The neostriatum is the main input structure of the basal ganglia, a system that is crucial not only for voluntary motor control, but also for reinforcement-mediated learning and higher cognitive functions. The importance of understanding the functioning of the nesotriatum is dramatically illustrated by the severe disability associated with numerous neurological and neuropsychiatric conditions that affect this brain structure. Developments in transgenic methods that allow visualization and targeting of genetically and functionally distinct types of neurons has recently led to the discovery of an unexpectedly large diversity of GABAergic interneurons in the neostriatum. As a result the striatum is now known to contain at least 7 types of GABAergic interneurons that include, in addition to the previously known fast spiking (FS) and the NPY expressing NPY-PLTS interneurons, 4 distinct classes of tyrosine hydroxylase (TH) containing interneurons and a new class of NPY expressing interneuron. We hypothesize, based on preliminary data and earlier studies that the newly discovered TH and NPY interneurons are integral and important constituents of a highly organized intrastriatal synaptic circuitry and play essential roles in determining the activity and computational function of the neostriatum. The goal of the proposed studies is to understand the synaptic organization of this circuitry and to assess the functional significance of the newly discovered interneuron classes in determining the activity of other constituent neurons, in particular, the activity of functionally distinct types of projection neurons. The circuit organization of TH and NPY interneurons will be mapped in in vitro optogenetic experiments using a series of double transgenic mice in which expression of Cre-recombinase and EGFP in distinct types of neurons will allow high-throughput bidirectional analysis of the connectivity among TH, NPY, and FS interneurons and projection neurons of the direct and indirect pathways. The functional impact of TH and NPY interneurons will be assessed in in vivo optogenetic recording experiments in mice trained to perform operant tasks. First, we will examine how the firing rate of these interneurons varies in relation to distinct phases of the operant tasks. Next, we will examine how optogenetic manipulation (silencing or activation) of the activity of TH and NPY interneurons affects the firing rate of projection neurons, cholinergic and FS interneurons, how these manipulations affect local field potential oscillations, and how qualitative or quantitative measures of behavioral performance are affected. These experiments are expected to yield important new insights into the functioning of the neostriatum and may help to identify new cellular substrates for therapeutic interventions in a variety of neurological and neuropsychiatric disorders.

Public Health Relevance

This project seeks to describe the specific and selective inputs and outputs of newly discovered GABAergic interneurons in the neostriatum, a part of the brain that is essential for many functions including normal voluntary motor behavior, prediction of reward, and certain types of learning. The project will use novel molecular and genetic techniques to be able to identify and manipulate these interneurons with optical stimulation for in vitro recordings and in vivo recordings in mice performing an operant task.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS034865-15
Application #
8632129
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sutherland, Margaret L
Project Start
1997-02-01
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$527,041
Indirect Cost
$185,551
Name
Rutgers University
Department
Type
Organized Research Units
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
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Ãœnal, Bengi; Shah, Fulva; Kothari, Janish et al. (2015) Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway. Brain Struct Funct 220:331-49
Faust, Thomas W; Assous, Maxime; Shah, Fulva et al. (2015) Novel fast adapting interneurons mediate cholinergic-induced fast GABAA inhibitory postsynaptic currents in striatal spiny neurons. Eur J Neurosci 42:1764-74
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Ibáñez-Sandoval, Osvaldo; Xenias, Harry S; Tepper, James M et al. (2015) Dopaminergic and cholinergic modulation of striatal tyrosine hydroxylase interneurons. Neuropharmacology 95:468-76
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Unal, Bengi; Ibanez-Sandoval, Osvaldo; Shah, Fulva et al. (2011) Distribution of tyrosine hydroxylase-expressing interneurons with respect to anatomical organization of the neostriatum. Front Syst Neurosci 5:41
Koos, Tibor; Tecuapetla, Fatuel; Tepper, James M (2011) Glutamatergic signaling by midbrain dopaminergic neurons: recent insights from optogenetic, molecular and behavioral studies. Curr Opin Neurobiol 21:393-401
Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi et al. (2011) A novel functionally distinct subtype of striatal neuropeptide Y interneuron. J Neurosci 31:16757-69

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