Current focus in the Neurophysiological Pharmacology Section is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. The Sections on-going neurophysiological studies in several different rat preparations - locally anaesthetized, immobilized and artificially respired rats, freely moving rats and systemically anesthetized rats - have provided evidence that normal levels of dopamine receptor stimulation act to prevent emergence of inappropriately synchronized and oscillatory neuronal firing activity in basal ganglia networks, while significant increases and decreases in dopamine receptor stimulation enhance the expression of these dysfunctional patterns. In the past year, we have been exploring the specifics of dysfunctional alterations in basal ganglia output in animal models of Parkinsons disease. In particular, we have focused on beta range (12 35 Hz) activity which appears enhanced in the subthalamic nucleus of parkinsonian patients and has been hypothesized to be antikinetic in nature. Studies in the current review period have also used the 1 Hz rhythm dominant in the cortex of the anesthetized rat to develop hypotheses about how loss of dopamine can lead to entrainment of basal ganglia output to cortical rhythms. The data from the anesthetized rat studies suggest that loss of dopamine affects the ability of the striatum to properly filter input from the cortex, and promotes entrainment of the basal ganglia to cortical rhythms. To further examine this hypothesis, we have developed an awake behaving rat model of Parkinsons disease which allows us to investigate changes in basal ganglia activity after loss of dopamine in conjunction with changes in gait. The goal was to determine whether increases in synchronized and oscillatory activity in the beta range would be evident in a rodent preparation and correlated with loss of dopamine and motor dysfunction. Such a model would allow us to explore a number of questions related to the source of the exaggerated beta activity expressed in the basal ganglia in Parkinsons disease, and the extent to which this activity is responsible for motor dysfunction in parkinsonian patients. Rats were trained to walk in a novel rotary treadmill while EMG activity in shoulder muscle and neuronal activity in basal ganglia output were recorded. After unilateral loss of dopamine, rats made progress walking counterclockwise on the rotary treadmill, but tended to freeze during clockwise walking as this required the affected side to make more demanding adjustments of gait and posture. Our first studies in the awake behaving rats focused on the effect of dopamine cell lesion on firing rate and pattern in the SNpr during epochs of treadmill walking and inattentive rest. We hypothesized that we would see elevations in beta range activity in the lesioned hemisphere, relative to the intact hemisphere, as predicted by observations of prominent beta activity in the subthalamic nucleus in Parkinson patients. Substantia nigra pars reticulata (SNpr) was chosen as our initial target for these studies because changes in basal ganglia output are critical to the ultimate impact of basal ganglia dysfunction on downstream sites, and data from the anesthetized preparation predicted that SNpr activity would be entrained by increased synchronization in basal ganglia circuits. Recordings began seven days after surgery for unilateral dopamine cell lesion and electrode bundle implantation, in order to allow the rat time to recover from those procedures. Epochs identified as inattentive rest showed that SNpr local field potential (LFP) power in the low beta range (relatively concentrated around the 1218 Hz) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned (opposite to the lesioned) or control (brains with no lesions) hemispheres. At the end of the rest epoch, a buzzer sounded, and the investigator adjusted the rat in the treadmill and turned it on. During this adjustment period, as rats became alert and began to move, low beta power was reduced in the SNpr in both intact and lesioned hemispheres and, strikingly, activity in the high beta range (25-40 Hz, technically high beta/low gamma) became quite prominent in the lesioned hemisphere only. During treadmill walking, this high beta band was consistently expressed in the lesioned hemisphere, centered around 33 Hz. Thus, in the hemiparkinson rat, dopamine loss is associated with increases in the synchronization of SNpr activity, with apparent differences in the peak frequency depending on the behavior expressed by the rat. To further examine factors modulating the expression of high beta oscillatory activity in the basal ganglia under conditions of dopamine cell loss, single neurons and LFPs in SNpr were simultaneously recorded from lesioned and non-lesioned hemispheres in the hemiparkinsonian rats during a range of behaviors including alert rest, grooming, REM sleep, and while under light anesthesia (urethane) with sensory stimulation, in addition to walking and inattentive rest. SNpr LFP high beta oscillations remained consistently elevated from 1 week to 8 weeks post lesion in the lesioned hemisphere during ipsiversive treadmill walking, with mean SNpr power in lesioned hemisphere 5 fold greater than in the non-lesioned SNpr. High beta power was greatest at walking onset and diminished during walking episodes to 2.5 fold increase by the fifth min. Results showed a subtle but significant decrease in the dominant frequency during the alert inactive state (29 Hz) relative to treadmill walking, and a further declined to approximately 21 Hz in the lightly anesthetized, lightly stimulated state. L-dopa treatment significantly reduced high beta power in the SNpr LFPs (by 80%) on the lesioned side and improved walking on the circular treadmill contraversive to the lesion. This treatment also reduced beta range activity in the lightly anesthetized state. The serotonin 1A agonist reversed L-dopas effects on SNpr high beta power during walking, consistent with evidence that serotoninergic terminals in the central nervous system are involved in conversion of L-dopa to dopamine and release of dopamine after dopamine cell death. The correlation between beta activity and motor deficits in this animal model of Parkinsons disease support the hypothesis that increased beta range synchronization of neuronal activity in basal ganglia output plays a role in the mediating deficits in gait expressed by these rats. The range of frequencies observed in the synchronized activity in the basal ganglia over a range of behaviors in the hemiparkinsonian rat suggests that the synchronized activity is generated by complex neuronal networks, like those in the cortex, as opposed to a more limited network like that defined by the reciprocal connections between the external globus pallidus and the subthalamic nucleus. Future studies will examine the effects of local manipulation of neuronal activity at different nodes in the basal ganglia circuit to better understand how alterations in basal ganglia activity lead to motor dysfunction in Parkinsons disease.

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Brazhnik, Elena; McCoy, Alex J; Novikov, Nikolay et al. (2016) Ventral Medial Thalamic Nucleus Promotes Synchronization of Increased High Beta Oscillatory Activity in the Basal Ganglia-Thalamocortical Network of the Hemiparkinsonian Rat. J Neurosci 36:4196-208
Dupre, Kristin B; Cruz, Ana V; McCoy, Alex J et al. (2016) Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease. Neurobiol Dis 86:1-15
Delaville, Claire; McCoy, Alex J; Gerber, Colin M et al. (2015) Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks. J Neurosci 35:6918-30
Brazhnik, Elena; Novikov, Nikolay; McCoy, Alex J et al. (2014) Functional correlates of exaggerated oscillatory activity in basal ganglia output in hemiparkinsonian rats. Exp Neurol 261:563-77
Quiroga-Varela, A; Walters, J R; Brazhnik, E et al. (2013) What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity. Neurobiol Dis 58:242-8
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Brazhnik, Elena; Cruz, Ana V; Avila, Irene et al. (2012) State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats. J Neurosci 32:7869-80
Avila, Irene; Parr-Brownlie, Louise C; Brazhnik, Elena et al. (2010) Beta frequency synchronization in basal ganglia output during rest and walk in a hemiparkinsonian rat. Exp Neurol 221:307-19
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