Cortical inhibitory cells are critical for regulating information processing and synaptic plasticity in neural circuits. This plasticity is essential for learning and memory, and is an important feature of the auditory cortex, especially for learning the significance of sensory signals such as speech. Long-term synaptic plasticity requires sensory experience and activation of neuromodulatory systems such as the cholinergic nucleus basalis, which conveys behavioral context to local cortical circuits. However, little is known about how cortical interneurons are involved in these mechanisms, or if different inhibitory cell types have different roles for developmental or adult plasticity. Recently we developed an approach to measure long-term excitatory and inhibitory synaptic modifications in vivo over hours to weeks. These experiments revealed that prior to experience with sounds, cortical inhibition was initially mismatched with excitation, but becomes `balanced' with excitation after experience or training. [These experiments now allow us to construct a new framework for understanding the roles of 5HT3aR and non-5HT3aR cortical interneurons during auditory behavior in mice, with a series of behavioral, imaging, and recording experiments integrated with the larger collaborative PPG structure. We hypothesize that there are important functional differences in these cell types, in terms of their relative contributions to auditory behavior (Aim 1), cholinergic modulation (Aim 2), and cortical microcircuit organization and plasticity (Aim 3). Specifically, in Aim 1 we will first examine the behavioral relevance of specific cortical interneuron subtypes, as initially-naive mice are trained to perform an auditory detection and recognition task we have used in the lab for years. We ask how sensory experience and behavioral training might recruit these cell types and naturally shape excitatory and inhibitory circuit elements, using whole-cell recordings combined with 2-photon Ca2+ imaging to directly measure excitation and various cell-type-specific sources of inhibition in vivo.
In Aim 2 we examine if these cell types are differentially affected by cholinergic modulation, perhaps due to differential sensitivity to acetylcholine or specific wiring of cholinergic input into cortex. Finally, in Aim 3 we will make recordings in cortical brain slices, to document how different cortical interneuron types are synaptically connected and modified for circuit operation.] In summary, here we will use in vivo and in vitro electrophysiology, imaging, and optogenetics to ask how different cortical interneurons (5HT3aR vs non-5HT3aR) govern sensory processing and plasticity. The two core concepts of these studies involve long-term synaptic plasticity, believed to be a major neural correlate of learning and memory, and excitatory-inhibitory balance- the precise regulation of excitation by inhibitory circuits. These processes are believed to be disrupted in a large number of neurological conditions and mental health disorders, highlighting an urgent need for a more complete description of cortical organization and function during behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS074972-06A1
Application #
9645483
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Type
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Wamsley, Brie; Fishell, Gord (2017) Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat Rev Neurosci 18:299-309
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
Ma, Lei; Qiao, Qian; Tsai, Jin-Wu et al. (2016) Experience-dependent plasticity of dendritic spines of layer 2/3 pyramidal neurons in the mouse cortex. Dev Neurobiol 76:277-286
Qiao, Qian; Ma, Lei; Li, Wei et al. (2016) Long-term stability of axonal boutons in the mouse barrel cortex. Dev Neurobiol 76:252-61
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

Showing the most recent 10 out of 31 publications