early life adversity (via caregiver deprivation) increases individual risk for developing later life physiological/psychological disorders such as anxiety and depression, which disproportionately affects women and places undue burden on society. The systematic study and identification of underlying mechanisms of risk (or resilience) in an animal model across development is necessary to identify opportunities for identifying those most at risk, and for developing targeted treatments/interventions in humans.

Honeycutt’s Research