Alexander Harris, MD, PhD

Stressful experiences are a crucial mediator of many psychiatric disorders, robbing susceptible people of their joy in life, while spurring resilient people to live with greater zest and purpose. My lab aims to determine the neural circuitry underlying stress-induced psychiatric symptoms and why different individuals prove susceptible or resilient. We study the neural underpinnings of reward processing, motivation, cognition and social behavior to ask how stress disrupts these neural circuit computations.

To do so, we study long-range brain circuits by recording in vivo electrophysiologic activity (single units and local field potentials) in multiple brain areas as freely moving mice engage in psychiatrically relevant behaviors (Harris et al. 2015). This approach allows us to identify the naturalistic patterns of dynamic neural activity, from oscillations to firing rates, that support behavior. To dissect the underlying circuitry, we use optogenetics and other systems neuroscience techniques to manipulate that dynamic neural circuit activity in specific cell types. Using these approaches, we have shown that long-range VTA GABAergic neurons projecting to the nucleus accumbens neurons produce a 4 Hz oscillation of local field potentials during acute stress that disrupts subsequent reward seeking (Lowes et al. 2021). We are currently determining if similar circuitry underlies chronic stress-induced persistent anhedonia. In another study, we found that novel experiences reduce theta range synchrony between the hippocampus and prefrontal cortex and facilitate new learning (Park et al. 2021). Follow up studies will determine the role of this newly discovered mechanism in cognitive and motivational disorders.

Our goal with these studies is to develop findings that can lead to treatments in patients with psychiatric disorders. With that in mind, we have projects for 1) predicting and building resilience by fostering hedonic circuit responses, 2) using female social defeat paradigm we developed (Harris et al. 2018) to examine sex-differences in the neural response to chronic stress, 3) developing translational approaches to bridge neural recordings in mice and people, 4) testing the impact of novelty on stress-induced impairments in cognition, and 5) developing novel treatments strategies.