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Nearly all psychiatric diseases involve alterations in subjective, lived experience. The scientific study of the biological basis of mental illness has generally focused on objective measures and observable behaviors, limiting the potential for our understanding of brain mechanisms of disease states and possible treatments. However, applying methods designed principally to interpret objective behavioral measures to the measurement and extrapolation of subjective states presents a number of challenges. In order to help bridge this gap, we draw on the tradition of phenomenology, a philosophical movement concerned with elucidating the structure of lived experience, which emerged in the early 20th century and influenced philosophy of mind, cognitive science, and psychiatry. A number of early phenomenologically-oriented psychiatrists made influential contributions to the field, but this approach retreated to the background as psychiatry moved towards more operationalized disease classifications. Recently, clinical-phenomenological research and viewpoints have re-emerged in the field. We argue that the potential for phenomenological research and methods to generate productive hypotheses about the neurobiological basis of psychiatric diseases has thus far been underappreciated. Using specific examples drawing on the subjective experience of mania and psychosis, we demonstrate that phenomenologically-oriented clinical studies can generate novel and fruitful propositions for neuroscientific investigation. Additionally, we outline a proposal for more rigorously integrating phenomenological investigations of subjective experience with the methods of modern neuroscience research, advocating a cross-species approach with a key role for human subjects research. Collaborative interaction between phenomenology, psychiatry, and neuroscience has the potential to move these fields towards a unified understanding of the biological basis of mental illness.

Adolescent binge drinking is a major risk factor for psychiatric disorders later in life including alcohol use disorder. Adolescent alcohol exposure induces epigenetic reprogramming at the enhancer region of the activity-regulated cytoskeleton-associated protein (Arc) immediate-early gene, known as synaptic activity response element (SARE), and decreases Arc expression in the amygdala of both rodents and humans. The causal role of amygdalar epigenomic regulation at Arc SARE in adult anxiety and drinking after adolescent alcohol exposure is unknown. Here, we show that dCas9-P300 increases histone acetylation at the Arc SARE and normalizes deficits in Arc expression, leading to attenuation of adult anxiety and excessive alcohol drinking in a rat model of adolescent alcohol exposure. Conversely, dCas9-KRAB increases repressive histone methylation at the Arc SARE, decreases Arc expression, and produces anxiety and alcohol drinking in control rats. These results demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure.