Aerobic exercise improves motor dysfunction in Parkinson's model mice via differential regulation of striatal medium spiny neuron.

The striatum plays a crucial role in providing input to the basal ganglia circuit and is implicated in the pathological process of Parkinson's disease (PD). Disruption of the dynamic equilibrium in the basal ganglia loop can be attributed to the abnormal functioning of the medium spiny neurons (MSNs) within the striatum, potentially acting as a trigger for PD. Exercise has been shown to mitigate striatal neuronal dysfunction through neuroprotective and neurorestorative effects and to improve behavioral deficits in PD model mice. In addition, this effect is offset by the activation of MSNs expressing dopamine D2 receptors (D2-MSNs). In the current study, we investigated the underlying neurobiological mechanisms of this effect. Our findings indicated that exercise reduces the power spectral density of the beta-band in the striatum and decreases the overall firing frequency of MSNs, particularly in the case of striatal D2-MSNs. These observations were consistent with the results of molecular biology experiments, which revealed that aerobic training specifically enhanced the expression of striatal dopamine D2 receptors (D2R). Taken together, our results suggest that aerobic training aimed at upregulating striatal D2R expression to inhibit the functional activity of D2-MSNs represents a potential therapeutic strategy for the amelioration of motor dysfunction in PD.

Exercise improves behavioral dysfunction and inhibits the spontaneous excitatory postsynaptic current of D2-medium spiny neurons.

The abnormal function of striatal medium spiny neurons (MSNs) leads to the excitation-inhibition imbalance of the basal ganglia, which is an important pathogenic factor of Parkinson's disease (PD). Exercise improves the dysfunction of basal ganglia through neuroprotective and neuroreparative effects, which may be related to the functional changes of expresses D2 receptors MSNs (D2-MSNs). In this study, D2-Cre mice were selected as the research objects, the PD model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the striatum, and the 4-week treadmill training method was used for exercise intervention. Using optogenetics and behavioral tests, we determined that the average total movement distance of PD and PD + Ex groups was significantly lower than that of the Control group, while that of the PD + Ex and PD + Laser groups was significantly higher than that of the PD group, and the two intervention methods of exercise and optogenetic-stimulation of the D2-MSNs had basically similar effects on improving the autonomic behavior of PD mice. To further investigate the cellular mechanisms, whole-cell patch clamp recordings were carried out on D2-MSNs. We found that exercise decreased the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC) and increased the paired-pulse radio of D2-MSNs while leaving basic electrophysiological properties of MSNs unaffected. Combined with behavioral improvement and enhanced D2R protein expression, our findings suggest the inhibited sEPSC of D2-MSNs may contribute to the behavioral improvement after exercise.

Glutamate receptor-interacting protein 1 in D1- and D2-dopamine receptor-expressing medium spiny neurons differentially regulates cocaine acquisition, reinstatement, and associated spine plasticity.

Background: The nucleus accumbens (NAc) is involved in the expression of cocaine addictive phenotypes, including acquisition, extinction, and reinstatement. In the NAc, D1-medium spiny neurons (MSNs) encode cocaine reward, whereas D2-MSNs encode aversive responses in drug addiction. Glutamate receptor-interacting protein 1 (GRIP1) is known to be associated with cocaine addiction, but the role of GRIP1 in D1-MSNs and D2-MSNs of the NAc in cocaine acquisition and reinstatement remains unknown. Methods: A conditioned place preference apparatus was used to establish cocaine acquisition, extinction, and reinstatement in mouse models. GRIP1 expression was evaluated using Western blotting. Furthermore, GRIP1-siRNA and GRIP1 overexpression lentivirus were used to interfere with GRIP1 in the NAc. After the behavioral test, green fluorescent protein immunostaining of brain slices was used to detect spine density. Results: GRIP1 expression decreased during cocaine acquisition and reinstatement. GRIP1-siRNA enhanced cocaine-induced CPP behavior in acquisition and reinstatement and regulated associated spine plasticity. Importantly, the decreased GRIP1 expression that mediated cocaine acquisition and reinstatement was mainly driven by the interference of the GRIP1-GluA2 interaction in D1-MSNs and could be blocked by the interference of the GRIP1-GluA2 interaction in D2-MSNs. Interference with the GRIP1-GluA2 interaction in D1- and D2-MSNs decreased spine density in D1- and D2-MSNs, respectively. Conclusion: GRIP1 in D1- and D2-MSNs of the NAc differentially modulates cocaine acquisition and reinstatement. GRIP1 downregulation in D1-MSNs has a positive effect on cocaine acquisition and reinstatement, while GRIP1 downregulation in D2-MSNs has a negative effect. Additionally, GRIP1 downregulation in D1-MSNs plays a leading role in cocaine acquisition and reinstatement.

Differential Alterations in Striatal Direct and Indirect Pathways Mediate Two Autism-like Behaviors in Valproate-Exposed Mice.

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration. Concurrent alteration in indirect pathway was a depressed state of basal activity, with enhancement in transient responsiveness of D2-MSNs during repetitive behaviors. A causal relationship linking such differential alterations in these two pathways to the coexistence of these two autism-like behaviors was demonstrated by the cell type-specific correction of abnormal basal activity in the D1-MSNs and D2-MSNs of valproate-exposed mice. The findings support those differential alterations in two striatal pathways mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations.SIGNIFICANCE STATEMENT Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although a number of recent studies have implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, but social behaviors need to be processed by a series of actions, and repetitive behaviors, especially the high-order repetitive behaviors such as restrictive interests, have its scope to cognitive and emotional domains. The current study, for the first time, revealed that prenatal valproate exposure induced coexisting and differential alterations in the dorsomedial striatal direct and indirect pathways, and that these alterations mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations to address the behavioral abnormalities.

Dexmedetomidine attenuates motor deficits via restoring the function of neurons in the nigrostriatal circuit in Parkinson's disease model mice.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive degeneration in nigrostriatal dopamine pathway that is essential to control motor functions. Dexmedetomidine (DEX), a sedative and analgesic drug, is often used in patients with PD undergoing surgery. Although DEX seems to have promising future applications in neuroprotection, whether and how DEX alter the function of nigrostriatal circuit and its roles on motor deficits in PD remain unclear. Here we report that DEX attenuated motor deficits in a dose-dependent manner and protected the degeneration of dopaminergic neurons in MPTP-induced PD model mice. The DEX acted on the neurons in the nigrostriatal circuits, including activation of dopaminergic neurons and the reduction of the excitabilities of striatal neurons via dopamine D2 receptors. We further found that DEX prevented the increase in glutamatergic transmission of cholinergic interneurons (CINs) to alleviate motor dysfunction. It also decreased the intrinsic excitability and glutamatergic transmission of striatal D2 medium spiny neurons (D2-MSNs). Finally, D2 receptor antagonists prevented the restoration of DEX on motor deficits. These results demonstrate that DEX, a neuroprotective drug, restores the function of nigrostriatal neurons and improves the motor deficits, providing a potential neural mechanism of the effects of anesthetic drugs on PD progression.

Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation.

Mitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.

High-Frequency Activation of Nucleus Accumbens D1-MSNs Drives Excitatory Potentiation on D2-MSNs.

Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.

Increased conditioned place preference for cocaine in high anxiety related behavior (HAB) mice is associated with an increased activation in the accumbens corridor.

Anxiety disorders and substance use disorders are strongly associated in humans. Accordingly, a widely held but controversial concept in the addiction field, the so-called "self-medication hypothesis," posits that anxious individuals are more vulnerable for drug dependence because they use drugs of abuse to alleviate their anxiety. We tested this hypothesis under controlled experimental conditions by quantifying the conditioned place preference (CPP) to 15 mg/kg i.p. cocaine given contingently (COCAINE) in CD1 mice selectively bred for high anxiety-related behavior (HAB) vs. normal anxiety-related behavior (NAB). Cocaine was conditioned to the initially non-preferred compartment in an alternate day design (cocaine vs. saline, four pairings each). HAB and NAB mice were also tested for the effects of non-contingent (NONCONT) cocaine administration. HAB mice showed a slightly higher bias for one of the conditioning compartments during the pretest than NAB mice that became statistically significant (p = 0.045) only after pooling COCAINE and NONCONT groups. Cocaine CPP was higher (p = 0.0035) in HAB compared to NAB mice. The increased cocaine CPP was associated with an increased expression of the immediate early genes (IEGs) c-Fos and Early Growth Related Protein 1 (EGR1) in the accumbens corridor, i.e., a region stretching from the anterior commissure to the interhemispheric border and comprising the medial nucleus accumbens core and shell, the major island of Calleja and intermediate part of the lateral septum, as well as the vertical limb of the diagonal band and medial septum. The cocaine CPP-induced EGR1 expression was only observed in D1- and D2-medium spiny neurons, whereas other types of neurons or glial cells were not involved. With respect to the activation by contingent vs. non-contingent cocaine EGR1 seemed to be a more sensitive marker than c-Fos. Our findings suggest that cocaine may be more rewarding in high anxiety individuals, plausibly due to an anxiolytic effect.

The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons.

The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum's two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction.