Thalamo-Cortical Plasticity: Pain, Executive Function and Loss of Dopamine

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Our main activity in this project area in the past year has focused on the role of the parafascicular thalamic nucleus (PF) in Parkinson disease (PD). Additional ongoing efforts under this project involve collaborations with past lab members directed toward finalizing three manuscripts addressing the role of the ventral medial (VM) thalamus in regulation of motor cortex and the anterior cingulate cortex (ACC) in PD using the hemiparkinsonian rat model. 1. The thalamic PF nucleus has been proposed as a target for therapeutic deep brain stimulation in PD and is known to influence activity in the striatum and subthalamic nucleus. Although the PF nucleus receives inputs from the basal ganglia and cortex as does the VM nucleus of the thalamus, unlike in the VM, we have found that recording of Local Field Potential (LFP) activity in the PF nucleus does not show exaggerated beta oscillations like those evident in recordings from the basal ganglia in the behaving, hemiparkinsonian rat. However, our results do call attention to the potential role of PF output in tonic modulation of the striatum and STN activity and support the idea that reductions in PF activity may have a therapeutic effect on motor dysfunction in PD. The results are interesting in the context of data showing possible selective remodeling of thalamostriatal glutamatergic synapses after dopamine depletion leading to increased activity in the striato-pallidal indirect pathway in PD and evidence that PF neurons appear to die over time in PD. The first of our results were presented as a poster presentation at the annual 2019 meeting of the Society for Neuroscience in Chicago. Our PF studies to date have examined the feasibility of using Cre-dependent inhibitory and excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) viruses to assess the effects of modulating activity in the motor circuits in hemiparkinsonian rats. We observed that stimulation of novel DREADD-induced inhibitory salvinorin B-sensitive receptors, induced by KORD (AAV2/8-hSyn-HA-KORD-IRES-mCitrine) mediated transfection, in the thalamic PF nucleus significantly improves treadmill walking, especially with respect to percent completed trials when rats were walking in the direction that is impaired by dopamine cell depletion. Consistently, stimulation of novel DREADD induce excitatory CNO-sensitive receptors in the thalamic PF nucleus showed the opposite effects, enhancing motor deficit. These results supported the view that Salvinorin-B sensitive receptor-mediated reduction of activity in PF projections to the basal ganglia, involving either the non-selective pool of PF neurons, or in PF neurons that selectively control the activity in the striatum and subthalamic nucleus, effectively modulates activity in basal ganglia output in a manner which reduces motor deficits. However, these results also showed that, although improvements in treadmill walking were clear with KORD-mediated transfection, the expression of novel DREADD-induced inhibitory salvinorin B-sensitive receptors in the thalamic parafascicular nucleus was quite low (less than 20%). To further confirm that the beneficial effects involved selective inactivation of the PF projections to striatum and STN in motor deficit reduction in PD rats, we infused a different viral vector, Cre- dependent hM4-DIO, (AAV2/5-hSyn-hM4-DIO-mCherry) into the PF, and infused the Cre-recombinase into the targets - striatum and STN. Stimulation of these DREADD-induce inhibitory CNO/Clozapine-sensitive receptors in the thalamic PF nucleus showed effects similar to those with KORD, improved walking. Notably, the expression of the induced receptors in PF cells and their terminals in the target regions, striatum and STN, was quite impressive. We have recently we added more rats to this study and are now finalizing the data for publication. The past years results are consistent with the view that inhibition of activity in the PF nucleus can reduce motor symptoms in PD. Moreover, in contrast to the effect of the DREADDS on treadmill walking in these experiments, neither the excitatory or inhibitory DREADDs induced marked changes in coherence between LFP high beta oscillations in the MCx and SNpr. This supports our other studies indicating that mean changes in LFP coherence and power in the high beta range in motor cortex and SNpr are not very sensitive markers for improved motor function and calls for further attention to changes in burst of LFP activity and the fine structure of this phenomena. 2. An additional project involves an on-going collaboration with a colleague, Dr. Louise Parr-Brownlie, at the Brain Health Research Center at the University of Otago, New Zealand, previously a postdoc in the NPS. This study is analyzing how the non-sinusoidal features of waveforms shape may inform underlying physiology and parkinsonian pathophysiology, using data from our recordings of slow-wave and high beta oscillations in LFP from the motor cortex and thalamus of anesthetized and unanesthetized hemiparkinsonian rats. 3. In addition, in the past year work has progressed on two manuscripts that are near completion. One addresses the role of the VM thalamic nucleus in induction of a phenomena referred to as finely tuned gamma or FTG, a pattern of exaggerated gamma range activity evident in the motor cortex in dyskinetic rats. This activity is hypothesized to be involved in the hyperactive dyskinetic behavioral of parkinsonian rats and patients after chronic treatment with L-dopa. We have shown that in the rat model, contrary to expectations, that one can block the expression of cortical FTG, and this does not stop the dyskinesia. This study, was done in collaboration with Kristin Dupre, PhD, previously a Postdoctoral Fellow in the Neurophysiological Pharmacology Section, currently working in NINDS OD. 4. A second manuscript is being finalized in collaboration with Alex Weiss, PhD. previously a graduate student in the Ox/Cam NIH Graduate Partnership Program and currently a Postdoctoral Fellow in Johns Hopkins Medical School. This study describes our investigation of neurophysiological changes anterior cingulate cortex (ACC) in the rat model of PD. Patients with PD are known to express dopamine-dependent cognitive impairments, implying effects of dopamine loss on prefrontal cortex function. The electrophysiological correlates of these cognitive symptoms are not well understood. In light of our finding that the ACC develops exaggerated beta range LFP activity in the parkinsonian rat, we have investigated the involvement of basal ganglia thalamocortical circuits in dopamine-impaired and healthy rats in response to a salient cue that predicts the onset of either tone-to-treadmill-induced walking (an expected event) or tone to-no-treadmill-induced walking (an unexpected event). Results show that the basal ganglia VM thalamocortical circuit develops both exaggerated oscillatory LFP and spiking activity during cognition in the hemiparkinsonian rat model of advanced stage PD. The manuscript discusses these results in the context of the goal of using the hemiparkinsonian rat to explore biomarkers for alteration of executive control in PD. As cognitive symptoms in PD patients become an increasingly recognized issue, preclinical animal models for the study of PD cognitive impairment have become increasingly necessary. Despite the limitations of the model, hemiparkinsonian rats display some of the most important cognitive symptoms seen in patients with PD, including impairment of executive function, and our results so far have been able to reproduce some of the electrophysiological dysfunctions in the same anatomical sites as observed in human subjects.