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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Sensorimotor Integration Study Section (SMI)
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Sutherland, Margaret L
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Rutgers University
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√únal, 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
English, Daniel F; Ibanez-Sandoval, Osvaldo; Stark, Eran et al. (2012) GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons. Nat Neurosci 15:123-30
Brazhnik, Elena; Shah, Fulva; Tepper, James M (2008) GABAergic afferents activate both GABAA and GABAB receptors in mouse substantia nigra dopaminergic neurons in vivo. J Neurosci 28:10386-98
Tepper, James M; Wilson, Charles J; Koos, Tibor (2008) Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons. Brain Res Rev 58:272-81
Duque, Alvaro; Tepper, James M; Detari, Laszlo et al. (2007) Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons. Brain Struct Funct 212:55-73
Lee, Christian R; Tepper, James M (2007) A calcium-activated nonselective cation conductance underlies the plateau potential in rat substantia nigra GABAergic neurons. J Neurosci 27:6531-41
Tepper, James M; Lee, Christian R (2007) GABAergic control of substantia nigra dopaminergic neurons. Prog Brain Res 160:189-208
Tepper, J M; Abercrombie, E D; Bolam, J P (2007) Basal ganglia macrocircuits. Prog Brain Res 160:3-7
Lee, Christian R; Tepper, James M (2007) Morphological and physiological properties of parvalbumin- and calretinin-containing gamma-aminobutyric acidergic neurons in the substantia nigra. J Comp Neurol 500:958-72
Tepper, James M; Koos, Tibor; Wilson, Charles J (2004) GABAergic microcircuits in the neostriatum. Trends Neurosci 27:662-9

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