Our studies this year have addressed four research areas. 1.Pain mechanisms in PD. Although primarily known as a movement-related disorder, Parkinsons disease (PD) has several non-motor symptoms, such as pain, that have gained increasing attention. High prevalence of pain and increased pain sensitivity have been observed in human PD patients and animal models of PD. Studies have shown the ventromedial thalamic nucleus (VM) to relay nociceptive information from the medullary subnucleus reticular dorsalis to both the basal ganglia and a cortical region known to be involved in pain processing, the anterior cingulate cortex (ACC). Recent work from our lab has shown that the ACC and VM, components of the basal ganglia-thalamocortical circuit, exhibit pathological beta activity in a parkinsonian rat model. We have hypothesized that the excessive beta oscillations will disrupt pain processing. We have used 6-hydroxydopamine to lesion dopamine neurons in one hemisphere, to induce a unilateral rat model of PD. Electrode bundles are chronically implanted into the subthalamic nucleus (STN), ACC, and VM of the dopamine cell lesioned left hemisphere of rats. To induce a pain response, 1.5% concentration of the toxin formalin was subcutaneously injected into the planar surface of the right hind paw. The formalin test produces a biphasic response consisting of a 3-5 minute interval of pain behavior immediately after injection, a 10-15 minute quiescent interphase during which the rats will not display nociceptive behavior, and finally a 20-40 minute period of inflammatory pain. Behavioral pain response, spiking and LFP activity were recorded for the two hours immediately after formalin injection. Our studies to date show that the lesioned rats injected with 1.5% formalin have greater alpha (12-19 Hz) LFP power in the VM than sham lesioned rats. Further analysis is ongoing. Additional study into pain mechanisms may lead to the development of better treatment options for PD patients experiencing pain. 2. Cognitive function in PD. In addition to increased pain sensitivity, patients may also develop a wide variety of other nonmotor symptoms including cognitive impairment, the mechanism of which is not well understood. A recent study comparing electrophysiological data from the BG of PD and non-PD patients during a cognitive task showed the possible presence of electrophysiological abnormalities associated with cognitive function in the BG that may be used as biomarkers to help understand the basis of PD cognitive impairment. We have been exploring this by exposing hemiparkinsonian rats to unpredicted cognitive events and analyzing the changes in LFP power, spiking, and coherence data from several areas of the BG thalamocortical circuit involved in decision-making, with the focus on beta (25 35 Hz) and theta (4 12 Hz) frequency ranges. We were interested to see if increased theta activity could be observed in the rat model during unexpected events, as in primates, theta activity in the ACC is thought to be involved in the adjustment of behavior following unexpected changes in task demands (3 - 8 Hz). In the beta frequency range, LFP power was significantly increased in all areas during the walk epochs and first rule reversal epoch with the exception of the STN during the rule reversal. Theta frequency in the ACC has been linked with error prediction. Our results show significant increase in theta power the ACC during the first rule reversal in the control rats but not the lesioned rats on day 7 post-lesion. However, theta activity increased significantly in the ACC in day 21 post-lesioned rats during the first rule reversal. We also observed significant increase of coherence in the theta range between the ACC and the VM from day 7 to day 21 post-lesion during the first rule reversal, as well as significant decrease in the coherence between ACC and the STN. These results will be further analyzed, and could provide clues to biomarkers for alteration of executive control in hemiparkinsonian rats. 3. PF nucleus and motor function in PD. The parafascicular thalamic nucleus (Pf) receives inhibitory input from BG and provides output to the striatum and subthalamic nucleus. It has been suggested that activity in the PF also contributes to the expression of exaggerated beta oscillations in the BG and may therefore play a role in supporting PD motor symptoms. However, our recent observations have shown that unlike the VM, exaggerated beta oscillations are not evident in LFP recordings from the PF thalamic nucleus in the hemiparkinsonian awake behaving rat model. This study uses the awake behaving hemiparkisonian rat with 6-OHDA-induced unilateral dopamine cell lesion to gain further insight into the potential role of the Pf nucleus in supporting expression of beta oscillations in the BG-motor circuits. Electrodes were implanted in the SNpr, dorsal striatum and motor cortex (MCx), and a cannula was inserted into the Pf to allow modification of Pf activity via local infusion of muscimol, a GABA-A agonist, or picrotoxin, a GABA-A antagonist. After unilateral dopamine cell lesion, the hemiparkinsonian rats can walk on a circular treadmill in the direction ipsiversive to the unilateral lesion, with their affected paws on the outside of the circular path, and have considerable difficulty walking in the opposite direction, contraversive to the lesion. Microinfusion of muscimol into the Pf substantially reduced beta LFP power in MCx and SNpr and MCx- SNpr coherence (by 50-58% of baseline at 1h post-infusion) while temporarily restoring contraversive walking (up to 3 h). These data support the view that following substantial loss of dopamine, manipulations that induce tonic inhibition of the Pf activity improve motor function and argue for consideration of this site for deep brain stimulation. 4. Medial dorsal thalamus and schizophrenia: Alterations in the function of the medial prefrontal cortex (mPFC) and its major thalamic source of innervation, the mediodorsal (MD) thalamus, have been hypothesized to contribute to the symptoms of schizophrenia. The glutamate antagonist ketamine elicits a brain state resembling early stage schizophrenia characterized by cognitive deficits and increases in cortical low gamma (40-70Hz) power. We have used our neurophysiological tools to determine how ketamine differentially affects spiking and gamma local field potential (LFP) activity in the mPFC and MD thalamus. Additionally, we investigated the ability of drugs targeting the dopamine D4 receptor (D4R) to modify the effects of ketamine on neuronal activity as a measure of potential cognitive therapeutic efficacy. Rats were trained to walk on a treadmill to reduce confounds related to hyperactivity after ketamine administration (10 mg/kg) while recordings were obtained from electrodes chronically implanted in the mPFC and MD thalamus. Ketamine increased gamma LFP power in the mPFC and MD thalamus in a similar frequency range, yet did not increase thalamocortical synchronization. The D4R antagonist alone (L-745,870) had no effect on gamma LFP power during treadmill walking, although it reversed the increases induced by the D4R agonist (A-412997) in both mPFC and MD thalamus. Neither drug altered ketamine-induced changes in gamma power or firing rates in the mPFC. However, in the MD thalamus, the D4R agonist increased ketamine-induced gamma power and prevented ketamines inhibitory effect on firing rates. Results provide new evidence that ketamine differentially modulates spiking and gamma power in MD thalamus and mPFC, supporting a potential role for both areas in contributing to ketamine-induced psychotomimetic and cognitive symptoms.
