Alex Kwan PhD
Assistant Professor of Psychiatry
Neuroscience; Neural circuits; Inhibitory neurons; Attention; Working memory; Executive functions; Two-photon microscopy; Electrophysiology
The goal of our research is to understand the neural basis of attentional and working memory behaviors. A major objective is to determine how the component processes underlying these cognitive behaviors are implemented at the level of neuronal circuits. Through the study of how cell types, cortical layers, and connectivity patterns contribute to cognition, we seek not only to reveal principles about cortical information processing, but also to understand why dysfunction of specific neural elements in the brain is the likely cause for the cognitive deficits associated with disorders such as depression, schizophrenia, and ADHD.
Our experiments are designed to characterize and manipulate neural activity of the mouse in normal behavior and in psychiatric disorder models. We specialize in optical approaches including two-photon calcium imaging and optogenetics that enable cellular-resolution recording and perturbation of neural circuits. We have also designed perceptual tasks that measure the cognitive abilities of the head-fixed mouse, allowing us to precisely and casually link the activity of neuronal ensembles with behavior.
Extensive Research Description
Prefrontal cortex, the brain’s command center, orchestrates our thoughts and links perception with action; thus, it is essential for any goal-directed behavior. How is it functionally organized? What are the relevant input and output signals and what is computed? How does it communicate with the rest of the brain? Answering these questions at the level of neuronal circuits is essential for understanding the biological basis of higher cognitive functions. Moreover, the prefrontal cortex is the primary site for a number of psychiatric disorders including depression, schizophrenia, and ADHD. Our studies may lead to a better understanding of the causes and potential cure for these devastating mental illnesses.
To effectively study cognitive functions, we need to bridge the gap between quantitative behavior and neural dynamics. This challenge is why we choose to focus on the neuronal circuitry of the mouse prefrontal cortex. The laboratory specializes in in vivo optical technologies, including two-photon calcium imaging and optogenetics, which enable us to record and manipulate large populations of neurons. To relate neural activity with physiology, we develop for the mice automated tasks that precisely measure parameters related to their attentional and working memory behaviors.
Top-down selective attention
At any moment, our senses are bombarded by all kinds of stimuli. To make sense of and efficiently process sensory information, our brain needs ways to filter the incoming signals: attenuate the unnecessary and focus only the relevant. Our recent results have identified in the mouse cortico-cortical pathways that have characteristics consistent with a functional role in top-down control of sensory processing. The laboratory is following up on this work by investigating the functional organization of the “top” frontal area as well as characterizing the information that is carried by the long-range axons to the “down” sensory regions.
The classic neural signature of the prefrontal cortex is the persistent spiking activity during working memory tasks. Such persistent activity has been hypothesized to be the biological substrate for short-term memory, by linking perception now to action in the future. The prefrontal cortex’s prominent role in short-term memory is also demonstrated by inactivation studies, where the most obvious deficit is the inability to generate a delayed response. For the mouse, we have developed head-fixed, behavioral tasks that recapitulate salient aspects of the working memory behavior. Current projects take advantage of the imaging, optogenetic, and molecular tools in the mouse to explore how persistent activity is generated and maintained by neuronal ensembles during behavior.
Mouse models of psychiatric disorders
Frontal lobe dysfunction is linked to numerous psychiatric disorders including ADHD, schizophrenia, and depression. Despite the devastating effects of these mental illnesses, we lack a reliable suite of biomarkers and a mechanistic understanding of the cognitive deficits. This is not surprising considering the complexity in both the etiology and the underlying neural circuitry, making any study that correlates these two aspects of a disorder difficult to interpret. We are working on chronic imaging solutions that overcome this problem by monitoring the structure and function of neuronal ensembles over time, in the same mouse, as the disorder progresses.