In the past year, progress has been made in assessing changes in thalamo-cortical relationships in association with two types of neuronal damage: peripheral nerve injury and dopamine cell death. Both insults are thought to lead to alterations in the activity of thalamic input to cortex - the sensory cortex in the case of peripheral nerve injury, and the motor cortex in the case of dopamine cell death - and both appear to induce changes in cortical function as a result of the changes in thalamic activity. Our initial studies on the effects of dopamine cell death on thalamocortical activity were conducted in urethane-anesthetized rats with unilateral dopamine cell lesion. Urethane anesthesia is associated with a 1 Hz rhythm in the cortex. The loss of dopamine leads to entrainment of the basal ganglia to the 1 Hz cortical rhythm by 1 week after lesion, presumably through loss of dopaminergic modulation in the striatum and increased transmission of cortical rhythms to downstream sites. Recently we have explored the possibility that the increase in 1 Hz burstiness in basal ganglia output might lead to the whole basal ganglia thalamocortical loop becoming entrained with this 1 Hz rhythm. We studied the effects of unilateral dopamine cell lesion on spiking and local field potential (LFP) activity in three areas in the motor thalamus: the ventral anterior, ventral lateral and ventral medial nuclei. One to three weeks after dopamine cell lesion, we observed a reduction in power in the 1 Hz range in recordings from the ventral medial nucleus, which, relative to the ventral anterior/ventral lateral nuclei, receives a large proportion of the basal ganglia output. In addition, recordings in layer 5 of putative pyramidal corticothalamic output neurons in motor cortex showed rate decreases after dopaminergic lesion, whereas layer 4 neuronal rate was not affected. This evidence of a dampening of 1 Hz activity in the ventromedial nucleus and reduced activity in layer 5 of the motor cortex in the dopamine lesioned rats argues against the idea that resonance in this frequency range develops throughout the basal ganglia thalamocortical loop. Indeed, results suggest the opposite, that coincident 1 Hz oscillatory input from inhibitory basal ganglia and excitatory motor cortex projections reduces the power of the 1 Hz oscillatory activity in the motor thalamus and motor cortex. This raised the question of how loss of dopamine would affect activity in this network in awake behaving rats where higher frequencies are more evident in the motor cortex under normal conditions. To this end we have assessed spike/LFP relationships between basal ganglia output, motor thalamus and motor cortex in hemiparkinsonian rats trained to walk on a circular treadmill. After unilateral dopamine cell lesions, the hemiparkinsonian rats can make reasonable progress on the circular treadmill if they are oriented in the direction ipsiversive to the unilateral lesion, with their affected paws on the outside of the circular path. During treadmill walking, in the hemiparkinsonian rat, dopamine loss is associated with dramatic increases in beta range activity, focused around 30 35 Hz, in basal ganglia output to the thalamus. Similar increases in LFP power in this frequency range are also observed in the motor cortex and ventral medial thalamus. This activity is not evident during epochs of inattentive rest. These results show that the effects of dopamine loss on the basal ganglia thalamocortical network vary with behavioral state. Further analysis of simultaneous recordings of LFP activity from multiple sites within the motor network have shown correlated increases in coherence between motor cortex and basal ganglia output, and between motor cortex and ventral medial thalamus in the 30 35 Hz range after dopamine cell lesion during treadmill walking. Most recently we have found similar increases in coherence in this same frequency range between LFP in the substantia nigra and the ventral medial nucleus of the thalamus. Collectively, these data argue that spiking activity becomes synchronized and enhanced in this high beta/low gamma frequency range throughout the basal ganglia thalamocortical network during walking in the rat model of Parkinsons disease. We have investigated this hypothesis with a focus on the contribution of neuronal activity in the ventral medial thalamus to increased coherence within this network after loss of dopamine. Infusion of the GABA agonist muscimol into the ventral medial nucleus reduced power in both motor cortex and substantia nigra LFP and induced an 18 fold reduction in coherence between these two sites in the high beta/low gamma range during treadmill walking. These effects are reversed by injection of L-dopa. These results support the view that neuronal activity in the thalamocortical projections contributes to the emergence of high beta/low gamma synchronization throughout the basal ganglia thalamocortical network in the awake behaving parkinsonian rat. Most recently we have explored the time course of these changes in basal ganglia thalamocortical network resonance after dopamine cell lesion in awake behaving rats. Data show that the increases in coherence evolve over the course of the first week after dopamine cell lesion. Moreover, between week 1 and week three, the dominant frequency of the synchronous oscillation becomes slightly but significantly higher, suggesting that some degree of plasticity occurs over time in this network. Future plans address strategies for gaining insight into the potential significance of evolving plasticity basal ganglia thalamocortical loops in both non-lesioned and lesioned hemispheres of the hemiparkinsonian rat after loss of dopamine. The long term goal is to translate this insight into better means of treatment and amelioration of Parkinsons disease symptoms. These studies have been complemented by investigation of bilateral changes in activity in the barrel cortex following unilateral denervation of the whiskers in collaboration with investigators in the Mouse Imaging Facility. These investigators have shown that unilateral infraorbital denervation, removing the innervation of the whiskers unilaterally, increases both contralateral and ipsilateral fMRI responses in association with stimulation of the intact whisker pad. In addition, fMRI response in thalamic whisker barrel nuclei providing input to the barrel cortex can be visualized in these anesthetized rats. Neurophysiological recordings of spiking and LFP response in the barrel cortex both ipsilateral and contralateral to the unilateral infraorbital denervation have shown increased response of neurons in the barrel cortex contralateral to stimulation of the intact whisker pad in rat with unilateral infraorbital denervation. Most of the neurons responding to contralateral stimulation have the extacellular waveforms characteristic of pyramidal neurons. In contrast, increases in neuronal response in the ipsilateral cortex have the waveform characteristics of interneurons. As the contralateral responses are thought to reflect thalamic input, and the ipsilateral responses may be more likely to reflect transcortical input, these results point to different types of post-lesion plasticity in somatosensory circuits after the unilateral lesion of whisker pad innervation. Interestingly, both types of change are associated with increased fMRI response. A future goal is to extend these studies to explore the neurophysiological response in the thalamic nuclei relaying the activity to the barrel cortex to obtain further insight into the relative roles of changes in transcallosal vs thalamic activity in inducing altered contralateral and ipsilateral fMRI responses to stimulation of the intact whisker pad following unilateral infraorbital denervation.

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Furth, Katrina E; McCoy, Alex J; Dodge, Caroline et al. (2017) Neuronal correlates of ketamine and walking induced gamma oscillations in the medial prefrontal cortex and mediodorsal thalamus. PLoS One 12:e0186732
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
Delaville, Claire; Cruz, Ana V; McCoy, Alex J et al. (2014) Oscillatory Activity in Basal Ganglia and Motor Cortex in an Awake Behaving Rodent Model of Parkinson's Disease. Basal Ganglia 3:221-227
Yu, Xin; Chung, Seungsoo; Chen, Der-Yow et al. (2012) Thalamocortical inputs show post-critical-period plasticity. Neuron 74:731-42
Pelled, Galit; Bergstrom, Debra A; Tierney, Patrick L et al. (2009) Ipsilateral cortical fMRI responses after peripheral nerve damage in rats reflect increased interneuron activity. Proc Natl Acad Sci U S A 106:14114-9