Substantia Nigra Pars Compacta Dopamine Research Articles

Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges.

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

The Role of α-Synuclein in the Regulation of Serotonin System: Physiological and Pathological Features

In patients affected by Parkinson's disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein (α-Syn). Much of PD research has focused on the role of α-Syn aggregates in the degeneration of SNc DA neurons due to the impact of striatal DA deficits on classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the midbrain raphe nuclei, which may contribute to non-motor symptoms. Indeed, dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD. However, little is known about the functional consequences of α-Syn inclusions in this neuronal population other than DA neurons. Here, we provide an overview of the current knowledge of α-Syn and its role in regulating the 5-HT function in health and disease. Understanding the relative contributions to α-Syn-linked alterations in the 5-HT system may provide a basis for identifying PD patients at risk for developing depression and could lead to a more targeted therapeutic approach.

Preservation of dendritic D2 receptor transmission in substantia nigra dopamine neurons with age

Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type dopamine receptors located at dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that the amplitude of D2-receptor inhibitory postsynaptic currents (D2-IPSCs) are moderately reduced in aged male mice. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism. Further experiments indicated that reduced D2 receptor signaling was not due to a general reduction in GIRK channel currents or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSC shape in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) was also not affected by age, indicating preservation of one mechanism of plasticity. These findings have implications for understanding dopamine transmission in aging, and reduced D2 receptor inhibition could contribute to increased susceptibility of males to SNc dopamine neuron degeneration in Parkinson’s disease.

Midbrain dopamine neurons arbiter OCD-like behavior

The neurobiological understanding of obsessive-compulsive disorder (OCD) includes dysregulated frontostriatal circuitry and altered monoamine transmission. Repetitive stereotyped behavior (e.g., grooming), a featured symptom in OCD, has been proposed to be associated with perturbed dopamine (DA) signaling. However, the precise brain circuits participating in DA's control over this behavioral phenotype remain elusive. Here, we identified that DA neurons in substantia nigra pars compacta (SNc) orchestrate ventromedial striatum (VMS) microcircuits as well as lateral orbitofrontal cortex (lOFC) during self-grooming behavior. SNc-VMS and SNc-lOFC dopaminergic projections modulate grooming behaviors and striatal microcircuit function differentially. Specifically, the activity of the SNc-VMS pathway promotes grooming via D1 receptors, whereas the activity of the SNc-lOFC pathway suppresses grooming via D2 receptors. SNc DA neuron activity thus controls the OCD-like behaviors via both striatal and cortical projections as dual gating. These results support both pharmacological and brain-stimulation treatments for OCD.

Medial septum activation improves strategy switching once strategies are well-learned via bidirectional regulation of dopamine neuron population activity.

Strategy switching is a form of cognitive flexibility that requires inhibiting a previously successful strategy and switching to a new strategy of a different categorical modality. It is dependent on dopamine (DA) receptor activation and release in ventral striatum and prefrontal cortex, two primary targets of ventral tegmental area (VTA) DA projections. Although the circuitry that underlies strategy switching early in learning has been studied, few studies have examined it after extended discrimination training. This may be important as DA activity and release patterns change across learning, with several studies demonstrating a critical role for substantia nigra pars compacta (SNc) DA activity and release once behaviors are well-learned. We have demonstrated that medial septum (MS) activation simultaneously increased VTA and decreased SNc DA population activity, as well as improved reversal learning via these actions on DA activity. We hypothesized that MS activation would improve strategy switching both early in learning and after extended training through its ability to increase VTA DA population activity and decrease SNc DA population activity, respectively. We chemogenetically activated the MS of male and female rats and measured their performance on an operant-based strategy switching task following 1, 10, or 15 days of discrimination training. Contrary to our hypothesis, MS activation did not affect strategy switching after 1 day of discrimination training. MS activation improved strategy switching after 10 days of training, but only in females. MS activation improved strategy switching in both sexes after 15 days of training. Infusion of bicuculline into the ventral subiculum (vSub) inhibited the MS-mediated decrease in SNc DA population activity and attenuated the improvement in strategy switching. Intra-vSub infusion of scopolamine inhibited the MS-mediated increase in VTA DA population activity but did not affect the improvement in strategy switching. Intra-vSub infusion of both bicuculline and scopolamine inhibited the MS-mediated effects on DA population activity in both the SNc and VTA and completely prevented the improvement in strategy switching. These data indicate that MS activation improves strategy switching once the original strategy has been sufficiently well-learned, and that this may occur via the MS's regulation of DA neuron responsivity.

Differential vulnerability of locus coeruleus and dorsal raphe neurons to chronic methamphetamine-induced degeneration.

Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in axons of substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) dopamine neurons. Chronic administration of meth results in SNc degeneration and MAO inhibition is neuroprotective, whereas, the VTA is resistant to degeneration. This differential vulnerability is attributed, at least in part, to the presence of L-type Ca2+ channel-dependent mitochondrial stress in SNc but not VTA dopamine neurons. MAO is also expressed in other monoaminergic neurons such as noradrenergic locus coeruleus (LC) and serotonergic dorsal raphe (DR) neurons. The impact of meth on mitochondrial stress in LC and DR neurons is unknown. In the current study we used a genetically encoded redox biosensor to investigate meth-induced MAO-dependent mitochondrial stress in LC and DR neurons. Similar to SNc and VTA neurons, meth increased MAO-dependent mitochondrial stress in axonal but not somatic compartments of LC norepinephrine and DR serotonin neurons. Chronic meth administration (5 mg/kg; 28-day) resulted in degeneration of LC neurons and MAO inhibition was neuroprotective whereas DR neurons were resistant to degeneration. Activating L-type Ca2+ channels increased mitochondrial stress in LC but not DR axons and inhibiting L-type Ca2+ channels in vivo with isradipine prevented meth-induced LC degeneration. These data suggest that similar to recent findings in SNc and VTA dopamine neurons, the differential vulnerability between LC and DR neurons can be attributed to the presence of L-type Ca2+ channel-dependent mitochondrial stress. Taken together, the present study demonstrates that both meth-induced MAO- and L-type Ca2+ channel-dependent mitochondrial stress are necessary for chronic meth-induced neurodegeneration.

Novel anti-apoptotic L-DOPA precursors SuperDopa and SuperDopamide as potential neuroprotective agents for halting/delaying progression of Parkinson\u2019s disease

Parkinson’s disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38MAPK). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.

Chronic methamphetamine-induced neurodegeneration: Differential vulnerability of ventral tegmental area and substantia nigra pars compacta dopamine neurons

Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in substantia nigra pars compacta (SNc) axons; chronic administration produces SNc degeneration that is prevented by MAO inhibition suggesting that MAO-dependent axonal mitochondrial stress is a causal factor. To test whether meth similarly increases mitochondrial stress in ventral tegmental area (VTA) axons, we used a genetically encoded redox biosensor to assess mitochondrial stress ex vivo. Meth increased MAO-dependent mitochondrial stress in both SNc and VTA axons. However, despite having the same meth-induced stress as SNc neurons, VTA neurons were resistant to chronic meth-induced degeneration indicating that meth-induced MAO-dependent mitochondrial stress in axons was necessary but not sufficient for degeneration. To determine whether L-type Ca2+ channel-dependent stress differentiates SNc and VTA axons, as reported in the soma, the L-type Ca2+ channel activator Bay K8644 was used. Opening L-type Ca2+ channels increased axonal mitochondrial stress in SNc but not VTA axons. To first determine whether mitochondrial stress was necessary for SNc degeneration, mice were treated with the mitochondrial antioxidant mitoTEMPO. Chronic meth-induced SNc degeneration was prevented by mitoTEMPO thereby confirming the necessity of mitochondrial stress. Similar to results with the antioxidant, both MAO inhibition and L-type Ca2+ channel inhibition also prevented SNc degeneration. Taken together the presented data demonstrate that both MAO- and L-type Ca2+ channel-dependent mitochondrial stress is necessary for chronic meth-induced degeneration.

Neonatal 6-OHDA lesion of the SNc induces striatal compensatory sprouting from surviving SNc dopaminergic neurons without VTA contribution.

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) are uniquely vulnerable to neurodegeneration in Parkinson's disease (PD). We hypothesize that their large axonal arbor is a key factor underlying their vulnerability, due to increased bioenergetic, proteostatic and oxidative stress. In keeping with this model, other DAergic populations with smaller axonal arbors are mostly spared during the course of PD and are more resistant to experimental lesions in animal models. Aiming to improve mouse PD models, we examined if neonatal partial SNc lesions could lead to adult mice with fewer SNc DA neurons that are endowed with larger axonal arbors because of compensatory mechanisms. We injected 6-hydroxydopamine (6-OHDA) unilaterally in the SNc at an early postnatal stage at a dose selected to induce loss of approximately 50% of SNc DA neurons. We find that at 10 and 90 days after the lesion, the axons of SNc DA neurons show massive compensatory sprouting, as revealed by the proportionally smaller decrease in tyrosine hydroxylase (TH) in the striatum compared with the loss of SNc DA neuron cell bodies. The extent and origin of this axonal sprouting was further investigated by AAV-mediated expression of eYFP in SNc or ventral tegmental area (VTA) DA neurons of adult mice. Our results reveal that SNc DA neurons have the capacity to substantially increase their axonal arbor size and suggest that mice designed to have reduced numbers of SNc DA neurons could potentially be used to develop better mouse models of PD, with elevated neuronal vulnerability.

Involvement of Midbrain Dopamine Neuron Activity in Negative Reinforcement Learning in Mice

The activity of the midbrain dopamine system reflects the valence of environmental events and modulates various brain structures to modify an organism's behavior. A series of recent studies reported that the direct and indirect pathways in the striatum are critical for instrumental learning, but the dynamic changes in dopamine neuron activity that occur during negative reinforcement learning are still largely unclear. In the present study, by using a negative reinforcement learning paradigm employing foot shocks as aversive stimuli, bidirectional changes in substantia nigra pars compacta (SNc) dopamine neuron activity in the learning and habituation phases were observed. The results showed that in the learning phase, before mice had mastered the skill of escaping foot shocks, the presence of foot shocks induced a transient reduction in the activity of SNc dopamine neurons; however, in the habituation phase, in which the learned skill was automated, it induced a transient increase. Microinjection of a dopamine D1 receptor (D1R) or D2 receptor (D2R) antagonist into the dorsomedial striatum (DMS) significantly impaired learning behavior, suggesting that the modulatory effects of dopamine on both the direct and indirect pathways are required. Moreover, during the learning phase, excitatory synaptic transmission to DMS D2R-expressing medium spiny neurons (D2-MSNs) was potentiated. However, upon completion of the learning and habituation phases, the synapses onto D1R-expressing medium spiny neurons (D1-MSNs) were potentiated, and those onto D2-MSNs were restored to normal levels. The bidirectional changes in both SNc dopamine neuron activity and DMS synaptic plasticity might be the critical neural correlates for negative reinforcement learning.

The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice

Appetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior—predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.

Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson's Disease.

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson’s Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

Early Dysfunction of Substantia Nigra Dopamine Neurons in the ParkinQ311X Mouse.

Mutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP), a neurodegenerative disease characterized by early dysfunction and loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). No therapy is currently available to prevent or slow down the neurodegeneration in ARJP patients. Preclinical models are key to clarifying the early events that lead to neurodegeneration and reveal the potential of novel neuroprotective strategies. ParkinQ311X is a transgenic mouse model expressing in DA neurons a mutant parkin variant found in ARJP patients. This model was previously reported to show the neuropathological hallmark of the disease, i.e., the progressive loss of DA neurons. However, the early dysfunctions that precede neurodegeneration have never been investigated. Here, we analyzed SNc DA neurons in parkinQ311X mice and found early features of mitochondrial dysfunction, extensive cytoplasmic vacuolization, and dysregulation of spontaneous in vivo firing activity. These data suggest that the parkinQ311X mouse recapitulates key features of ARJP and provides a useful tool for studying the neurodegenerative mechanisms underlying the human disease and for screening potential neuroprotective drugs.

Stress Controllability Modulates Basal Activity of Dopamine Neurons in the Substantia Nigra Compacta.

Prolonged stress induces neural maladaptations in the mesolimbic dopamine (DA) system and produces emotional and behavioral disorders. However, the effects of stress on activity of DA neurons are diverse and complex that hinge on the type, duration, intensity, and controllability of stressors. Here, controlling the duration, intensity, and type of the stressors to be identical, we observed the effects of stressor controllability on the activity of substantia nigra pars compacta (SNc) DA neurons in mice. We found that both lack and loss of control (LOC) over shock enhance the basal activity and intrinsic excitability of SNc DA neurons via modulation of Ih current, but not via corticosterone serum level. Moreover, LOC over shock produces more significant enhancement in the basal activity of SNc DA neurons than that produced by shock per se, and therefore attenuates the response to natural reward. This attenuation can be reversed by control over shock. These results indicate that although chronic stress per se tends to enhance the basal activity of SNc DA neurons, LOC over the stressor is able to induce a larger enhancement in the basal activity of SNc DA neurons and produce more severe behavioral deficits. However, control over stress ameliorates the deleterious effects of stress, highlighting the role of stress controllability.

Activity-dependent somatodendritic dopamine release in the substantia nigra autoinhibits the releasing neuron

SUMMARYSomatodendritic dopamine (DA) release from midbrain DA neurons activates D2 autoreceptors on these cells to regulate their activity. However, the source of autoregulatory DA remains controversial. Here, we test the hypothesis that D2 autoreceptors on a given DA neuron in the substantia nigra pars compacta (SNc) are activated primarily by DA released from that same cell, rather than from its neighbors. Voltage-clamp recording allows monitoring of evoked D2-receptor-mediated inhibitory currents (D2ICs) in SNc DA neurons as an index of DA release. Single-cell application of antibodies to Na+ channels via the recording pipette decreases spontaneous activity of recorded neurons and attenuates evoked D2ICs; antibodies to SNAP-25, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, also decrease D2IC amplitude. Evoked D2ICs are nearly abolished by the light chain of botulinum neurotoxin A, which cleaves SNAP-25, whereas synaptically activated GABAB-receptor-mediated currents are unaffected. Thus, somatodendritic DA release in the SNc autoinhibits the neuron that releases it.

Depression and Nigral Neuron Density in Lewy Body Spectrum Diseases.

Parkinson's disease and other Lewy body spectrum diseases (LBDs) are associated with a specific risk for clinical depression. In the present clinicopathological study with 73 patients with LBD, we observed that the substantia nigra pars compacta dopamine neuron density was markedly lower in patients who had comorbid depression antemortem than in nondepressed patients (1.52 vs 2.32 n/mm2 , p = 0.004). There were no differences in cognition, motor disease severity, antiparkinsonian medications, or disease duration between groups. The results implicate the substantia nigra as an important psychomotor modulatory area of mood in patients with Lewy body disorders. ANN NEUROL 2021;;89:1046-1050.

Age-related changes in expression of lysine48 and lysine63 ubiquitin linkages in dopamine neurons of midbrain in mice.

Ubiquitination of target proteins is mediated via different ubiquitin lysine (K) linkages and determines the protein fates. In particular, K48 ubiquitin linkage targets proteins for degradation, whereas K63 ubiquitin linkage plays a nondegradative role. Parkinson's disease is an age-onset neurodegenerative disorder, which shows selective loss of dopamine neurons in substantia nigra pars compacta (SNC) and ubiquitinated protein aggregates. However, age-related expression of K48 and K63 ubiquitin linkages in SNC dopamine neurons remains elusive. We thus sought to explore the expression of K48 and K63 ubiquitin linkages in dopamine neurons in SNCs of mice at different ages with morphological and biochemical assays. Here our results indicated that in 5-week-old mice, dopamine neurons presented higher levels of K48 and K63 ubiquitin linkages than nondopamine neural cells. Aging promoted the formation of protein aggregates that are positive for both K48 and K63 ubiquitin linkages, together with tyrosine hydroxylase, a dopamine neuron marker. Moreover, 21-month-old mice showed fewer neural cells and tyrosine hydroxylase positive neurons in the SNCs than younger mice. Through biochemical analysis, the 21-month-old mice were shown to express more K48 ubiquitin linkages and less tyrosine hydroxylase and NeuN than the 5-week-old mice. These results suggest the first time that expression of K48 and K63 ubiquitin lysine linkages in midbrain dopamine neurons is age-related and may be involved in the loss of dopamine neurons.

Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

Degeneration of substantia nigra pars compacta dopamine neurons is a central feature in the pathology of Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. Preclinical work has scarcely considered the influence of these 2 factors to disease risk and presentation. Here, we observed a progressive decline in dopamine neuron firing activity in male C57BL/6 mice by 18 months of age, while dopamine neurons from females remained largely unaffected. This was accompanied by increased mRNA expression of PINK1 in both males and females, and PARK2 primarily in males, both of which have been linked to Parkinson’s. Since the declining cell properties were accompanied by only slight decreases in locomotion in both sexes, it is likely that these age-related impairments in males represent a vulnerability to further insults that could predispose the neurons to neurodegenerative processes such as in Parkinson’s.

RGS Proteins as Critical Regulators of Motor Function and Their Implications in Parkinson's Disease.

Parkinson disease (PD) is a devastating, largely nonfamilial, age-related disorder caused by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Release of DA from these neurons into the dorsal striatum is crucial for regulating movement and their loss causes PD. Unfortunately, the mechanisms underlying SNc neurodegeneration remain unclear, and currently there is no cure for PD, only symptomatic treatments. Recently, several regulator of G protein signaling (RGS) proteins have emerged as critical modulators of PD pathogenesis and/or motor dysfunction and dyskinesia: RGSs 4, 6, 9, and 10. Striatal RGS4 has been shown to exacerbate motor symptoms of DA loss by suppressing M4-autoreceptor-Gα i/o signaling in striatal cholinergic interneurons. RGS6 and RGS9 are key regulators of D2R-Gα i/o signaling in SNc DA neurons and striatal medium spiny neurons, respectively. RGS6, expressed in human and mouse SNc DA neurons, suppresses characteristic PD hallmarks in aged mice, including SNc DA neuron loss, motor deficits, and α-synuclein accumulation. After DA depletion, RGS9 (through its inhibition of medium spiny neuron D2R signaling) suppresses motor dysfunction induced by L-DOPA or D2R-selective agonists. RGS10 is highly expressed in microglia, the brain's resident immune cells. Within the SNc, RGS10 may promote DA neuron survival through the upregulation of prosurvival genes and inhibition of microglial inflammatory factor expression. Thus, RGSs 4, 6, 9, and 10 are critical modulators of cell signaling pathways that promote SNc DA neuron survival and/or proper motor control. Accordingly, these RGS proteins represent novel therapeutic targets for the treatment of PD pathology. SIGNIFICANCE STATEMENT: Parkinson disease (PD), the most common movement disorder, is a progressive neurodegenerative disease characterized by substantia nigra pars compacta (SNc) dopamine (DA) neuron loss and subsequent motor deficits. Current PD therapies only target disease motor symptomology and are fraught with side effects. Therefore, researchers have begun to explore alternative therapeutic options. Regulator of G protein signaling (RGS) proteins, whether primarily expressed in SNc DA neurons (RGS6), striatal neurons (RGSs 4 and 9), or microglia (RGS10), modulate key signaling pathways important for SNc DA neuron survival and/or proper motor control. As such, RGS proteins represent novel therapeutic targets in PD.

Temporally restricted dopaminergic control of reward-conditioned movements.

Midbrain dopamine (DA) neurons encode both reward and movement-related events, and are implicated in disorders of reward processing as well as movement. Consequently, disentangling the contribution of DA neurons in reinforcing versus generating movements is challenging and has led to lasting controversy. We dissociated these functions by parametrically varying the timing of optogenetic manipulations in a Pavlovian conditioning task, and examining the influence on anticipatory licking prior to reward delivery. Inhibiting both ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) DA neurons in the post-reward period had a significantly greater behavioral effect than inhibition in the pre-reward period of the task. Furthermore, the contribution of DA neurons to behavior decreased linearly as a function of elapsed time after reward. Together, the results indicate a temporally restricted role of DA neurons primarily related to reinforcing stimulus-reward associations, and suggest that directly generating movements is a comparatively less important function.