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 recent studies of the effects of dopamine cell death on thalamo-cortical plasticity have addressed the question of how loss of dopamine affects activity in this network in awake behaving rats. Increases in synchronized and oscillatory activity in the basal ganglia have been linked to motor deficits in Parkinsonss disease (PD). To examine the role of thalamo-cortical component of the basal ganglia- thalamo-cortical loop in the emergence of this activity, we have been increasing our sample size and analyzing data from recordings of spike/LFP relationships between basal ganglia output, motor thalamus and motor cortex in hemiparkinsonian rats trained to walk on a circular treadmill. These recordings of LFP activity from multiple sites within the motor network show correlated increases in coherence between motor cortex and basal ganglia output, between motor cortex and ventral medial thalamus, and between basal ganglia output and ventral medial thalamus in the 30-35 Hz range after dopamine cell lesion during treadmill walking. These effects are reversed by treatment of the rats with L-dopa to compensate for dopamine cell loss. We find power in this frequency range and coherence between the different nodes in this basal ganglia thalamocortical loop are significantly reduced by this treatment. Collectively, these data show that spiking activity becomes synchronized and, at the population level, rhythmic in this high beta/low gamma frequency range throughout the basal ganglia thalamocortical network during walking in the rat model of Parkinsons disease. These results have led to the hypothesis that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger network after loss of dopamine. To further examine this, we have extended our series of experiments using infusion of the GABA agonist muscimol into the ventral medial nucleus to show reduced power in both motor cortex and substantia nigra LFP and reduced coherence between these two sites in the high beta/low gamma range during treadmill walking during muscimol infusion. 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. We have also found that muscimol infusion in both the unilaterally lesioned rat and the normal rat reduce walking in the circular treadmill. This data supports a role for the ventral medial thalamus in maintenance of normal motor function and the manuscript is in preparation. 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 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 include 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 develop a better understanding of the significance and mechanisms underlying these network changes with respect to strategies for 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. Recent related studies carried out in the Mouse Imaging Facility have utilized brain slice electrophysiology to demonstrate thalamocortical input strengthening onto the cortical L4 stellate cells which appears to be due to an increase in postsynaptic strength and the number of functional synapses. A future goal is to extend the in vivo 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. An additional goal is to incorporate optogenetic techniques into the imaging and neurophysiological studies.
