The ability to select proper actions is critical for flexible adaptive behavior. In vertebrates, multiple neural systems have evolved to coordinate different aspects of motor selection, execution, and learning. Key among these systems is the basal ganglia, a set of subcortical nuclei that are critical for motor planning and habit learning, and which are also implicated in Parkinson disease (PD), among the most commonly-diagnosed movement disorders. The anatomical connectivity of the basal ganglia is well characterized, and general hypotheses about basal ganglia function and the role of dopamine have been proposed. However, the mechanisms underlying dysfunction of basal ganglia circuits in PD is not well understood. In order to gain new insight into the dysfunction of the basal ganglia, we will target two new understudied aspects of basal ganglia circuitry: (1) the inputs from the thalamus to the striatum, and (2) the outputs from the substantia nigra reticulata/entopeduncular nucleus to the pedunculopontine tegmentum (PPTg). We have obtained compelling preliminary evidence that these regions are involved in motor dysfunction in animal models of PD, and we propose to thoroughly investigate the cellular, synaptic, and circuit mechanisms that underlie this dysfunction. The goal is to identify new therapeutic targets and strategies for treating PD, without the debilitating side effects associated with long-term use of dopamine replacement therapy.

Public Health Relevance

The ability to select appropriate actions is critical for survival. Movement disorders such as Parkinson's disease (PD) are characterized by difficulties selecting or changing actions. This results from dysfunction of neural circuits in the striatum, a core regio of the brain involved in motor planning. Here, we will investigate two new therapeutic targets for treating PD: the thalamostriatal synapse and the pedunculopontine nucleus. Each of these areas is relatively understudied, yet has great potential to lead to new therapeutic strategies for the treatment of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS064984-06A1
Application #
8817895
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sieber, Beth-Anne
Project Start
2009-04-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Roseberry, Thomas K; Lee, A Moses; Lalive, Arnaud L et al. (2016) Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia. Cell 164:526-37
Parker, Philip R L; Lalive, Arnaud L; Kreitzer, Anatol C (2016) Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice. Neuron 89:734-40
Nelson, Alexandra B; Kreitzer, Anatol C (2014) Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci 37:117-35
Nelson, Alexandra B; Hammack, Nora; Yang, Cindy F et al. (2014) Striatal cholinergic interneurons Drive GABA release from dopamine terminals. Neuron 82:63-70
Nelson, Alexandra B; Bussert, Timothy G; Kreitzer, Anatol C et al. (2014) Striatal cholinergic neurotransmission requires VGLUT3. J Neurosci 34:8772-7
Wall, Nicholas R; De La Parra, Mauricio; Callaway, Edward M et al. (2013) Differential innervation of direct- and indirect-pathway striatal projection neurons. Neuron 79:347-60
Kravitz, Alexxai V; Tye, Lynne D; Kreitzer, Anatol C (2012) Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci 15:816-8
Lerner, Talia N; Kreitzer, Anatol C (2012) RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits. Neuron 73:347-59
Nelson, Alexandra B; Hang, Giao B; Grueter, Brad A et al. (2012) A comparison of striatal-dependent behaviors in wild-type and hemizygous Drd1a and Drd2 BAC transgenic mice. J Neurosci 32:9119-23
Gittis, Aryn H; Kreitzer, Anatol C (2012) Striatal microcircuitry and movement disorders. Trends Neurosci 35:557-64

Showing the most recent 10 out of 20 publications