The striatum 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 the striatum is illustrated by the severe disabilities associated with numerous neurological and neuropsy- chiatric conditions that affect this brain structure. The recent introduction of methods for targeting and manipulating genetically and physiologically defined cell types is currently revolutionizing our understanding of the neostriatum. Our preliminary studies, together with recent research demonstrate that the classically known cell types represent less than a third of the interneuron classes in the striatum, and reveal an intricate and precisely organized circuitry of these neurons. The prosed study will test 4 novel hypotheses which were formulated on the basis of preliminary data and capture functionally important principles of organization of the network of striatal interneurons. First, we will investigate the connectivity of genetically identified interneurons and test the hypotheses that their connectivity is highly cell type specific and structured to form at least 2 separate interneuron sub- networks within the neostriatum. Second, building on our previous research and novel preliminary data we hypothesize that cholinergic interneurons (CINs), which traditionally have been thought of as neuromodulatory elements, participate in a fast bi-directional synaptic network with multiple GABAergic interneurons utilizing nicotinic excitatory connections. Importantly, our preliminary data also suggest the existence of a novel source of nicotinic excitation from the brainstem that appears to selectively target a distinct subset of GABAergic interneurons. Third, we will test the hypothesis that a subset of interneurons are hierarchically organized in the sense that one or more classes of interneurons exist which are specialized to control the activity of other interneurons. These interneuron-specific interneurons are of great interest because their impact may be widely distributed and disproportionally amplified via hierarchical control of other interneurons. Finally, based on preliminary data we hypothesize that a class of novel GABAergic interneurons are essential for normal goal-directed behavior, and we will explore the mechanism of action of these neurons using in vivo electrophysiological and Ca2+-imaging methods. These experiments will yield important new insights into the functioning of the striatum 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 extend our previous findings with respect to specific and selective inputs and outputs of novel GABAergic interneurons of the neostriatum, a part of the brain that is essential for many functions including normal voluntary motor behavior, reward prediction error, and several types of learning. We will use state-of-the art electrophysiological, molecular and genetic techniques to be able to identify and manipulate striatal GABAergic interneurons with optical or pharmacological stimulation. We will use ex vivo whole cell, cell attached and paired recordings, and in vivo calcium imaging or tetrode recordings of identified GABAergic interneurons in mice performing an operant task to determine the intrastriatal microcircuitry and behavioral functions of the interneurons.

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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Miller, Daniel L
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Rutgers University
Other Basic Sciences
Schools of Arts and Sciences
United States
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Assous, Maxime; Faust, Thomas W; Assini, Robert et al. (2018) Identification and Characterization of a Novel Spontaneously Active Bursty GABAergic Interneuron in the Mouse Striatum. J Neurosci 38:5688-5699
Tepper, James M; Koós, Tibor; Ibanez-Sandoval, Osvaldo et al. (2018) Heterogeneity and Diversity of Striatal GABAergic Interneurons: Update 2018. Front Neuroanat 12:91
Assous, Maxime; Kaminer, Jaime; Shah, Fulva et al. (2017) Differential processing of thalamic information via distinct striatal interneuron circuits. Nat Commun 8:15860
Faust, Thomas W; Assous, Maxime; Tepper, James M et al. (2016) Neostriatal GABAergic Interneurons Mediate Cholinergic Inhibition of Spiny Projection Neurons. J Neurosci 36:9505-11
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
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
Xenias, Harry S; Ibáñez-Sandoval, Osvaldo; Koós, Tibor et al. (2015) Are striatal tyrosine hydroxylase interneurons dopaminergic? J Neurosci 35:6584-99
Ünal, 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
Oladapo, Abiola O; Rascati, Karen L (2012) Review of survey articles regarding medication therapy management (MTM) services/programs in the United States. J Pharm Pract 25:457-70
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

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