Alex Kwan, PhD
Research & Publications
Biography
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Research Summary
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).
Coauthors
Research Interests
Antidepressive Agents; Decision Making; Dendrites; Depressive Disorder; Electrophysiology; Microscopy, Fluorescence; Prefrontal Cortex; Optogenetics
Selected Publications
- A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics.Savalia NK, Shao LX, Kwan AC. A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics. Trends In Neurosciences 2020.
- Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines.Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, Kwan AC. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nature Communications 2020, 11:72.
- Cumulative Effects of Social Stress on Reward-Guided Actions and Prefrontal Cortical Activity.Barthas F, Hu MY, Siniscalchi MJ, Ali F, Mineur YS, Picciotto MR, Kwan AC. Cumulative Effects of Social Stress on Reward-Guided Actions and Prefrontal Cortical Activity. Biological Psychiatry 2020, 88:541-553.
- Interpreting in vivo calcium signals from neuronal cell bodies, axons, and dendrites: a review.Ali F, Kwan AC. Interpreting in vivo calcium signals from neuronal cell bodies, axons, and dendrites: a review. Neurophotonics 2020, 7:011402.
- Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation.Ali F, Shao LX, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, Kwan AC. Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation. Molecular Psychiatry 2020.
- Enhanced Population Coding for Rewarded Choices in the Medial Frontal Cortex of the Mouse.Siniscalchi MJ, Wang H, Kwan AC. Enhanced Population Coding for Rewarded Choices in the Medial Frontal Cortex of the Mouse. Cerebral Cortex (New York, N.Y. : 1991) 2019, 29:4090-4106.
- Secondary Motor Cortex: Where 'Sensory' Meets 'Motor' in the Rodent Frontal Cortex.Barthas F, Kwan AC. Secondary Motor Cortex: Where 'Sensory' Meets 'Motor' in the Rodent Frontal Cortex. Trends In Neurosciences 2017, 40:181-193.
- Fast and slow transitions in frontal ensemble activity during flexible sensorimotor behavior.Siniscalchi MJ, Phoumthipphavong V, Ali F, Lozano M, Kwan AC. Fast and slow transitions in frontal ensemble activity during flexible sensorimotor behavior. Nature Neuroscience 2016, 19:1234-42.
- Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex.Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex. ENeuro 2016, 3.