The long-term goal of our research program is to understand the neural circuit mechanisms underlying motivated behavior. The exquisite neural architecture of microcircuits in prefrontal cortex (PFC) is thought to underlie the flexibility and dynamics responsible for cognition. This proposal aims to understand the role of distinct interneuron types in prefrontal cortical function. Our general approach is predicated on the idea that access to cell-type identity is essential to unlocking the function of neocortical circuits. Because interneurons constitute a highly diverse neural population, some with well-understood anatomical specializations, they represent both an important opportunity to reveal microcircuit function as well as an excellent showcase for demonstrating the use of cell-type identity based functional studies. Our first objective therefore is to develop an optogenetic toolkit for this purpose. We will design and validate a miniature microdrive for combined electrophysiological recordings and fiberoptic stimulation that is light-weight and suitable for chronic recordings from freely behaving mice - enabling us to identify, record and manipulate genetically labeled cell-types. We propose to study three non-overlapping classes of interneurons: the parvalbumin (PV), somatostain (SOM), and vasoactive intestinal peptide (VIP) positive cells using knock-in Cre-driver lines, each with distinct functions. Using these tools we will examine how distinct cortical brain rhythms, signatures of coordinated neural activity, are correlated with the firing of distinct interneuron subtypes. Our optogenetic approach will not only establish the correlation of interneuron subtypes with oscillations but also enable selective control over the activity of distinct interneuron subtypes to pursue the mechanisms for generating different brain rhythms. We will employ a loss-and-gain-of-function approach to abolish and induce different brain rhythms in behaving animals. If successful, the proposed research is expected to result in a detailed understanding of the role of distinct interneuron subtypes in prefrontal cortical function and behavior. Because maladaptive changes inhibitory interneurons have been linked with a diverse set of diseases from epilepsy to schizophrenia and autism, our results will have direct implications for interpreting deficits in these disease states and potentially suggest avenues for remediation.

Public Health Relevance

This proposal will lead to a better understanding about how different inhibitory neuron populations contribute to the generation of brain oscillations and behavior. Disruptions in inhibitory circuitry are implicated in epilepsy, as a well as in schizophrenia and autism. Because our studies will be conducted in rodents, we expect to gain mechanistic insights in terms of the neural subtypes and circuits involved, which will have the potential to generate improved strategies for treating these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075531-04
Application #
8664452
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Gnadt, James W
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$409,303
Indirect Cost
$192,741
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Hangya, Bal√°zs; Pi, Hyun-Jae; Kvitsiani, Duda et al. (2014) From circuit motifs to computations: mapping the behavioral repertoire of cortical interneurons. Curr Opin Neurobiol 26:117-24
Kepecs, Adam; Fishell, Gordon (2014) Interneuron cell types are fit to function. Nature 505:318-26
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
Ranade, Sachin; Hangya, Balazs; Kepecs, Adam (2013) Multiple modes of phase locking between sniffing and whisking during active exploration. J Neurosci 33:8250-6
Pi, Hyun-Jae; Hangya, Balazs; Kvitsiani, Duda et al. (2013) Cortical interneurons that specialize in disinhibitory control. Nature 503:521-4
Kvitsiani, D; Ranade, S; Hangya, B et al. (2013) Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498:363-6