The effects of L-DOPA on gait abnormalities in a unilateral 6-OHDA rat model of Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses, patients display disruptions in gait such as changes in posture, bradykinesia, and shortened stride. DA replacement via L-DOPA alleviates many PD symptoms, though its effects on gait are not well demonstrated. This study aimed to assess the relationship between DA lesion, gait, and deficit-induced reversal with L-DOPA. To do so, Sprague-Dawley rats (N = 25, 14 males, 11 females) received unilateral medial forebrain bundle (MFB) DA lesions with 6-hydroxydopamine (6-OHDA). An automated gait analysis system assessed spatiotemporal gait parameters pre- and post-lesion, and after various doses of L-DOPA (0, 3, or 6 mg/kg; s.c.). The forepaw adjusting steps (FAS) test was implemented to evaluate lesion efficacy while the abnormal involuntary movements (AIMs) scale monitored the emergence of L-DOPA-induced dyskinesia (LID). High performance liquid chromatography (HPLC) assessed changes in brain monoamines on account of lesion and treatment. Results revealed lesion-induced impairments in gait, inclusive of max-contact area and step-sequence alterations that were not reversible with L-DOPA. However, the emergence of AIMs were observed at higher doses. Post-mortem, 6-OHDA lesions induced a loss of striatal DA and norepinephrine (NE), while prefrontal cortex (PFC) displayed noticeable reduction in NE but not DA. Our findings indicate that hemiparkinsonian rats display measurable gait disturbances similar to PD patients that are not rescued by DA replacement. Furthermore, non-DA mechanisms such as attention-related NE in PFC may contribute to altered gait and may constitute a novel target for its treatment.

Hyperkinetic and Hypokinetic Movement Disorders in SSPE: A Systematic Review of Case Reports and Case Series.

Background: Subacute Sclerosing Panencephalitis (SSPE) typically presents with periodic myoclonus; however, a spectrum of movement disorders including dystonia, chorea, tremor, and parkinsonism have also been described. This review aims to evaluate the array of movement disorders in SSPE, correlating them with neuroimaging findings, disease stages, and patient outcomes. Methods: A comprehensive review of published case reports and case series was conducted on patients with SSPE exhibiting movement disorders other than periodic myoclonus. PRISMA guidelines were followed, and the protocol was registered with PROSPERO (2023 CRD42023434650). A comprehensive search of multiple databases yielded 37 reports detailing 39 patients. Dyken's criteria were used for SSPE diagnosis, and the International Movement Disorders Society definitions were applied to categorize movement disorders. Results: The majority of patients were male, with an average age of 13.8 years. Approximately, 80% lacked a reliable vaccination history, and 39% had prior measles infections. Dystonia was the most common movement disorder (49%), followed by parkinsonism and choreoathetosis. Rapid disease progression was noted in 64% of cases, with a disease duration of ≤6 months in 72%. Neuroimaging showed T2/FLAIR MR hyperintensities, primarily periventricular, with 26% affecting the basal ganglia/thalamus. Brain biopsies revealed inflammatory and neurodegenerative changes. Over half of the patients (56%) reached an akinetic mute state or died. Conclusion: SSPE is associated with diverse movement disorders, predominantly hyperkinetic. The prevalence of dystonia suggests basal ganglia dysfunction.

Effects of Unilateral High Frequency Stimulation of the Subthalamic Nucleus on Risk-avoidant Behavior in a Partial 6-hydroxydopamine Model of Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients' quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. METHODS: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. RESULTS: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. CONCLUSIONS: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.

Parkinsonism originates in a discrete secondary and dystonia in a primary motor cortical-basal ganglia subcircuit.

Although manifesting contrasting phenotypes, Parkinson's disease and dystonia, the two most common movement disorders, can originate from similar pathophysiology. Previously, we demonstrated that lesioning (silencing) of a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot-induced dystonia. Presently, we injected fluorescent-tagged multi-synaptic tracers into these pallidal hotspots (n = 36 Long Evans rats) and permitted 4 days for the viruses to travel along restricted connecting pathways and reach the motor cortex before sacrificing the animals. Viral injections in the Parkinson's hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice.

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.

Real-Time Precise Targeting of the Subthalamic Nucleus via Transfer Learning in a Rat Model of Parkinson's Disease Based on Microelectrode Arrays.

In neurodegenerative disorders, neuronal firing patterns and oscillatory activity are remarkably altered in specific brain regions, which can serve as valuable biomarkers for the identification of deep brain regions. The subthalamic nucleus (STN) has been the primary target for DBS in patients with Parkinson's disease (PD). In this study, changes in the spike firing patterns and spectral power of local field potentials (LFPs) in the pre-STN (zona incerta, ZI) and post-STN (cerebral peduncle, cp) regions were investigated in PD rats, providing crucial evidence for the functional localization of the STN. Sixteen-channel microelectrode arrays (MEAs) with sites distributed at different depths and widths were utilized to record neuronal activities. The spikes in the STN exhibited higher firing rates than those in the ZI and cp. Furthermore, the LFP power in the delta band in the STN was the greatest, followed by that in the ZI, and was greater than that in the cp. Additionally, increased LFP power was observed in the beta bands in the STN. To identify the best performing classification model, we applied various convolutional neural networks (CNNs) based on transfer learning to analyze the recorded raw data, which were processed using the Gram matrix of the spikes and the fast Fourier transform of the LFPs. The best transfer learning model achieved an accuracy of 95.16%. After fusing the spike and LFP classification results, the time precision for processing the raw data reached 500 ms. The pretrained model, utilizing raw data, demonstrated the feasibility of employing transfer learning for training models on neural activity. This approach highlights the potential for functional localization within deep brain regions.

Lesions of the lateral habenula excite dopamine neurons in the ventral tegmental area and serotonin neurons in the dorsal raphe nuclei in hemiparkinsonian rats.

The lateral habenula (LHb) projects to the ventral tegmental area (VTA) and dorsal raphe nuclei (DRN) that deliver dopamine (DA) and serotonin (5-HT) to cortical and limbic regions such as the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). Dysfunctions of VTA-related mesocorticolimbic dopaminergic and DRN-related serotonergic systems contribute to non-motor symptoms in Parkinson's disease (PD). However, how the LHb affects the VTA and DRN in PD remains unclear. Here, we used electrophysiological and neurochemical approaches to explore the effects of LHb lesions on the firing activity of VTA and DRN neurons, as well as the levels of DA and 5-HT in related brain regions in unilateral 6-hydroxydopamie (6-OHDA)-induced PD rats. We found that compared to sham lesions, lesions of the LHb increased the firing rate of DA neurons in the VTA and 5-HT neurons in the DRN, but decreased the firing rate of GABAergic neurons in the same nucleus. In addition, lesions of the LHb increased the levels of DA and 5-HT in the mPFC, ventral hippocampus and BLA compared to sham lesions. These findings suggest that lesions of the LHb enhance the activity of mesocorticolimbic dopaminergic and serotonergic systems in PD.

Sleep deprivation induces late deleterious effects in a pharmacological model of Parkinsonism.

Parkinson's disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6 h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.

Kinect-based objective assessment of the acute levodopa challenge test in parkinsonism: a feasibility study.

INTRODUCTION: The acute levodopa challenge test (ALCT) is an important and valuable examination but there are still some shortcomings with it. We aimed to objectively assess ALCT based on a depth camera and filter out the best indicators. METHODS: Fifty-nine individuals with parkinsonism completed ALCT and the improvement rate (IR, which indicates the change in value before and after levodopa administration) of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was calculated. The kinematic features of the patients' movements in both the OFF and ON states were collected with an Azure Kinect depth camera. RESULTS: The IR of MDS-UPDRS III was significantly correlated with the IRs of many kinematic features for arising from a chair, pronation-supination movements of the hand, finger tapping, toe tapping, leg agility, and gait (rs = - 0.277 ~ - 0.672, P < 0.05). Moderate to high discriminative values were found in the selected features in identifying a clinically significant response to levodopa with sensitivity, specificity, and area under the curve (AUC) in the range of 50-100%, 47.22%-97.22%, and 0.673-0.915, respectively. The resulting classifier combining kinematic features of toe tapping showed an excellent performance with an AUC of 0.966 (95% CI = 0.922-1.000, P < 0.001). The optimal cut-off value was 21.24% with sensitivity and specificity of 94.44% and 87.18%, respectively. CONCLUSION: This study demonstrated the feasibility of measuring the effect of levodopa and objectively assessing ALCT based on kinematic data derived from an Azure Kinect-based system.

ATP13A2 modifies mitochondrial localization of overexpressed TOM20 to autolysosomal pathway.

Mutations in ATP13A2 cause Kufor-Rakeb Syndrome (KRS), a juvenile form of Parkinson's Disease (PD). The gene product belongs to a diverse family of ion pumps and mediates polyamine influx from lysosomal lumen. While the biochemical and structural studies highlight its unique mechanics, how PD pathology is linked to ATP13A2 function remains unclear. Here we report that localization of overexpressed TOM20, a mitochondrial outer-membrane protein, is significantly altered upon ATP13A2 expression to partially merge with lysosome. Using Halo-fused version of ATP13A2, ATP13A2 was identified in lysosome and autophagosome. Upon ATP13A2 co-expression, overexpressed TOM20 was found not only in mitochondria but also within ATP13A2-containing autolysosome. This modification of TOM20 localization was inhibited by adding 1-methyl-4-phenylpyridinium (MPP+) and not accompanied with mitophagy induction. We suggest that ATP13A2 may participate in the control of overexpressed proteins targeted to mitochondrial outer-membrane.

Locus Coeruleus Integrity from 7 T MRI Relates to Apathy and Cognition in Parkinsonian Disorders.

BACKGROUND: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. OBJECTIVES: This study aimed to characterize the spatial patterns of LC pathological change in PD and PSP and the transdiagnostic relationship between LC signals and neuropsychiatric symptoms. METHODS: Twenty-five people with idiopathic PD, 14 people with probable PSP-Richardson's syndrome, and 24 age-matched healthy controls were recruited. Participants underwent clinical assessments and high-resolution (0.08 mm3 ) 7 T-magnetization-transfer imaging to measure LC integrity in vivo. Spatial patterns of LC change were obtained using subregional mean contrast ratios and significant LC clusters; we further correlated the LC contrast with measures of apathy and cognition, using both mixed-effect models and voxelwise analyses. RESULTS: PSP and PD groups showed significant LC degeneration in the caudal subregion relative to controls. Mixed-effect models revealed a significant interaction between disease-group and apathy-related correlations with LC degeneration (ß = 0.46, SE [standard error] = 0.17, F(1, 35) = 7.46, P = 0.01), driven by a strong correlation in PSP (ß = -0.58, SE = 0.21, t(35) = -2.76, P = 0.009). Across both disease groups, voxelwise analyses indicated that lower LC integrity was associated with worse cognition and higher apathy scores. CONCLUSIONS: The relationship between LC and nonmotor symptoms highlights a role for noradrenergic dysfunction across both PD and PSP, confirming the potential for noradrenergic therapeutic strategies to address transdiagnostic cognitive and behavioral features in neurodegenerative disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys.

AIMS: The striatum is mainly composed of projection neurons. It also contains interneurons, which modulate and control striatal output. The aim of the present study was to assess the percentages of projection neurons and interneuron populations in the striatum of control monkeys and of parkinsonian monkeys. METHODS: Unbiased stereology was used to estimate the volume density of every neuron population in the caudate, putamen and ventral striatum of control monkeys and of monkeys treated with MPTP, which results in striatal dopamine depletion. The various neuron population phenotypes were identified by immunohistochemistry. All analyses were performed within the same subjects using similar processing and analysis parameters, thus allowing for reliable data comparisons. RESULTS: In control monkeys, the projection neurons, which express the dopamine-and-cAMP-regulated-phosphoprotein, 32-KDa (DARPP-32), were the most abundant: ~86% of the total neurons counted. The interneurons accounted for the remaining 14%. Among the interneurons, those expressing calretinin were the most abundant (Cr+: ~57%; ~8% of the total striatal neurons counted), followed those expressing Parvalbumin (Pv+: ~18%; 2.6%), dinucleotide phosphate-diaphorase (NADPH+: ~13%; 1.8%), choline acetyltransferase (ChAT+: ~11%; 1.5%) and tyrosine hydroxylase (TH+: ~0.5%; 0.1%). No significant changes in volume densities occurred in any population following dopamine depletion, except for the TH+ interneurons, which increased in parkinsonian non-symptomatic monkeys and even more in symptomatic monkeys. CONCLUSIONS: These data are relevant for translational studies targeting specific neuron populations of the striatum. The fact that dopaminergic denervation does not cause neuron loss in any population has potential pathophysiological implications.

Dopamine depletion selectively disrupts interactions between striatal neuron subtypes and LFP oscillations.

Dopamine degeneration in Parkinson's disease (PD) dysregulates the striatal neural network and causes motor deficits. However, it is unclear how altered striatal circuits relate to dopamine-acetylcholine chemical imbalance and abnormal local field potential (LFP) oscillations observed in PD. We perform a multimodal analysis of the dorsal striatum using cell-type-specific calcium imaging and LFP recording. We reveal that dopamine depletion selectively enhances LFP beta oscillations during impaired locomotion, supporting beta oscillations as a biomarker for PD. We further demonstrate that dynamic cholinergic interneuron activity during locomotion remains unaltered, even though cholinergic tone is implicated in PD. Instead, dysfunctional striatal output arises from elevated coordination within striatal output neurons, which is accompanied by reduced locomotor encoding of parvalbumin interneurons and transient pathological LFP high-gamma oscillations. These results identify a pathological striatal circuit state following dopamine depletion where distinct striatal neuron subtypes are selectively coordinated with LFP oscillations during locomotion.

Pycnogenol ameliorates motor function and gene expressions of NF-ƙB and Nrf2 in a 6-hydroxydopamine-induced experimental model of Parkinson's disease in male NMRI mice.

We investigated the effect of Pycnogenol as an antioxidant on improving motor function, depression, and the expression of NF-ƙB and Nrf2 genes in the experimental model of Parkinson's disease. Forty adult male NMRI mice weighing about 30 g were randomly divided into five groups of eight. Saline group: received 3 µl of saline, as 6-hydroxydopamine (6-OHDA) solvent, unilaterally in the left striatum, treatment groups: first received 3 µl 6-OHDA unilaterally inside the ipsilateral striatum and then divided into subgroup A: received distilled water, Pycnogenol solvent, by gavage for 7 days (lesion group), and subgroup B: received Pycnogenol at doses of 10, 20, and 30 mg/kg by gavage for 7 days. Seven days after Parkinson's model induction, the apomorphine test, the degree of catalepsy by bar test, the duration of immobility (depression) by forced swimming test (FST) were measured. In addition, the expression of NF-ƙB and Nrf2 genes was measured using the real-time PCR technique. The total number of rotations in the apomorphine test decreased significantly in the groups receiving Pycnogenol. Administration of Pycnogenol significantly reduced catalepsy. The study of depression in the group receiving Pycnogenol showed a significant reduction. Also, Pycnogenol increased the expression of the Nrf2 anti-inflammatory gene, but it had no significant difference in the expression of NF-ƙB gene. Pycnogenol, presumably with its antioxidative and genomic effects, improves the expression of the anti-inflammatory gene and found that neuroprotection effect in the brain.

Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism.

The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson's disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD.

Serotonin 1A receptor agonist modulation of motor deficits and cortical oscillations by NMDA receptor interaction in parkinsonian rats.

Although serotonin 1A (5-HT1A) receptor agonists are widely used as the additive compound to reduce l-dopa-induced dyskinesia in Parkinson's disease (PD), few studies focused on the effect and mechanism of 5-HT1A receptor agonist on the motor symptoms of PD. Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were used and implantation of electrodes was performed in the motor cortex of these rats. So the effect of 5-HT1A receptor agonist 8-OH-DPAT on motor behaviors and oscillatory activities were evaluated. In addition, 8-OH-DPAT combined with D2 receptor antagonist raclopride, NMDA receptor antagonist MK-801, or its agonist d-cycloserine (DCS) were co-administrated. 8-OH-DPAT administration significantly improved spontaneous locomotor activity and asymmetric forepaw function in 6-OHDA-lesioned rats. Meanwhile, 8-OH-DPAT identified selective modulation of the abnormal high beta oscillations (25-40 Hz) in the motor cortex of 6-OHDA-lesioned rats, without inducing pathological finely tuned gamma around 80 Hz. Different from 8-OH-DPAT, l-dopa treatment produced a prolonged improvement on motor performances and differential regulation of high beta and gamma oscillations. However, dopamine D2 receptor antagonist had no influence on the 8-OH-DPAT-mediated-motor behaviors and beta oscillations in 6-OHDA-lesioned rats. In contrast, subthreshold NMDA receptor antagonist MK-801 obviously elevated the 8-OH-DPAT-mediated-motor behaviors, while NMDA receptor agonist DCS partially impaired the 8-OH-DPAT-mediated symptoms in 6-OHDA-lesioned rats. This study suggests that 5-HT1A receptor agonist 8-OH-DPAT improves motor activity and modulates the oscillations in the motor cortex of parkinsonian rats. Different from l-dopa, 8-OH-DPAT administration ameliorates motor symptoms of PD through glutamatergic rather than the dopaminergic pathway.

Modulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations.

Βeta oscillatory activity (human: 13-35 Hz; primate: 8-24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson's disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson's following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks.

Input Zone-Selective Dysrhythmia in Motor Thalamus after Dopamine Depletion.

The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow (∼1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: (1) BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; and (2) BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested that their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism.SIGNIFICANCE STATEMENT Motor thalamus neurons mediate the influences of basal ganglia and cerebellum on the cerebral cortex to govern movement. Chronic depletion of dopamine from the basal ganglia causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters the ways motor thalamus neurons engage with two distinct oscillations emerging in cortico-basal ganglia circuits in vivo We discovered that, after dopamine depletion, neurons in the thalamic zone receiving basal ganglia inputs are particularly prone to becoming dysrhythmic, changing the phases and/or synchronization (but not rate) of their action potential firing. This bolsters cortical dysrhythmia. Our results provide important new insights into how aberrant rhythmicity in select parts of motor thalamus could detrimentally affect neural circuit dynamics and behavior in Parkinsonism.

Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.

Parkinson's disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson's disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry's degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.