In healthy individuals, the activities of neurons in the subthalamic nucleus (STN), the external globus pallidus(GPe) and basal ganglia output nuclei are poorly correlated, arrhythmic and related to normal movement in acomplex manner. In Parkinson's disease (PD) emergent, correlated, rhythmic burst activity in STN, GPe andbasal ganglia output neurons is associated with the debilitating symptoms of akinesia, tremor, bradykinesiaand rigidity. Reciprocally connected glutamatergic STN and GABAergic GPe neurons that innervate commonbasal ganglia output neurons are believed to be key mediators of pathological activity. Dopamine depletion inPD may enhance the tendency of the STN-GPe network to support intrinsic oscillatory activity and/or becomeentrained to low-frequency cortical rhythms via the direct cortical-STN connection. Treatments that correct/interrupt the pathological activity pattern, such as administration of dopamine precursors/dopamine receptoragonists or high-frequency electrical stimulation of the STN, profoundly ameliorate the symptoms of PD.Deeper understanding of the factors that control the activity pattern of STN and GPe neurons may thereforereveal novel and more effective strategies for the correction/interruption of pathological activity.The central hypothesis of Project 2 is that the abnormal patterning of the STN by cortical and GPe inputsin PD is due (in part) to a reduction in the direct dopaminergic modulation of STN neurons and pathological,adaptive alterations in the intrinsic membrane properties of STN neurons. We will therefore determine howintrinsic membrane properties and synaptic inputs interact to pattern the activity of STN neurons in uirroand in vivo, in normal and dopamine-depleted rodents and non-human primates. Using a combination ofelectrophysiological, pharmacological, molecular and optical approaches, the laboratories of Drs Bevan, Kita,Osten and Wilson will address 3 Specific Aims: i) determine how voltage- and Ca2+-dependent membraneproperties of STN neurons influence the patterning of STN activity by synaptic input m vitro; 2) determinehow dopamine and dopamine depletion modulate the intrinsic membrane properties of STN neurons andthe patterning of STN activity by synaptic input m vitro; 3) determine the relative contributions of intrinsicproperties and synaptic inputs to the firing pattern of STN neurons in normal and dopamine-depleted animalsin vivo.Lay summary: In PD, the STN exhibits a pathological pattern of activity that is associated with motordysfunction. Correction/interruption of pathological STN activity ameliorates the symptoms of PD. Project2 will therefore determine the principles underlying pathological STN activity so that more effective therapiesfor the treatment of PD can be developed.
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