GABAergic interneurons have critical roles in signal processing in the cerebral cortex. Moreover, malfunction of these neurons has been implicated in a number of diseases ranging from epilepsy to schizophrenia, anxiety disorders and autism. The goal of Project 2 is to elucidate the functional roles of a group of neocortical GABAergic interneurons that express the ionotropic serotonin (5-HT) receptor 5HT3aR. 5HT3aRexpressing interneurons are the major population of GABAergic neurons in the superficial or associative layers of the cortex. However, largely as a result of the lack of experimental tools to identify and manipulate 5HT3aR interneurons litfie is known about the function of these cells in neocortical signal processing. Based on their location and prevalence, we hypothesize that 5HT3aR interneurons have crucial roles in sensory processing and in long-range interareal cortical communication. Moreover, studies indicate that all 5HT3aR neurons are potently modulated by 5-HT and acetylcholine (ACh) acting on ionotropic 5HT3a and nicotinic receptors, and that they are the main targets of the fast action of these neuromodulators in cortex, as well as of metabotropic responses in some 5HT3aR subpopulations. We hypothesize that these modulations are important in information processing and are involved in shaping cortical circuits during specific brain states and behavioral contexts. These observations have led to the overall hypothesis that 5HT3aR neurons have important roles in context-dependent sensory processing. This project will take advantage of new experimental reagents to begin testing these hypotheses. Electrophysiological recordings combined with optogenetic approaches will be used to study the functional connectivity of 5HT3aR neurons in primary somatosensory cortex with motor cortex and with the higher-order somatosensory thalamic nucleus, the posteromedial nucleus (POm). Photo-stimulation of channel rhodopsin expressing cholinergic and serotonergic axons will be used to study the modulation of 5HT3aR interneuron activity by these subcortical systems, and targeted-patch clamp recordings in-vivo will be used to study the changes in activity of 5HT3aR interneurons during different brain states and in response to sensory simulation and motor activity

Public Health Relevance

GABAergic INs is critical for the normal and pathological function of the brain. This Program Project will investigate the roles of 5HT3aR INs;the least understood but largest population of GABAergic neurons in superficial cortical layers, on the development, function, and plasticity of the cerebral cortex. This component of the PPG will study the connectivity, modulation and activity of 5HT3aR INs during different behavioral states to determine their role in context-dependent sensory processing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS074972-02
Application #
8551741
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$301,659
Indirect Cost
$123,163
Name
New York University
Department
Type
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Yang, Guang; Lai, Cora Sau Wan; Cichon, Joseph et al. (2014) Sleep promotes branch-specific formation of dendritic spines after learning. Science 344:1173-8
Kepecs, Adam; Fishell, Gordon (2014) Interneuron cell types are fit to function. Nature 505:318-26
Muñoz, William; Tremblay, Robin; Rudy, Bernardo (2014) Channelrhodopsin-assisted patching: in vivo recording of genetically and morphologically identified neurons throughout the brain. Cell Rep 9:2304-16
Muñoz, William; Rudy, Bernardo (2014) Spatiotemporal specificity in cholinergic control of neocortical function. Curr Opin Neurobiol 26:149-60
De Marco Garcia, Natalia V; Fishell, Gord (2014) Subtype-selective electroporation of cortical interneurons. J Vis Exp :e51518
Takada, Naoki; Pi, Hyun Jae; Sousa, Vitor H et al. (2014) A developmental cell-type switch in cortical interneurons leads to a selective defect in cortical oscillations. Nat Commun 5:5333
Karayannis, T; Au, E; Patel, J C et al. (2014) Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Nature 511:236-40
Rossignol, Elsa; Kruglikov, Illya; van den Maagdenberg, Arn M J M et al. (2013) CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann Neurol 74:209-22
Lee, Soohyun; Kruglikov, Illya; Huang, Z Josh et al. (2013) A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat Neurosci 16:1662-70
Fishell, Gord; Heintz, Nathaniel (2013) The neuron identity problem: form meets function. Neuron 80:602-12

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