Morphological changes in the substantia nigra pars reticulata of the mice during kindling.

Substantia nigra pars reticulata (SNpr) has been implicated in modulation, propagation and cessation of seizures. This study aimed to determine whether structural changes occur in SNpr during kindling. Male mice were randomly divided into four groups including early and late-phase kindled groups and their time-matched controls. Kindling was induced by every other day administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.). The first occurrence of seizure behaviors was used to categorize the early and late phases of kindling. There was no significant difference in the volume of SNpr between the early- and late-phase kindled groups. The diameter of SNpr was significantly increased in the early phase group and decreased in the late phase group as compared to their matched controls (p < 0.05). Reduced neural cells and increased dead cell numbers were observed in the SNpr of the late-phase group in comparison to its control group (p < 0.05). These findings suggest that SNpr is a sensitive and vulnerable structure involving seizure propagation in the processes of epileptogenesis.

Disrupted basal ganglia output during movement preparation in hemiparkinsonian mice is consistent with behavioral deficits.

Parkinsonian motor deficits are associated with elevated inhibitory output from the basal ganglia (BG). However, several features of Parkinson's disease (PD) have not been accounted for by this simple "classical rate model" framework, including the observation in patients with PD that movements guided by external stimuli are less impaired than otherwise identical movements generated based on internal goals. Is this difference due to divergent processing within the BG itself or due to the recruitment of extra-BG pathways by sensory processing? In addition, surprisingly little is known about precisely when, in the sequence from selecting to executing movements, BG output is altered by PD. Here, we address these questions by recording activity in the substantia nigra pars reticulata (SNr), a key BG output nucleus, in hemiparkinsonian mice performing a well-controlled behavioral task requiring stimulus-guided and internally specified directional movements. We found that hemiparkinsonian mice exhibited a bias ipsilateral to the side of dopaminergic cell loss that was stronger when movements were internally specified rather than stimulus guided, consistent with clinical observations in patients with Parkinson's disease. We further found that changes in parkinsonian SNr activity during movement preparation were consistent with the ipsilateral behavioral bias, as well as its greater magnitude for internally specified movements. Although these findings are inconsistent with some aspects of the classical rate model, they are accounted for by a related "directional rate model" positing that SNr output phasically overinhibits motor output in a direction-specific manner. These results suggest that parkinsonian changes in BG output underlying movement preparation contribute to the greater deficit in internally specified than stimulus-guided movements.NEW & NOTEWORTHY Movements of patients with Parkinson's disease are often less impaired when guided by external stimuli than when generated based on internal goals. Whether this effect is due to distinct processing in the basal ganglia (BG) or due to compensation from other motor pathways is an open question with therapeutic implications. We recorded BG output in behaving parkinsonian mice and found that BG activity during movement preparation was consistent with the differences between these forms of movement.

Dopaminergic Projection from Ventral Tegmental Area to Substantia Nigra Pars Reticulata Mediates Chronic Social Defeat Stress-Induced Hypolocomotion.

Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.

Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice.

Delta oscillations (0.5-4 Hz) are a robust feature of basal ganglia pathophysiology in patients with Parkinson's disease (PD) in relationship to tremor, but their relationship to other parkinsonian symptoms has not been investigated. While delta oscillations have been observed in mouse models of PD, they have only been investigated in anesthetized animals, suggesting that the oscillations may be an anesthesia artifact and limiting the ability to relate them to motor symptoms. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine-depleted mice. We find that approximately half of neurons in the substantia nigra pars reticulata (SNr) exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting, and synchrony. These oscillations are typically weakened, but not ablated, during movement. We further establish that these oscillations are caused by the loss of D2-receptor activation and do not originate from motor cortex, contrary to previous findings in anesthetized animals. Instead, SNr oscillations precede those in M1 at a 100- to 300-ms lag, and these neurons' relationship to M1 oscillations can be used as the basis for a novel classification of SNr into two subpopulations. These results give insight into how dopamine loss leads to motor dysfunction and suggest a reappraisal of delta oscillations as a marker of akinetic symptoms in PD.NEW & NOTEWORTHY This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson's disease (PD) treatment.

Case Studies in Neuroscience: Lack of inhibitory synaptic plasticity in the substantia nigra pars reticulata of a patient with lithium-induced tremor.

Tremor is a well-known side effect from many psychiatric medications, including lithium and dopamine antagonists. In patients whose psychiatric symptoms are stabilized and only respond to certain medications, deep brain stimulation may offer relief of the consequent motor complications. We report the case of an elderly male with disabling tremor related to lithium therapy for bipolar affective disorder, who was subsequently treated with deep brain stimulation. In this patient, we obtained recordings from the substantia nigra pars reticulata and performed a high-frequency stimulation protocol that robustly elicits long-term potentiation (LTP)-like changes in patients with Parkinson's disease. We hypothesized that in this patient, who did not have Parkinson's disease, the levels of inhibitory plasticity would be much greater. However, we found an unanticipated lack of plasticity in the patient with lithium-induced tremor, compared with two de novo control patients with Parkinson's disease. This patient was successfully treated with deep brain stimulation in the vicinity of the ventral oral posterior nucleus, an area of the thalamus that receives inputs from the basal ganglia. We postulate that the lithium-induced blockade of LTP may bring about motor complications such as tremor while simultaneously contributing to the therapeutic mechanism for treating the symptoms of psychiatric disorders such as bipolar affective disorder.NEW & NOTEWORTHY Use of a dual-microelectrode technique enabled us to compare long-term potentiation (LTP)-like changes in a patient with lithium-induced tremor to that of patients with Parkinson's disease. This study corroborated the findings in rodent brain slices that chronic lithium treatment may block LTP. Whereas a deficit in LTP may underlie the therapeutic mechanism for treating psychiatric disorders such as bipolar affective disorder, it may simultaneously contribute to consequent appearance of tremor.

State transitions in the substantia nigra reticulata predict the onset of motor deficits in models of progressive dopamine depletion in mice.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose cardinal motor symptoms are attributed to dysfunction of basal ganglia circuits under conditions of low dopamine. Despite well-established physiological criteria to define basal ganglia dysfunction, correlations between individual parameters and motor symptoms are often weak, challenging their predictive validity and causal contributions to behavior. One limitation is that basal ganglia pathophysiology is studied only at end-stages of depletion, leaving an impoverished understanding of when deficits emerge and how they evolve over the course of depletion. In this study, we use toxin- and neurodegeneration-induced mouse models of dopamine depletion to establish the physiological trajectory by which the substantia nigra reticulata (SNr) transitions from the healthy to the diseased state. We find that physiological progression in the SNr proceeds in discrete state transitions that are highly stereotyped across models and correlate well with the prodromal and symptomatic stages of behavior.

Modulation of inhibitory plasticity in basal ganglia output nuclei of patients with Parkinson's disease.

Deep brain stimulation of certain target structures within the basal ganglia is an effective therapy for the management of the motor symptoms of Parkinson's disease. However, its mechanisms, as well as the pathophysiology of Parkinson's disease, are varied and complex. The classical model of Parkinson's disease states that symptoms may arise as a result of increased neuronal activity in the basal ganglia output nuclei due to downregulated GABAergic striato-nigral/-pallidal projections. We sought to investigate the stimulation and levodopa induced effects on inhibitory synaptic plasticity in these basal ganglia output nuclei, and to determine the clinical relevance of altered plasticity with respect to patients' symptoms. Two closely spaced microelectrodes were advanced into the substantia nigra pars reticulata (potential novel therapeutic target for axial motor symptoms) or globus pallidus internus (conventional therapeutic target) in each of 28 Parkinson's disease patients undergoing subthalamic or pallidal deep brain stimulation surgery. Sets of 1 Hz test-pulses were delivered at different cathodal pulse widths (25, 50, 100, 150, 250 µs) in randomized order, before and after a train of continuous high frequency stimulation at 100 Hz. Increasing the pulse width led to progressive increases in both the amplitudes of extracellular focally evoked inhibitory field potentials and durations of neuronal silent periods. Both of these effects were augmented after a train of continuous high frequency stimulation. Additionally, reductions in the baseline neuronal firing rate persisted beyond 1 min after high frequency stimulation. We found greater enhancements of plasticity in the globus pallidus internus compared to the substantia nigra pars reticulata, and that intraoperative levodopa administration had a potent effect on the enhancement of nigral plasticity. We also found that lower levels of nigral plasticity were associated with higher severity motor symptoms. The findings of this study demonstrate that the efficacy of inhibitory synaptic transmission may be involved in the pathophysiology of Parkinson's disease, and furthermore may have implications for the development of novel stimulation protocols, and advancement of DBS technologies.

Granger causality supports abnormal functional connectivity of beta oscillations in the dorsolateral striatum and substantia nigra pars reticulata in hemiparkinsonian rats.

Synchronized oscillatory neuronal activity in the beta frequency range has been reported in the basal ganglia (BG) of patients with Parkinson disease (PD) and PD animal models. The coherent abnormal oscillatory activities in the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr) that accompany parkinsonian states have not been resolved. In this study, we recorded local field potentials (LFPs) in the dStr and SNr of 6-hydroxydopamine (6-OHDA)-induced dopamine (DA)-lesioned rats in an awake, resting state. Analyses of power spectral density and coherence data demonstrated augmented LFP power in the 24-36-Hz (high beta) range in both the dStr and SNr together with increased dStr-SNr coherence in the 24-36-Hz range, relative to sham controls; both effects were reversed by levodopa (L-dopa) treatment. Partial Granger causality analysis revealed a dStr→SNr propagation directionality of these beta oscillations. These findings support the involvement of increased synchronization of high beta activity in the dStr and the SNr, and suggest that dorsolateral striatal activity plays a determinant role in leading the coherent activity with the SNr in the development of parkinsonian pathophysiology.

Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia.

Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats.

The pathophysiology of Parkinson's disease (PD) and of L-DOPA-induced dyskinesia (LID) is associated with dysfunctional neuronal activity in several nuclei of the basal ganglia. Moreover, high levels of oscillatory activity and synchronization have also been described in both intra- and inter-basal ganglia nuclei and the cerebral cortex. However, the relevance of these alterations in the motor symptomatology related to Parkinsonism and LID is not fully understood. Recently, we have shown that subthalamic neuronal activity correlates with axial abnormal movements and that a subthalamic nucleus (STN) lesion partially reduces LID severity as well as the expression of some striatal molecular modifications. The aim of the present study was to assess, through single-unit extracellular recording techniques under urethane anaesthesia, neuronal activity of the substantia nigra pars reticulata (SNr) and its relationship with LID and STN hyperactivity together with oscillatory and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned and dyskinetic rats. Twenty-four hours after the last injection of L-DOPA the firing rate and the inhibitory response to an acute challenge of L-DOPA of SNr neurons from dyskinetic animals were increased with respect to those found in intact and 6-OHDA-lesioned rats. Moreover, there was a significant correlation between the mean firing rate of SNr neurons and the severity of the abnormal movements (limb and orolingual subtypes). There was also a significant correlation between the firing activity of SNr and STN neurons recorded from dyskinetic rats. In addition, low frequency band oscillatory activity and synchronization both within the SNr or STN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals and not or slightly affected by chronic treatment with L-DOPA. Altogether, these results indicate that neuronal SNr firing activity is relevant in dyskinesia and may be driven by STN hyperactivity. Conversely, low frequency oscillatory activity and synchronization seem to be more important in PD because they are not influenced by prolonged L-DOPA administration.

Effects of deep brain stimulation on balance and gait in patients with Parkinson's disease: A systematic neurophysiological review.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) provides an efficient treatment for the alleviation of motor signs in patients with Parkinson's disease. The effects of DBS on gait and balance disorders are less successful and may even lead to an aggravation of freezing of gait and imbalance. The identification of a substantia nigra pars reticulata (SNr)-mesencephalic locomotor region (MLR) network in the control of locomotion and postural control and of its dysfunction/lesion in PD patients with gait and balance disorders led to suggestion that DBS should be targeting the SNr and the pedunculopontine nucleus (part of the MLR) for PD patients with these disabling axial motor signs. However, the clinical results to date have been disappointing. In this review, we discuss the effects of DBS of these basal ganglia and brainstem structures on the neurophysiological parameters of gait and balance control in PD patients. Overall, the data suggest that both STN and GPi-DBS improve gait parameters and quiet standing postural control in PD patients, but have no effect or may even aggravate dynamic postural control, in particular with STN-DBS. Conversely, DBS of the SNr and PPN has no effect on gait parameters but improves anticipatory postural adjustments and gait postural control.

Bursting activity of substantia nigra pars reticulata neurons in mouse parkinsonism in awake and anesthetized states.

Electrophysiological changes in basal ganglia neurons are hypothesized to underlie motor dysfunction in Parkinson's disease (PD). Previous results in head-restrained MPTP-treated non-human primates have suggested that increased bursting within the basal ganglia and related thalamic and cortical areas may be a hallmark of pathophysiological activity. In this study, we investigated whether there is increased bursting in substantia nigra pars reticulata (SNpr) output neurons in anesthetized and awake, head-restrained unilaterally lesioned 6-OHDA mice when compared to control mice. Confirming previous studies, we show that there are significant changes in the firing rate and pattern in SNpr neuron activity under urethane anesthesia. The regular firing pattern of control urethane-anesthetized SNpr neurons was not present in the 6-OHDA-lesioned group, as the latter neurons instead became phase locked with cortical slow wave activity (SWA). Next, we examined whether such robust electrophysiological changes between groups carried over to the awake state. SNpr neurons from both groups fired at much higher frequencies in the awake state than in the anesthetized state and surprisingly showed only modest changes between awake control and 6-OHDA groups. While there were no differences in firing rate between groups in the awake state, an increase in the coefficient of variation (CV) was observed in the 6-OHDA group. Contrary to the bursting hypothesis, this increased CV was not due to changes in bursting but was instead due to a mild increase in pausing. Together, these results suggest that differences in SNpr activity between control and 6-OHDA lesioned mice may be strongly influenced by changes in network activity during different arousal and behavioral states.

Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism.

Pathophysiological activity of basal ganglia neurons accompanies the motor symptoms of Parkinson's disease. High-frequency (>90 Hz) deep brain stimulation (DBS) reduces parkinsonian symptoms, but the mechanisms remain unclear. We hypothesize that parkinsonism-associated electrophysiological changes constitute an increase in neuronal firing pattern disorder and a concomitant decrease in information transmission through the ventral basal ganglia, and that effective DBS alleviates symptoms by decreasing neuronal disorder while simultaneously increasing information transfer through the same regions. We tested these hypotheses in the freely behaving, 6-hydroxydopamine-lesioned rat model of hemiparkinsonism. Following the onset of parkinsonism, mean neuronal firing rates were unchanged, despite a significant increase in firing pattern disorder (i.e., neuronal entropy), in both the globus pallidus and substantia nigra pars reticulata. This increase in neuronal entropy was reversed by symptom-alleviating DBS. Whereas increases in signal entropy are most commonly indicative of similar increases in information transmission, directed information through both regions was substantially reduced (>70%) following the onset of parkinsonism. Again, this decrease in information transmission was partially reversed by DBS. Together, these results suggest that the parkinsonian basal ganglia are rife with entropic activity and incapable of functional information transmission. Furthermore, they indicate that symptom-alleviating DBS works by lowering the entropic noise floor, enabling more information-rich signal propagation. In this view, the symptoms of parkinsonism may be more a default mode, normally overridden by healthy basal ganglia information. When that information is abolished by parkinsonian pathophysiology, hypokinetic symptoms emerge.

Electrical stimulation of the substantia nigra pars reticulata (SNr) suppresses chemically induced neocortical seizures in rats.

Deep brain stimulation is an alternate treatment strategy for intractable epilepsy. The effects of low- and high-frequency electrical stimulation to the substantia nigra pars reticulata (SNr) of different sides on chemically induced neocortical seizure were investigated in the present study. After neocortical seizure was induced by ferric chloride injection into the left sensorimotor cortex, SNr was stimulated ipsilaterally, contralaterally, or bilaterally at frequencies of 130 or 20 Hz in rats. Unilateral and bilateral stimulation at 130 Hz reduced significantly the number of seizures but not their duration. Ipsilateral, contralateral as well as bilateral stimulations at 130 Hz were all equally effective, producing reductions in seizures of 63.62, 77.84, and 68.74% compared with the control group, respectively. Electrical stimulation at 20 Hz did not reduce the number or duration of seizures regardless of the side stimulated. Both unilateral and bilateral stimulations of SNr at 130 Hz can suppress ictogenesis in the cortex, but electrical stimulation at 130 or 20 Hz does not reduce the severity of individual seizures. The frequency of stimulation is paramount in suppressing neocortical seizures in which DBS at least targets SNr.