Early decreases in cortical mid-gamma peaks coincide with the onset of motor deficits and precede exaggerated beta build-up in rat models for Parkinson's disease.

Evidence suggests that exaggerated beta range local field potentials (LFP) in basal ganglia-thalamocortical circuits constitute an important biomarker for feedback for deep brain stimulation in Parkinson's disease patients, although the role of this phenomenon in triggering parkinsonian motor symptoms remains unclear. A useful model for probing the causal role of motor circuit LFP synchronization in motor dysfunction is the unilateral dopamine cell-lesioned rat, which shows dramatic motor deficits walking contralaterally to the lesion but can walk steadily ipsilaterally on a circular treadmill. Within hours after 6-OHDA injection, rats show marked deficits in ipsilateral walking with early loss of significant motor cortex (MCx) LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere; both effects were reversed by dopamine agonist administration. Increases in MCx and substantia nigra pars reticulata (SNpr) coherence and LFP power in the 29-40 Hz range emerged more gradually over 7 days, although without further progression of walking deficits. Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging over 7 days, as assessed during periods of walking before the morning treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. Earlier changes in cortical circuits, reflected in the rapid decreases in MCx LFP mid-gamma LFP activity, may contribute to evolving plasticity supporting increased beta range synchronized activity in basal ganglia-thalamocortical circuits after loss of dopamine receptor stimulation.

EXPRESSION OF THE RENIN-ANGIOTENSIN SYSTEM COMPONENTS IN ONCOLOGIC DISEASES.

The literature devoted to changes in the expression of the renin-angiotensin system (RAS) proteins of cancer cells was analyzed. The dynamics of RAS protein expression in malignant tumors and the possible role of epigenetic mechanisms in these processes are briefly reviewed. Through research of the epigenetic mechanisms in cancer, principally new techniques for their correction based on the use of selective regulatory systems of covalent modification of histone proteins (for example, deacetylase inhibitor) and microRNA synthesis technologies have been developed. Literature data show promising pharmacological correction of epigenetic modification of chromatin in the treatment of cancer.

Ventral Medial Thalamic Nucleus Promotes Synchronization of Increased High Beta Oscillatory Activity in the Basal Ganglia-Thalamocortical Network of the Hemiparkinsonian Rat.

Loss of dopamine is associated with increased synchronization and oscillatory activity in the subthalamic nucleus and basal ganglia (BG) output nuclei in both Parkinson's disease (PD) patients and animal models of PD. We have previously observed substantial increases in spectral power in the 25-40 Hz range in LFPs recorded in the substantia nigra pars reticulata (SNpr) and motor cortex (MCx) in the hemiparkinsonian rat during treadmill walking. The current study explores the hypothesis that SNpr output entrains activity in the ventral medial thalamus (VM) in this frequency range after loss of dopamine, which in turn contributes to entrainment of the MCx and BG. Electrode bundles were implanted in MCx, SNpr, and VM of rats with unilateral dopamine cell lesions. Spiking and LFP activity were recorded during epochs of rest and walking on a circular treadmill. After dopamine cell lesion, 30-36 Hz LFP activity in the VM became more robust during treadmill walking and more coherent with LFP activity in the same range in MCx and SNpr. Infusion of the GABAA antagonist picrotoxin into the VM reduced both high beta power in MCx and SNpr and coherence between MCx and SNpr while temporarily restoring walking ability. Infusion of the GABAA agonist muscimol into the VM also reduced MCx-SNpr coherence and beta power but failed to improve walking. These results support the view that synchronized neuronal activity in the VM contributes to the emergence of high beta oscillations throughout the BG-thalamocortical network in the behaving parkinsonian rat. SIGNIFICANCE STATEMENT: Parkinson's disease symptoms are associated with dramatic increases in synchronized beta range (15-35 Hz) oscillatory local field activity in several brain areas involved in motor control, but the mechanisms promoting this activity and its functional significance remain unresolved. This oscillatory activity can be recorded in awake behaving rats with unilateral dopamine cell lesions using chronically implanted electrodes. Although these rats have motor deficits, they can walk on a circular treadmill in the direction ipsilateral to their lesion. This study establishes a critical role for the ventral medial thalamus in the propagation of this exaggerated beta range oscillatory activity and the sequential entrainment of structures throughout the basal ganglia-thalamocortical loop in the lesioned hemisphere of hemiparkinsonian rats during treadmill walking.

Functional correlates of exaggerated oscillatory activity in basal ganglia output in hemiparkinsonian rats.

Exaggerated beta range (13-30Hz) synchronized activity is observed in the basal ganglia of Parkinson's disease (PD) patients during implantation of deep brain stimulation electrodes and is thought to contribute to the motor symptoms of this disorder. To explore the translational potential of similar activity observed in a rat model of PD, local field potentials (LFPs) and spiking activity in basal ganglia output were characterized in rats with unilateral dopamine cell lesion during a range of behaviors. A circular treadmill was used to assess activity during walking; hemiparkinsonian rats could maintain a steady gait when oriented ipsiversive to the lesioned hemisphere, but were less effective at walking when oriented contraversive to lesion. Dramatic increases in substantia nigra pars reticulata (SNpr) LFP oscillatory activity and spike-LFP synchronization were observed within the beta/low gamma range (12-40Hz) in the lesioned hemisphere, relative to the non-lesioned hemisphere, with the dominant frequency of spike-LFP entrainment and LFP power varying with behavioral state. At 3weeks postlesion, the mean dominant entrainment frequency during ipsiversive treadmill walking and grooming was 34Hz. Other behaviors were associated with lower mean entrainment frequencies: 27-28Hz during alert non-walking and REM, 17Hz during rest and 21Hz during urethane anesthesia with sensory stimulation. SNpr spike-LFP entrainment frequency was stable during individual treadmill walking epochs, but increased gradually over weeks postlesion. In contrast, SNpr LFP power in the 25-40Hz range was greatest at the initiation of each walking epoch, and decreased during walking to stabilize by 6min at 49% of initial values. Power was further modulated in conjunction with the 1.5s stepping rhythm. Administration of l-dopa improved contraversive treadmill walking in correlation with a reduction in SNpr 25-40Hz LFP power and spike synchronization in the dopamine cell lesioned hemisphere. These effects were reversed by the serotonergic 1A agonist, 8-OH-DPAT. While the prominent spike-LFP phase locking observed during ongoing motor activity in the hemiparkinsonian rats occurs at frequencies intriguingly higher than in PD patients, the synchronized activity in the SNpr of this animal model has much in common with oscillatory activity recorded from the basal ganglia of the PD patients. Results support the potential of this model for providing insight into relationships between synchronization of basal ganglia output induced by loss of dopamine and motor symptoms in PD.

Oscillatory Activity in Basal Ganglia and Motor Cortex in an Awake Behaving Rodent Model of Parkinson's Disease.

Exaggerated beta range (15-30 Hz) oscillatory activity is observed in the basal ganglia of Parkinson's disease (PD) patients during implantation of deep brain stimulation electrodes. This activity has been hypothesized to contribute to motor dysfunction in PD patients. However, it remains unclear how these oscillations develop and how motor circuits become entrained into a state of increased synchronization in this frequency range after loss of dopamine. It is also unclear whether this increase in neuronal synchronization actually plays a significant role in inducing the motor symptoms of this disorder. The hemiparkinsonian rat has emerged as a useful model for investigating relationships between loss of dopamine, increases in oscillatory activity in motor circuits and behavioral state. Chronic recordings from these animals show exaggerated activity in the high beta/low gamma range (30-35 Hz) in the dopamine cell-lesioned hemisphere. This activity is not evident when the animals are in an inattentive rest state, but it can be stably induced and monitored in the motor cortex and basal ganglia when they are engaged in an on-going activity such as treadmill walking. This review discusses data obtained from this animal model and the implications and limitations of this data for obtaining further insight into the significance of beta range activity in PD.

State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats.

Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, 7 d after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8-25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25-40 Hz band with a peak frequency at 30-35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons, and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25-40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity.