Alex Kwan, PhD

We are broadly interested in the function of the frontal cortex. Many of our experiments involve cellular-resolution optical imaging and head-fixed mouse behavior. We have made progress in two specific areas:

Flexible decision-making

In a dynamic environment, animals must adjust their action plans to match the behavioral demands. For example, the same sensory stimulus may require different motor responses depending on the context. The mammalian prefrontal cortex is thought to be a central node mediating flexible behavior, however the synaptic and circuit mechanisms remain poorly understood. In the lab, we are adapting classic decision-making tasks for head-fixed mice. These tasks involve switching sensory-response contingencies or uncertain response-outcome relations. We perform optical imaging and perturbation experiments to study the task-related neural dynamics. We use computational models to dissect the choice behavior, for example by fitting reinforcement learning algorithms. Recent studies in the lab have focused on the role of the mouse secondary motor cortex (M2 / MOs) and cingulate cortex (Cg1 / ACAd), medial frontal regions that are involved in binding prior events to current decisions.

Dendritic dysfunction in neuropsychiatric disorders

A central feature of many psychiatric and neurological disorders is dendritic pathology in the frontal cortex. Because dendrites are sites of synaptic integration and activity-dependent plasticity, their alteration is expected to have a profound impact on cortical function. However, to date most of our knowledge of the pathophysiological mechanisms have come from studies of neuronal cultures and brain slices. In awake animals, dendritic excitability is strongly influenced by background activity, neuromodulation, and inhibitory inputs. In the lab, we are using two-photon microscopy to characterize dendritic spine turnover and dendritic calcium signaling in awake mice. We are determining how psychoactive drugs and genetic mutations influence dendritic signaling in vivo. Current projects focus on compounds with rapid onset of action (ketamine, psilocybin) and autism risk genes (Shank3, Scn2a).