The functions of the cerebral cortex rely upon highly interconnected and dynamic microcircuits composed of two types of neurons: glutamatergic excitatory neurons that propagate signals through the various stages of processing, and GABAergic interneurons that regulate this information flow and sculpt cortical circuit dynamics. Signal processing in the cortex critically depends on the activity of specific interneuron subtypes. While the PV and SST interneuron populations have been well studied, this Program Project is focused on the 5HT3aR family of GABAergic interneurons whose prevalence, breadth and contributions to cortical function have been previously underestimated. 5HT3aR interneurons represent about 30% of the total interneuron population in the neocortex and are concentrated within the superficial associative layers, where they comprise the majority of interneurons. During development, 5HT3aR interneurons originate from the caudal ganglionic eminence (CGE), become positioned within the cortex late during the first postnatal week and contribute to both the function and plasticity of the cortex thereafter. Here we will investigate the roles of cortical 5HT3aR interneurons during development, as well as their function and plasticity within the somatosensory and auditory cortices. The Program Project will consist of three interrelated research projects and two cores (an Administrative Core and a Molecular and Transgenic Core) to support the work of the three projects. A focus of all three projects will be neocortical layer 1 (L1), the main cortical layer receiving contextual information. All neurons in L1 are interneurons of the 5HT3aR family. Project 1 (by Gordon Fishell), will elucidate the mechanisms that determine the development of the 5HT3aR interneuron population. It will investigate the genetic program that governs the differentiation of 5HT3aR interneuron precursors, their connectivity throughout development and the role of activity (with a particular focus on L-type Ca++ signaling) on their maturation in the cortex. Project 2 (by Bernardo Rudy) will advance our understanding of the role of 5HT3aR interneurons in cortical function by focusing on the interneuron subtypes that we have identified in L1 during the previous funding period. Specifically, Project 2 will investigate their input and output connectivity and their contributions to context-dependent sensory processing. Project 3 (by Robert Froemke) will examine the contributions of the same populations to both auditory processing and plasticity. This project will examine the role of L1 5HT3aR interneurons in awake behaving mice in an auditory recognition task and determine the requirement of cholinergic neuromodulation for this process. Together these projects will provide a comprehensive assessment of the 5HT3aR populations? development, plasticity and function.

Public Health Relevance

GABAergic interneurons (INs) are critical for the normal function of the brain and have been implicated in human disease. This Program Project is focused on 5HT3aR interneurons, which are cortical INs that have been understudied, are enriched in the superficial layers of the cerebral cortex, and are important in regulation of perception and high order cognitive function. The Program Project will use novel experimental approaches and generate new transgenic mice and viral vectors in order to examine the development of 5HT3aR INs, their contribution to the establishment of cortical circuitry in the superficial layers of the cortex, and the mechanisms by which these neurons regulate sensory perception and learning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS074972-06A1
Application #
9645478
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Talley, Edmund M
Project Start
2012-09-30
Project End
2023-12-31
Budget Start
2019-01-15
Budget End
2019-12-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Leffler, Abba E; Kuryatov, Alexander; Zebroski, Henry A et al. (2017) Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models. Proc Natl Acad Sci U S A 114:E8100-E8109
Wilson, Daniel E; Smith, Gordon B; Jacob, Amanda L et al. (2017) GABAergic Neurons in Ferret Visual Cortex Participate in Functionally Specific Networks. Neuron 93:1058-1065.e4
Muñoz, William; Tremblay, Robin; Levenstein, Daniel et al. (2017) Layer-specific modulation of neocortical dendritic inhibition during active wakefulness. Science 355:954-959
Quattrocolo, Giulia; Fishell, Gord; Petros, Timothy J (2017) Heterotopic Transplantations Reveal Environmental Influences on Interneuron Diversity and Maturation. Cell Rep 21:721-731
Tuncdemir, Sebnem N; Wamsley, Brie; Stam, Floor J et al. (2016) Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits. Neuron 89:521-35
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McKenzie, Melissa; Fishell, Gord (2016) Human brains teach us a surprising lesson. Science 354:38-39
Mayer, Christian; Bandler, Rachel C; Fishell, Gord (2016) Lineage Is a Poor Predictor of Interneuron Positioning within the Forebrain. Neuron 92:45-51

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