Substantia Nigra Pars Reticulata Neurons Research Articles

Distribution, connection and function of ALDH1A1+/TH+ neurons in substantia nigra pars reticulata of mouse

The massive cell death of dopaminergic neurons (DANs) in substantia nigra pars compacta (SNC) is associated with motor diseases, such as Parkinson’s disease. Moreover, as a subtype of DANs in SNC, ALDH1A1+ neurons show better resistance to PD related neurotoxin. DANs can also be found in the substantia nigra pars reticulata (SNR), however, whether they are ALDH1A1+ neurons are rarely reported, as well as their projection, function, and reaction in the PD pathology. We studied the distribution of ALDH1A1+ neurons and track their projection by injecting pAAV. We figured out that, in SNR, 87 % neurons are ALDH1A1+/TH+ in ALDH1A1+ cluster averagely, while ALDH1A1+/TH+: TH+ is 52 % averagely. There are two enrichment regions of ALDH1A1+/TH+ neurons at brgma −3.40 mm and brgma −3.70 mm in the SNR of the nTg mice. Nevertheless, in one type of PD-liked mice model, the proportion of ALDH1A1+/TH+: ALDH1A1+ neurons are 98 % averagely, while ALHD1A1+/TH+: TH+ is 57 %. Intriguingly, neuro-tracing discovered that there may be a previously unreported connection between SNR and anterior dorsal thalamus (ADT). The mouse received MPTP stereotactic injection to destroy TH+ neurons in SNR showed depression behavior, indicated the DANs death in SNR may contribute to depression behavior.

Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice

The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the underlying mechanisms nor the type of neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr neurons (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other SNr cells. We also report that only SNr-PV+ neurons' intrinsic excitability is reduced by downregulation of sodium leak channels in a PD mouse model. Interestingly, in anesthetized parkinsonian mice invivo, SNr-PV+ neurons display a bursty pattern of activity dependent on glutamatergic tone. Finally, we demonstrate that chemogenetic inhibition of SNr-PV+ neurons is sufficient to alleviate motor impairments in parkinsonian mice. Overall, our findings establish cell-type-specific dysfunction in experimental parkinsonism in the SNr and provide a potential cellular therapeutic target to alleviate motor symptoms in PD.

Activity of the Substantia Nigra pars Reticulata During Saccade Adaptation.

When movements become inaccurate, the resultant error induces motor adaptation to improve accuracy. This error-based motor learning is regarded as a cerebellar function. However, the influence of the other brain areas on adaptation is poorly understood. During saccade adaptation, a type of error-based motor learning, the superior colliculus (SC) sends a post-saccadic error signal to the cerebellum to drive adaptation. Since the SC is directly inhibited by the substantia nigra pars reticulata (SNr), we hypothesized that the SNr might influence saccade adaptation by affecting the SC error signal. In fact, previous studies indicated that the SNr encodes motivation and motivation influences saccade adaptation. In this study, we first established that the SNr projects to the rostral SC, where small error signals are generated, in non-human primates. Then, we examined SNr activity while the animal underwent adaptation. SNr neurons paused their activity in association with the error. This pause was shallower and delayed compared to those of no-error trial saccades. The pause at the end of the adaptation was shallower and delayed compared to that at the beginning of the adaptation. The change in the inter-trial interval, an indicator of motivation, and adaptation speed had a positive correlation with the changes in the error-related pause. These results suggest that 1: the SNr exhibits a unique activity pattern during the error interval, 2: SNr activity increases during adaptation, consistent with the decrease in SC activity, and 3: motivational decay during the adaptation session might increase SNr activity and influence the adaptation speed.Significance StatementMovements impaired due to stroke, injury, or aging recover gradually. To repair an inaccurate movement, the brain measures the error of the movement and changes the movement to minimize the error. This process is called motor adaptation. Although it has been established that the cerebellum plays an essential role in this adaptation, the influence of the other brain areas on the adaptation process is not well defined. The observation that motivation levels influence adaptation led us to suspect that the basal ganglia may influence adaptation. Here, we reveal the substantia nigra pars reticulata activity changes during saccade adaptation in monkeys and suggest how the basal ganglia influence the error signal.

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia.

Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID. The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model. We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation. Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation. Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Propagation of Oscillations in the Indirect Pathway of the Basal Ganglia.

Oscillatory signals propagate in the basal ganglia from prototypic neurons in the external globus pallidus (GPe) to their target neurons in the substantia nigra pars reticulata (SNr), internal pallidal segment, and subthalamic nucleus. Neurons in the GPe fire spontaneously, so oscillatory input signals can be encoded as changes in timing of action potentials within an ongoing spike train. When GPe neurons were driven by an oscillatory current in male and female mice, these spike-timing changes produced spike-oscillation coherence over a range of frequencies extending at least to 100 Hz. Using the known kinetics of the GPe→SNr synapse, we calculated the postsynaptic currents that would be generated in SNr neurons from the recorded GPe spike trains. The ongoing synaptic barrage from spontaneous firing, frequency-dependent short-term depression, and stochastic fluctuations at the synapse embed the input oscillation into a noisy sequence of synaptic currents in the SNr. The oscillatory component of the resulting synaptic current must compete with the noisy spontaneous synaptic barrage for control of postsynaptic SNr neurons, which have their own frequency-dependent sensitivities. Despite this, SNr neurons subjected to synaptic conductance changes generated from recorded GPe neuron firing patterns also became coherent with oscillations over a broad range of frequencies. The presynaptic, synaptic, and postsynaptic frequency sensitivities were all dependent on the firing rates of presynaptic and postsynaptic neurons. Firing rate changes, often assumed to be the propagating signal in these circuits, do not encode most oscillation frequencies, but instead determine which signal frequencies propagate effectively and which are suppressed.SIGNIFICANCE STATEMENT Oscillations are present in all the basal ganglia nuclei, include a range of frequencies, and change over the course of learning and behavior. Exaggerated oscillations are a hallmark of basal ganglia pathologies, and each has a specific frequency range. Because of its position as a hub in the basal ganglia circuitry, the globus pallidus is a candidate origin for oscillations propagating between nuclei. We imposed low-amplitude oscillations on individual globus pallidus neurons at specific frequencies and measured the coherence between the oscillation and firing as a function of frequency. We then used these responses to measure the effectiveness of oscillatory propagation to other basal ganglia nuclei. Propagation was effective for oscillation frequencies as high as 100 Hz.

Transmission of delta band (0.5-4 Hz) oscillations from the globus pallidus to the substantia nigra pars reticulata in dopamine depletion.

Parkinson's disease (PD) and animal models of PD feature enhanced oscillations in several frequency bands in the basal ganglia (BG). Past research has emphasized the enhancement of 13-30 Hz beta oscillations. Recently, however, oscillations in the delta band (0.5-4 Hz) have been identified as a robust predictor of dopamine loss and motor dysfunction in several BG regions in mouse models of PD. In particular, delta oscillations in the substantia nigra pars reticulata (SNr) were shown to lead oscillations in motor cortex (M1) and persist under M1 lesion, but it is not clear where these oscillations are initially generated. In this paper, we use a computational model to study how delta oscillations may arise in the SNr due to projections from the globus pallidus externa (GPe). We propose a network architecture that incorporates inhibition in SNr from oscillating GPe neurons and other SNr neurons. In our simulations, this configuration yields firing patterns in model SNr neurons that match those measured in vivo. In particular, we see the spontaneous emergence of near-antiphase active-predicting and inactive-predicting neural populations in the SNr, which persist under the inclusion of STN inputs based on experimental recordings. These results demonstrate how delta oscillations can propagate through BG nuclei despite imperfect oscillatory synchrony in the source site, narrowing down potential targets for the source of delta oscillations in PD models and giving new insight into the dynamics of SNr oscillations.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus

ObjectiveDeep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei—including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)—across different DBS frequencies. Materials and MethodsBoth synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim—across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. ResultsOur model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. ConclusionsThe result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

A nigro–subthalamo–parabrachial pathway modulates pain-like behaviors

The basal ganglia including the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr) are involved in pain-related responses, but how they regulate pain processing remains unknown. Here, we identify a pathway, consisting of GABAergic neurons in the SNr (SNrGABA) and glutamatergic neurons in the STN (STNGlu) and the lateral parabrachial nucleus (LPBGlu), that modulates acute and persistent pain states in both male and female mice. The activity of STN neurons was enhanced in acute and persistent pain states. This enhancement was accompanied by hypoactivity in SNrGABA neurons and strengthening of the STN–LPB glutamatergic projection. Reversing the dysfunction in the SNrGABA-STNGlu-LPBGlu pathway attenuated activity of LPBGlu neurons and mitigated pain-like behaviors. Therefore, the SNrGABA-STNGlu-LPBGlu pathway regulates pathological pain and is a potential target for pain management.

Preferential Modulatory Action of 5-HT2A Receptors on the Dynamic Regulation of Basal Ganglia Circuits.

In rodents, cortical information is transferred to the substantia nigra pars reticulata (SNr) through motor and medial prefrontal (mPF) basal ganglia (BG) circuits implicated in motor and cognitive/motivational behaviors, respectively. The serotonergic 5-HT2A receptors are located in both of these neuronal networks, displaying topographical differences with a high expression in the associative/limbic territories, and a very low expression in the subthalamic nucleus. This study investigated whether the stimulation of 5-HT2A receptors could have a specific signature on the dynamic regulation of BG circuits, preferentially modulating the mPF information processing through trans-striatal pathways. We performed in vivo single-unit extracellular recordings to assess the effect of the 5-HT2A agonist TCB-2 on the spontaneous and cortically evoked activity of lateral and medial SNr neurons in male rats (involved in motor and mPF circuits, respectively). TCB-2 (50-200 µg/kg, i.v.) increased the basal firing rate and enhanced the cortically evoked inhibitory response of medial SNr neurons (transmission through the direct striato-nigral pathway). A prior administration of the preferential 5-HT2A receptor antagonist MDL11939 (200 µg/kg, i.v.) did not modify any electrophysiological parameter, but occluded TCB-2-induced effects. In animals treated with the 5-HT synthesis inhibitor pCPA (4-chloro-dl-phenylalanine methyl ester hydrochloride), TCB-2 failed to induce the above-mentioned effects, thus suggesting the contribution of endogenous 5-HT. However, the mobilization of 5-HT induced by the acute administration of fluoxetine (10 mg/kg, i.p.) did not mimic the effects triggered by TCB-2. Overall, these data suggest that 5-HT2A receptors have a preferential modulatory action on the dynamic regulation of BG circuitry.SIGNIFICANCE STATEMENT Motor and medial prefrontal (mPF) basal ganglia (BG) circuits play an important role in integrative brain functions like movement control or cognitive/motivational behavior, respectively. Although these neuronal networks express 5-HT2A receptors, the expression is higher in associative/limbic structures than in the motor ones. We show a topographical-dependent dissociation in the effects triggered by the 5HT2A agonist TCB-2, which specifically increases the medial substantia nigra pars reticulata neuron activity and has a preferential action on mPF information processing through the striato-nigral direct pathway. These are very likely to be 5-HT2A receptor-mediated effects that require mobilization of the endogenous 5-HT system. These findings provide evidence about the specific signature of 5-HT2A receptors on the dynamic regulation of BG circuits.

Neuronal Firing and Glutamatergic Synapses in the Substantia Nigra Pars Reticulata of LRRK2-G2019S Mice.

Pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequent causes of familial Parkinson's Disease (PD), an increasingly prevalent neurodegenerative disease that affects basal ganglia circuitry. The cellular effects of the G2019S mutation in the LRRK2 gene, the most common pathological mutation, have not been thoroughly investigated. In this study we used middle-aged mice carrying the LRRK2-G2019S mutation (G2019S mice) to identify potential alterations in the neurophysiological properties and characteristics of glutamatergic synaptic transmission in basal ganglia output neurons, i.e., substantia nigra pars reticulata (SNr) GABAergic neurons. We found that the intrinsic membrane properties and action potential properties were unaltered in G2019S mice compared to wild-type (WT) mice. The spontaneous firing frequency was similar, but we observed an increased regularity in the firing of SNr neurons recorded from G2019S mice. We examined the short-term plasticity of glutamatergic synaptic transmission, and we found an increased paired-pulse depression in G2019S mice compared to WT mice, indicating an increased probability of glutamate release in SNr neurons from G2019S mice. We measured synaptic transmission mediated by NMDA receptors and we found that the kinetics of synaptic responses mediated by these receptors were unaltered, as well as the contribution of the GluN2B subunit to these responses, in SNr neurons of G2019S mice compared to WT mice. These results demonstrate an overall maintenance of basic neurophysiological and synaptic characteristics, and subtle changes in the firing pattern and in glutamatergic synaptic transmission in basal ganglia output neurons that precede neurodegeneration of dopaminergic neurons in the LRRK2-G2019S mouse model of late-onset PD.

Altered basal ganglia output during self-restraint.

Suppressing actions is essential for flexible behavior. Multiple neural circuits involved in behavioral inhibition converge upon a key basal ganglia output nucleus, the substantia nigra pars reticulata (SNr). To examine how changes in basal ganglia output contribute to self-restraint, we recorded SNr neurons during a proactive behavioral inhibition task. Rats responded to <i>Go!</i> cues with rapid leftward or rightward movements, but also prepared to cancel one of these movement directions on trials when a <i>Stop!</i> cue might occur. This action restraint - visible as direction-selective slowing of reaction times - altered both rates and patterns of SNr spiking. Overall firing rate was elevated before the <i>Go!</i> cue, and this effect was driven by a subpopulation of direction-selective SNr neurons. In neural state space, this corresponded to a shift away from the restrained movement. SNr neurons also showed more variable inter-spike intervals during proactive inhibition. This corresponded to more variable state-space trajectories, which may slow reaction times via reduced preparation to move. These findings open new perspectives on how basal ganglia dynamics contribute to movement preparation and cognitive control.

Motor cortico-nigral and cortico-entopeduncular information transmission and its modulation by buspirone in control and after dopaminergic denervation.

Cortical information is transferred to the substantia nigra pars reticulata (SNr) and the entopeduncular nucleus (EP), the output structures of the basal ganglia (BG), through three different pathways: the hyperdirect trans-subthalamic and the direct and indirect trans-striatal pathways. The nigrostriatal dopamine (DA) and the activation of 5-HT1A receptors, distributed all along the BG, may modulate cortical information transmission. We aimed to investigate the effect of buspirone (5-HT1A receptor partial agonist) and WAY-100635 (5-HT1A receptor antagonist) on cortico-nigral and cortico-entopeduncular transmission in normal and DA loss conditions. Herein, simultaneous electrical stimulation of the motor cortex and single-unit extracellular recordings of SNr or EP neurons were conducted in urethane-anesthetized sham and 6-hydroxydopamine (6-OHDA)-lesioned rats before and after drug administrations. Motor cortex stimulation evoked monophasic, biphasic, or triphasic responses, combination of an early excitation, an inhibition, and a late excitation in both the SNr and EP, while an altered pattern of evoked response was observed in the SNr after 6-OHDA lesion. Systemic buspirone potentiated the direct cortico-SNr and cortico-EP transmission in sham animals since increased duration of the inhibitory response was observed. In DA denervated animals, buspirone administration enhanced early excitation amplitude in the cortico-SNr transmission. In both cases, the observed effects were mediated via a 5-HT1A-dependent mechanism as WAY-100635 administration blocked buspirone’s effect. These findings suggest that in control condition, buspirone potentiates direct pathway transmission and DA loss modulates responses related to the hyperdirect pathway. Overall, the results may contribute to understanding the role of 5-HT1A receptors and DA in motor cortico-BG circuitry functionality.

Electrical activation of the pedunculopontine tegmental nucleus modulates the neuronal activities of the subthalamic nucleus and the substantia nigra pars reticulata in anesthetized rats.

The subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and pedunculopontine tegmental nucleus (PPTg) are reciprocally connected brain regions that play significant roles in the motor control. However, the electrophysiological relationship among the STN, SNr, and PPTg remains controversial. The present study was designed to further explore the mutual electrophysiological relationship of these brain regions from the perspective of the PPTg-STN-SNr neural circuit. The neuronal activities in the STN and SNr were simultaneously recorded while the PPTg was stimulated in anesthetized rats. The activation of PPTg induced excitatory responses of both the STN and SNr neurons. Comparisons of excitation latencies between the STN and SNr were made to distinguish the excitation evoked from the PPTg-STN-SNr pathway. Additionally, two types of excitatory responses and various inhibitory responses with different latencies in the SNr were recorded. The SNr responses could also be classified into five different response categories, which might attribute to projections within different neural circuits. Neuronal recordings were analyzed in different electrophysiological features (i.e., interspike interval [ISI] mode, ISI asymmetry index, ISI coefficient of variance, firing rate, burst index, and trough peak duration), and different response patterns of neurons had their specific features in neuronal activities. These findings indicated the complex interactions among the STN, SNr, and PPTg electrophysiologically, and provided insights into exploring information transmission mechanisms underlying these circuits.

Processing of information from the parafascicular nucleus of the thalamus through the basal ganglia.

Accumulating evidence implicates the parafascicular nucleus of the thalamus (Pf) in basal ganglia (BG)-related functions and pathologies. Despite Pf connectivity with all BG components, most attention is focused on the thalamostriatal system and an integrated view of thalamic information processing in this network is still lacking. Here, we addressed this question by recording the responses elicited by Pf activation in single neurons of the substantia nigra pars reticulata (SNr), the main BG output structure in rodents, in anesthetized mice. We performed optogenetic activation of Pf neurons innervating the striatum, the subthalamic nucleus (STN), or the SNr using virally mediated transcellular delivery of Cre from injection in either target in Rosa26-LoxP-stop-ChR2-EYFP mice to drive channelrhodopsin expression. Photoactivation of Pf neurons connecting the striatum evoked an inhibition often followed by an excitation, likely resulting from the activation of the trans-striatal direct and indirect pathways, respectively. Photoactivation of Pf neurons connecting the SNr or the STN triggered one or two early excitations, suggesting partial functional overlap of trans-subthalamic and direct thalamonigral projections. Excitations were followed in about half of the cases by an inhibition that might reflect recruitment of intranigral inhibitory loops. Finally, global Pf stimulation, electrical or optogenetic, elicited similar complex responses comprising up to four components: one or two short-latency excitations, an inhibition, and a late excitation. These data provide evidence for functional connections between the Pf and different BG components and for convergence of the information processed through these pathways in single SNr neurons, stressing their importance in regulating BG outflow.

Motor context modulates substantia nigra pars reticulata spike activity in patients with Parkinson’s disease

ObjectiveThe severity of motor symptoms in Parkinson’s disease (PD) depends on environmental conditions. For example, the presence of external patterns such as a rhythmic tone can attenuate bradykinetic impairments. However,...

Bidirectional Control of Orienting Behavior by the Substantia Nigra Pars Reticulata: Distinct Significance of Head and Whisker Movements.

Detection of an unexpected, novel, or salient stimulus typically leads to an orienting response by which animals move the head, in concert with the sensors (e.g., eyes, pinna, whiskers), to evaluate the stimulus. The basal ganglia are known to control orienting movements through tonically active GABAergic neurons in the substantia nigra pars reticulata (SNr) that project to the superior colliculus. Using optogenetics, we explored the ability of GABAergic SNr neurons on one side of the brain to generate orienting movements. In a strain of mice that express channelrhodopsin (ChR2) in both SNr GABAergic neurons and afferent fibers, we found that continuous blue light produced a robust sustained excitation of SNr neurons which generated ipsiversive orienting. Conversely, in the same animal, trains of blue light excited afferent fibers more effectively than continuous blue light, producing a robust sustained inhibition of SNr neurons which generated contraversive orienting. When ChR2 expression was restricted to either GABAergic SNr neurons or GABAergic afferent fibers from the striatum, blue light patterns in SNr produced only ipsiversive or contraversive orienting movements, respectively. Interestingly, whisker positioning and the reaction to an air-puff on the whiskers were incongruent between SNr-evoked ipsiversive and contraversive head movements, indicating that orienting driven by exciting or inhibiting SNr neurons have different behavioral significance. In conclusion, unilateral SNr neuron excitation and inhibition produce orienting movements in opposite directions and, apparently, with distinct behavioral significance.

A cortico-basal ganglia-thalamo-cortical channel underlying short-term memory

Persistent activity underlying short-term memory encodes sensory information or instructs specific future movement and, consequently, has a crucial role in cognition. Despite extensive study, how the same set of neurons respond differentially to form selective persistent activity remains unknown. Here, we report that the cortico-basal ganglia-thalamo-cortical (CBTC) circuit supports the formation of selective persistent activity in mice. Optogenetic activation or inactivation of the basal ganglia output nucleus substantia nigra pars reticulata (SNr)-to-thalamus pathway biased future licking choice, without affecting licking execution. This perturbation differentially affected persistent activity in the frontal cortex and selectively modulated neural trajectory that encodes one choice but not the other. Recording showed that SNr neurons had selective persistent activity distributed across SNr, but with a hotspot in the mediolateral region. Optogenetic inactivation of the frontal cortex also differentially affected persistent activity in the SNr. Together, these results reveal a CBTC channel functioning to produce selective persistent activity underlying short-term memory.

Pain modulates dopamine neurons via a spinal-parabrachial-mesencephalic circuit.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.

Abnormal Cortico-Basal Ganglia Neurotransmission in a Mouse Model of l-DOPA-Induced Dyskinesia.

l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20-100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID.

Basal Ganglia Output Has a Permissive Non-Driving Role in a Signaled Locomotor Action Mediated by the Midbrain.

The basal ganglia are important for movement and reinforcement learning. Using mice of either sex, we found that the main basal ganglia GABAergic output in the midbrain, the substantia nigra pars reticulata (SNr), shows movement-related neural activity during the expression of a negatively reinforced signaled locomotor action known as signaled active avoidance; this action involves mice moving away during a warning signal to avoid a threat. In particular, many SNr neurons deactivate during active avoidance responses. However, whether SNr deactivation has an essential role driving or regulating active avoidance responses is unknown. We found that optogenetic excitation of SNr or striatal GABAergic fibers that project to an area in the pedunculopontine tegmentum (PPT) within the midbrain locomotor region abolishes signaled active avoidance responses, while optogenetic inhibition of SNr cells (mimicking the SNr deactivation observed during an active avoidance behavior) serves as an effective conditioned stimulus signal to drive avoidance responses by disinhibiting PPT neurons. However, preclusion of SNr deactivation, or direct inhibition of SNr fibers in the PPT, does not impair the expression of signaled active avoidance, indicating that SNr output does not drive the expression of a signaled locomotor action mediated by the midbrain. Consistent with a permissive regulatory role, SNr output provides information about the state of the ongoing action to downstream structures that mediate the action.SIGNIFICANCE STATEMENT During signaled active avoidance behavior, subjects move away to avoid a threat when directed by an innocuous sensory stimulus. Excitation of GABAergic cells in the substantia nigra pars reticulata (SNr), the main output of the basal ganglia, blocks signaled active avoidance, while inhibition of SNr cells is an effective stimulus to drive active avoidance. Interestingly, many SNr cells inhibit their firing during active avoidance responses, suggesting that SNr inhibition could be driving avoidance responses by disinhibiting downstream areas. However, interfering with the modulation of SNr cells does not impair the behavior. Thus, SNr may regulate the active avoidance movement in downstream areas that mediate the behavior, but does not drive it.