Persistent, synchronous, rhythmic activity throughout the cortico-basal ganglia thalamocortical loop is thought to underlie the debilitating motor symptoms of idiopathic and experimental Parkinson's disease (PD). 13-30 Hz b activity is linked to the expression of akinesia, bradykinesia and rigidity, whereas 4-7 Hz rhythmic activity is associated with resting tremor. Motor cortical inputs to the subthalamic nucleus (STN) are involved in the generation of this abnormal pattern of activity but the underlying mechanisms are poorly defined. We hypothesize that in PD loss of direct dopaminergic neuromodulation and alterations in the synaptic and intrinsic properties of neurons in the STN and reciprocally connected external globus pallidus (GPe) am- plify the response of the STN to rhythmic motor cortical inputs, leading to the emergence and propagation of abnormal activity throughout the cortico-basal ganglia thalamocortical loop. Indeed, manipulation of motor cortex-STN activity is posited to underlie the therapeutic effects of STN deep brain stimulation in PD. Thus, we propose to apply in control and chronic dopamine-depleted adult mice: 1) optogenetic and genetic approaches to manipulate motor cortex-STN and GPe-STN synaptic transmission and plasticity;2) electrophysiology and 2-photon laser scanning microscopy to study motor cortex-STN synaptic function/dysfunction and plasticity ex vivo;3) anatomical approaches at the light and electron microscopic levels and molecular profiling to determine the structural and molecular properties of motor cortex-STN synaptic transmission. We will address 4 Specific Aims: 1. Determine the synaptic and intrinsic mechanisms underlying the motor cortical patterning of STN activity and whether motor cortical inputs exhibit NMDA receptor-dependent long-term potentiation;2. Determine whether dopamine directly modulates the transmission, plasticity and in- tegration of motor cortex-STN synaptic inputs;3. Determine whether chronic dopamine depletion increases the strength of motor cortex-STN synaptic transmission through NMDA receptor-dependent plasticity;4. Deter- mine whether loss of autonomous STN activity and alterations in GPe-STN inhibition following dopamine deple- tion increase the impact of motor cortex-STN inputs. Together the data arising from this research will refine our model of basal ganglia function and dysfunc- tion and inform in Project 5 the preclinical development of gene therapies that aim, through manipulation of STN and GPe NMDA receptors, to correct the motor symptoms of PD by normalizing the pattern of cortico-basal ganglia thalamocortical activity.

Public Health Relevance

In experimental and idiopathic Parkinson's disease (PD), the cerebral cortex and subthalamic nucleus (STN) exhibit persistent, synchronous, rhythmic activity. Although correction of this abnormal activity pattern by dopamine replacement therapy or deep brain electrical stimulation of the STN profoundly improves motor func- tion, these therapies are limited in their application by associated side effects. We therefore propose to study the mechanisms underlying the emergence of abnormal activity so that better treatments can be developed to treat the motor symptoms of PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS047085-11
Application #
8608922
Study Section
Special Emphasis Panel (ZNS1-SRB-J (03))
Project Start
Project End
Budget Start
2013-09-30
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$296,298
Indirect Cost
$101,434
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hegeman, Daniel J; Hong, Ellie S; Hernández, Vivian M et al. (2016) The external globus pallidus: progress and perspectives. Eur J Neurosci 43:1239-65
Glajch, Kelly E; Kelver, Daniel A; Hegeman, Daniel J et al. (2016) Npas1+ Pallidal Neurons Target Striatal Projection Neurons. J Neurosci 36:5472-88
Higgs, Matthew H; Wilson, Charles J (2016) Unitary synaptic connections among substantia nigra pars reticulata neurons. J Neurophysiol 115:2814-29
Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2016) Calcium and Parkinson's disease. Biochem Biophys Res Commun :
Cooper, Garry; Lasser-Katz, Efrat; Simchovitz, Alon et al. (2015) Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus. J Neurophysiol 114:1513-20
Chu, Hong-Yuan; Atherton, Jeremy F; Wokosin, David et al. (2015) Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron 85:364-76
Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling et al. (2015) Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus. J Neurosci 35:11830-47
Surmeier, D James; Graves, Steven M; Shen, Weixing (2014) Dopaminergic modulation of striatal networks in health and Parkinson's disease. Curr Opin Neurobiol 29:109-17
Gittis, Aryn H; Berke, Joshua D; Bevan, Mark D et al. (2014) New roles for the external globus pallidus in basal ganglia circuits and behavior. J Neurosci 34:15178-83
Wilson, Charles J (2014) Oscillators and Oscillations in the Basal Ganglia. Neuroscientist :

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