The classification of cell types in the cerebral cortex is a major goal in neuroscience, guided by the expectation that elaborating a complete neuronal census will provide important insights into both healthy brain function and the pathophysiology of disease. Traditional schemes for grouping cells have largely focused on morphological, electrophysiological, and hodological features derived from ex vivo preparations. However, the development of tools for labeling and recording neurons in vivo presents substantial opportunities to broaden our knowledge of what constitutes a class of cells. Here, we propose that in vivo activity is an additional axis on which to categorize neuronal types. Our overall goal is to develop a novel strategy for linking behaviorally relevant activity with a traditional characterization of cellular properties. To that end, we focus on the role of behavioral state in modulating the firing patterns of neurons in the mouse neocortex. Several recent studies have demonstrated that locomotion is associated with significant but heterogeneous alteration in activity, with different cells showing enhanced or suppressed output during periods of motor behavior. We will take advantage of a novel green fluorescent protein, called CaMPARI2, enabling us to label cortical neurons that are active during arousal by coupling light stimulation with real-time detection of locomotion. This approach is followed by ex vivo analyses comparing locomotion-sensitive (photo-converted, red) and -insensitive (green) cells side by side.
In Aim 1, we characterize the regional and laminar differences in cells throughout the neocortex whose activity is modulated by locomotion.
In Aim 2, we examine the electrophysiological, morphological, and transcriptional properties of these cells. Overall, these efforts to gain a complete picture of functional neuronal diversity will be essential for understanding healthy brain function and for driving new interventions aimed at the prevention and treatment of neuropsychiatric disorders.

Public Health Relevance

The classification of neuron types based on a variety of cellular properties is a key element in the development of models for healthy brain function and its disruption in disease. In this proposal, we have designed a novel approach for linking neuronal activity patterns associated with behavior to post-hoc ex vivo characterization of the electrophysiological, morphological, and transcriptional properties of single neurons. These studies will drive further understanding of how different kinds of brain cells contribute to both healthy behavior and neuropsychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Sensorimotor Integration Study Section (SMI)
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Alvarez, Ruben P
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Yale University
Schools of Medicine
New Haven
United States
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