Major projects

1. Visualizing synapses in action during cortical circuit function

Single neurons are driven by huge populations of synapses. In the visual system, single neurons are highly selective for features in the world (often in an invariant manner). In carnivores and primates, a tremendous amount of visual selectivity emerges in the primary visual cortex. This project aims to understand how selectivity emerges in single neurons; how synaptic inputs are transformed into somatic outputs (i.e. spikes). This project uses in vivo multiphoton calcium imaging of synaptic networks on single pyramidal cortical neurons, taking advantage of dendritic spines which are major site of excitatory input innervation. Understanding input/output transformations in single neurons in the visual system will provide much needed insight into the nature of neural computation.

2. Probing the behavior of cortical circuits in action

Each neuron’s population of presynaptic partners determines how incoming information is processed. A majority of synaptic inputs originate from local networks through horizontal (recurrent) connections. Theoretical models of the visual system suggest these inputs perform a fundamental function in cortical circuits: selective modulation. Specifically, selective amplification or attenuation in a manner dependent on the strength and statistics of incoming sensory information. But this process has not been elucidated at the synaptic level, and the mechanisms proposed by stem from studies of rodents and have not been tested in different mammalian systems. This project aims to map presynaptic excitatory and inhibitory cells of single layer 2/3 neurons and dissect how they act to selectively modulate the behavior of neural circuits in a carnivore. This project utilizes a combination of in vivo multiphoton optogenetic neural control, multiphoton calcium imaging, and intracellular electrophysiology.

3. Redefining visual development through natural behavior (hunting ferrets) and neural dynamics

Neural development is generally considered a feed- forward process: experience shapes neural activity, thereby influencing the structure, gene expression, and function of brain circuits. Missing from this picture is the dynamic nature of experience itself, which is shaped by developing brain circuits, and how natural behaviors concurrently emerge with maturing visual circuits. To address this challenge, we propose a return-to-first-principles approach using the ferret model system. We characterize the developmental trajectory of natural visually-guided behaviors and map the concurrent maturation of neuronal circuits. We are using modern methods and computational tools to track the natural development of visually-guided behaviors, kinematics, and eye-movements in ferrets. We will incorporate head-fixed and head-mounted in vivo two-photon (2P) microscopy to map the structural and functional dynamics of neural networks at synaptic and cellular scales. This project will produce a novel platform for studying the intersection between dynamic experience, changes in statistics of the outside world, constraints of neural circuits, and the development of natural behaviors

4. Single-cell CRISPR/Cas9 manipulations to study molecular mechanisms and synaptic pathology in cortical spines, cells, and circuits

Synaptic pathology is a prominent feature of psychiatric illness and many neurological disorders. For example, synaptic dysfunction is presumed to be an underlying cause of Autism Spectrum Disorder, as genomic studies have identified risk genes regulating synaptic structure and physiology, and NMDA receptor dysfunction is highly implicated in the emergence of schizophrenia, based on numerous studies from mouse to primates and humans. One gene strongly associated with ASD and other CNS disorders is Phosphatase and tensin homolog located on chromosome 10 (Pten). But while global mouse models with dysfunctional Pten exhibit synaptic pathology and mimic ASD symptoms, it is unknown how synaptic integration, organization, and function are impacted within individual neurons. This project aims to understand how Pten signaling shapes synaptic integration and functional architecture in single neurons. This collaborative project uses CRISPR/Cas9 edits in single neurons in combination with in vivo synaptic calcium imaging measurements.