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.
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.
| Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698 |
| Guzman, Jaime N; Ilijic, Ema; Yang, Ben et al. (2018) Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest 128:2266-2280 |
| Surmeier, D James; Obeso, José A; Halliday, Glenda M (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101-113 |
| Chu, Hong-Yuan; McIver, Eileen L; Kovaleski, Ryan F et al. (2017) Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons. Neuron 95:1306-1318.e5 |
| Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926 |
| Surmeier, D James; Halliday, Glenda M; Simuni, Tanya (2017) Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. Exp Neurol 298:202-209 |
| Galtieri, Daniel J; Estep, Chad M; Wokosin, David L et al. (2017) Pedunculopontine glutamatergic neurons control spike patterning in substantia nigra dopaminergic neurons. Elife 6: |
| Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2017) Calcium and Parkinson's disease. Biochem Biophys Res Commun 483:1013-1019 |
| Burbulla, Lena F; Song, Pingping; Mazzulli, Joseph R et al. (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255-1261 |
| Dodla, Ramana; Wilson, Charles J (2017) Effect of Phase Response Curve Shape and Synaptic Driving Force on Synchronization of Coupled Neuronal Oscillators. Neural Comput 29:1769-1814 |
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