Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder affecting up to 25% of individuals over 65 years of age. Data from patients and animal models of PD have shown that the development of parkinsonisms is associated with the emergence of abnormally strong and widely synchronized oscillatory activity (OS) of the basal ganglia that developed after degeneration of midbrain dopamine containing neurons. Based on recent studies, we hypothesize that abnormal OS in the dopamine-depleted basal ganglia of PD patients is critically dependent on the development of abnormal OS in a nucleus called the external segment of the globus pallidus (GPe), which has strong neuronal connections with most of other nuclei in the basal ganglia. The main goal of this project is to reveal alterations of the functional and anatomical connectivity of GPe that underlie the generation of abnormal OS. Specifically, the aims of this grant are to reveal how dopamine depletion alters 1) the firing behavior of GPe neurons, 2) the conductivity of abnormal OS in the cortico-striato- GPe pathway, and 3) the properties of subthalamo-GPe loop that amplifies abnormal OS, all of which will provide information for designing experimental therapeutic strategies to reduce behavioral deficits in PD subjects. The results of the proposed studies will advance our understanding of the functional organization of the basal ganglia in pathological conditions and provide clear directions for future investigations including the formulation of treatment strategies of human parkinsonisms.

Public Health Relevance

The proposed research is relevant to public health because a large number of people, up to 25% of aging population over 65 years of age, suffer from parkinsonisms. Growing evidence suggests that abnormal signal transfer associated with abnormal neuronal activity underlies the development of parkinsonisms. We believe that new understandings of how the abnormal activity develops, along with newly developed methodologies to suppress identified abnormal activity in the basal ganglia, will provide a valuable foundation for the development of treatment strategies for parkinsonisms.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS057236-06A1
Application #
8750386
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38103
Kita, Takako; Osten, Pavel; Kita, Hitoshi (2014) Rat subthalamic nucleus and zona incerta share extensively overlapped representations of cortical functional territories. J Comp Neurol 522:4043-56
Kim, Juhyon; Kita, Hitoshi (2013) Short-term plasticity shapes activity pattern-dependent striato-pallidal synaptic transmission. J Neurophysiol 109:932-9
Kita, Takako; Kita, Hitoshi (2012) The subthalamic nucleus is one of multiple innervation sites for long-range corticofugal axons: a single-axon tracing study in the rat. J Neurosci 32:5990-9
Kita, Takako; Kita, Hitoshi (2011) Cholinergic and non-cholinergic mesopontine tegmental neurons projecting to the subthalamic nucleus in the rat. Eur J Neurosci 33:433-43
Tachibana, Yoshihisa; Iwamuro, Hirokazu; Kita, Hitoshi et al. (2011) Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia. Eur J Neurosci 34:1470-84
Nishibayashi, Hiroki; Ogura, Mitsuhiro; Kakishita, Koji et al. (2011) Cortically evoked responses of human pallidal neurons recorded during stereotactic neurosurgery. Mov Disord 26:469-76
Jaeger, D; Kita, H (2011) Functional connectivity and integrative properties of globus pallidus neurons. Neuroscience 198:44-53
Kita, Hitoshi; Kita, Takako (2011) Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia. J Neurosci 31:10311-22
Watanabe, Katsushige; Kita, Takako; Kita, Hitoshi (2009) Presynaptic actions of D2-like receptors in the rat cortico-striato-globus pallidus disynaptic connection in vitro. J Neurophysiol 101:665-71