Dorsolateral Striatum Research Articles

Dopaminergic Input Regulates the Sensitivity of Indirect Pathway Striatal Spiny Neurons to Brain-Derived Neurotrophic Factor.

Motor dysfunction in Parkinson's disease (PD) is closely linked to the dopaminergic depletion of striatal neurons and altered synaptic plasticity at corticostriatal synapses. Dopamine receptor D1 (DRD1) stimulation is a crucial step in the formation of long-term potentiation (LTP), whereas dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in striatal spiny projection neurons (SPNs). Tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal synapses. DRD1 activation enhances TrkB's sensitivity for BDNF in direct pathway spiny projection neurons (dSPNs). In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs from Pitx3-/- mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD.

Home cage voluntary alcohol consumption increases binge drinking without affecting abstinence-related depressive-like behaviors or operant responding in crossed high alcohol-preferring mice (cHAPs)

Chronic alcohol consumption can lead to tolerance and escalation of drinking in humans and animals, but mechanisms underlying these changes are not fully characterized. Preclinical models can delineate which mechanisms are involved. The chronic intermittent ethanol exposure (CIE) procedure uses forced exposure to vaporized alcohol that elicits withdrawal and increased responding for alcohol in operant tasks in C57BL/6J inbred mice. Chronic two-bottle choice (2BC) drinking in the same strain elicits abstinent-related depression-like behavior, suggestive of allostatic changes. Selected lines such as crossed High Alcohol Preferring (cHAP) mice voluntarily drink to blood alcohol concentrations comparable to those attained in CIE and could be used to assess how alcohol affects these same endpoints without the confounds of involuntary vapor inhalation. In three experiments, we assess how 2BC drinking in cHAP mice affects abstinence-related depressive- and anxiety-like behavior, operant responding for alcohol, and binge consumption using drinking-in-the-dark (DID). We hypothesized that cHAPs with home-cage drinking experience would exhibit more depressive behavior after abstinence, increased responding for alcohol in the operant box, and increased DID intake. Of these, a drinking history increased DID intake in female cHAPs only and increased sucrose preference and intake following abstinence, but had no effects on operant responding or NSFT latency and FST immobility following forced abstinence. These results are consistent with recent findings using slice electrophysiology showing tolerance to alcohol's actions on the dorsolateral striatum following 2BC drinking in female, but not male cHAP mice. Overall, these data suggest that cHAPs may require procedures allowing rapid intoxication, such as DID, to demonstrate changes in alcohol's rewarding effects.

Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson’s disease (PD) and following the development of l-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of l-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of l-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg l-DOPA doses. However, after reaching the 72 mg/kg l-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of l-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.

The development of compulsive coping behavior depends on dorsolateral striatum dopamine-dependent mechanisms

Humans greatly differ in how they cope with stress, a natural behavior learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduces stress. Some individuals, in particular those that use alcohol to self-medicate, tend to lose control over such coping behaviors, which become excessive and compulsive. However, the psychological and neural mechanisms underlying this individual vulnerability have not been elucidated. Here we tested the hypothesis that the development of compulsive adjunctive behaviors stems from the functional engagement of the dorsolateral striatum (DLS) dopamine-dependent habit system after a prolonged history of adjunctive responding. We measured in longitudinal studies in male Sprague Dawley rats the sensitivity of early established vs compulsive polydipsic water or alcohol drinking to a bilateral infusion into the anterior DLS (aDLS) of the dopamine receptor antagonist α-flupentixol. While most rats acquired a polydipsic drinking response with water, others only did so with alcohol. Whether drinking water or alcohol, the acquisition of this coping response was insensitive to aDLS dopamine receptor blockade. In contrast, after prolonged experience, adjunctive drinking became dependent on aDLS dopamine at a time when it was compulsive in vulnerable individuals. These data suggest that habits may develop out of negative reinforcement and that the engagement of their underlying striatal system is necessary for the manifestation of compulsive adjunctive behaviors.

Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor

The development of genetically encoded dopamine sensors such as dLight has provided a new approach to measuring slow and fast dopamine dynamics both in brain slices and in vivo, possibly enabling dopamine measurements in areas like the dorsolateral striatum (DLS) where previously such recordings with fast-scan cyclic voltammetry (FSCV) were difficult. To test this, we first evaluated dLight photometry in mouse brain slices with simultaneous FSCV and found that both techniques yielded comparable results, but notable differences in responses to dopamine transporter inhibitors, including cocaine. We then used in vivo fiber photometry with dLight in mice to examine responses to cocaine in DLS. We also compared dopamine responses during Pavlovian conditioning across the striatum. We show that dopamine increases were readily detectable in DLS and describe transient dopamine kinetics, as well as slowly developing signals during conditioning. Overall, our findings indicate that dLight photometry is well suited to measuring dopamine dynamics in DLS.

A novel inhibitory corticostriatal circuit that expresses mu opioid receptor-mediated synaptic plasticity

Corticostriatal circuits are generally characterized by the release of glutamate neurotransmitter from cortical terminals within the striatum. It is well known that cortical excitatory input to the dorsal striatum regulates addictive drug-related behaviors. We previously reported that anterior insular cortex (AIC) synaptic inputs to the dorsolateral striatum (DLS) control binge alcohol drinking in mice. These AIC-DLS glutamate synapses are also the sole sites of corticostriatal mu opioid receptor-mediated excitatory long-term depression (MOR-LTD) in the DLS. Recent work demonstrates that some regions of cortex send long-range, direct inhibitory inputs into the dorsal striatum. Nothing is known about the existence and regulation of AIC-DLS inhibitory synaptic transmission. Here, using a combination of patch clamp electrophysiology and optogenetics, we characterized a novel AIC-DLS corticostriatal inhibitory circuit and its regulation by MOR-mediated inhibitory LTD (MOR-iLTD). First, we found that the activation of presynaptic MORs produces MOR-iLTD in the DLS and dorsomedial striatum. Then, we showed that medium spiny neurons within the DLS receive direct inhibitory synaptic input from the cortex, specifically from the motor cortex and AIC. Using transgenic mice that express cre-recombinase within parvalbumin-expressing inhibitory neurons, we determined that this specific cortical neuron subtype sends direct GABAergic projections to the DLS. Moreover, these AIC-DLS inhibitory synaptic input subtypes express MOR-iLTD. These data suggest a novel GABAergic corticostriatal circuit that could be involved in the regulation of drug and alcohol consumption-related behaviors.

Striatonigral direct pathway 2-arachidonoylglycerol contributes to ethanol effects on synaptic transmission and behavior

Endocannabinoids (eCB) and cannabinoid receptor 1 (CB1) play important roles in mediating short- and long-term synaptic plasticity in many brain regions involved in learning and memory, as well as the reinforcing effects of misused substances. Ethanol-induced plasticity and neuroadaptations predominantly occur in striatal direct pathway projecting medium spiny neurons (dMSNs). It is hypothesized that alterations in eCB neuromodulation may be involved. Recent work has implicated a role of eCB 2-arachidonoylglycerol (2-AG) in the rewarding effects of ethanol. However, there is insufficient research to answer which cellular subtype is responsible for mediating the 2-AG eCB signal that might be involved in the rewarding properties of ethanol and the mechanisms by which that occurs. To examine the role of dMSN mediated 2-AG signaling in ethanol related synaptic transmission and behaviors, we used conditional knockout mice in which the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) was deleted in dMSNs, DGLαD1-Cre+. Using acute brain slice photometry and a genetically encoded fluorescent eCB sensor, GRABeCB2.0, to assess real-time eCB mediated activity of sensorimotor inputs from primary motor cortices (M1/M2) to the dorsolateral striatum, we showed that DGLαD1-Cre+ mice had blunted evoked eCB-mediated presynaptic eCB signaling compared to littermate controls. Furthermore, ethanol induced eCB inhibition was significantly reduced in DGLαD1-Cre+ deficient mice. Additionally, there was a reduction in the duration of loss of righting reflex (LORR) to a high dose of ethanol in the DGLαD1-Cre+ mice compared to controls. These mice also showed a male-specific decrease in ethanol preference accompanied by an increase in ethanol-induced water consumption in a voluntary drinking paradigm. There were no significant differences observed in sucrose and quinine consumption between the genotypes. These findings reveal a novel role for dMSN mediated 2-AG signaling in modulating ethanol effects on presynaptic function and behavior.

Enriched Rehabilitation Reduces Abnormal Motor Synergies and Enhances Motor Plasticity Following Severe Stroke in Rats.

Stroke results in loss of upper motor neuron control over voluntary movements and emergence of abnormal synergies. Presently, it is unclear to what extent poststroke recovery reflects true recovery (restitution), compensation, or some combination of these processes. Here, we investigated this question using behavioral and kinematic analyses of skilled reaching in rats subjected to severe stroke that affected both the forelimb motor cortex and dorsolateral striatum. After stroke, male rats either spontaneously recovered or received enriched rehabilitation. We assessed forelimb motor recovery using behavioral and kinematic outcome measures. To provide insights into the mechanisms underlying the effects of rehabilitation on behavior, we used intracortical microstimulation and FosB (protein fosB) immunostaining techniques. Enriched rehabilitation significantly improved food pellet retrieval in the staircase-reaching task. Rehabilitation resulted in several poststroke flexion synergies returning to prestroke patterns, and across subjects, these changes correlated with the intensity of rehabilitation. Enriched rehabilitation increased the proportion of distal movement representation in the perilesional cortex and increased use-dependent activation in the ipsilesional red nucleus. These results provide evidence that enriched rehabilitation enhances recovery, at least in part, by restitution of forelimb function following severe stroke. Furthermore, the restitution of function is associated with changes in multiple motor-related structures at different levels of the central nervous system. A better understanding of the processes that underlie improved motor performance, along with the identification of midbrain circuits activated by rehabilitation, represent new insights and potential targets for optimizing poststroke recovery.

The Partial M1 Muscarinic Cholinergic Receptor Agonist, CDD-0102A, Differentially Modulates Glutamate Efflux in Striatal Subregions during Stereotyped Motor Behavior in the BTBR Mouse Model of Autism.

The BTBR T+ Itpr3tf/J (BTBR) mouse displays elevated repetitive motor behaviors. Treatment with the partial M1 muscarinic receptor agonist, CDD-0102A, attenuates stereotyped motor behaviors in BTBR mice. The present experiment investigated whether CDD-0102A modifies changes in striatal glutamate concentrations during stereotyped motor behavior in BTBR and B6 mice. Using glutamate biosensors, change in striatal glutamate efflux was measured during bouts of digging and grooming behavior with a 1 s time resolution. Mice displayed both decreases and increases in glutamate efflux during such behaviors. Magnitude of changes in glutamate efflux (decreases and increases) from dorsomedial and dorsolateral striatum were significantly greater in BTBR mice compared to those of B6 mice. In BTBR mice, CDD-0102A (1.2 mg/kg) administered 30 min prior to testing significantly reduced the magnitude change in glutamate decreases and increases from the dorsolateral striatum and decreased grooming behavior. Conversely, CDD-0102A treatment in B6 mice potentiated glutamate decreases and increases in the dorsolateral striatum and elevated grooming behavior. The findings suggest that activation of M1 muscarinic receptors modifies glutamate transmission in the dorsolateral striatum and self-grooming behavior.

External globus pallidus input to the dorsal striatum regulates habitual seeking behavior in male mice

The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant conditioning. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe→DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation globally reduced seeking behaviors, which was blocked by systemic D1R agonism. Our findings reveal a role of this arkyGPe→DLS circuit in constraining habitual seeking in male mice, which is relevant to addictive behaviors and other compulsive disorders.

The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia.

The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = -0.18, p = 0.62; TMT B: rho = -0.06, p = 0.81). These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS.

Relationship between carotid intima-media thickness (cIMT) and dual-system imbalance in tobacco dependence: An rs-fMRI research.

According to the classic cognitive behavioral theory proposes, dysfunctional goal-directed and habit control systems are considered central to the pathogenesis of dependent behavior and impair recovery from addictions. The functional connectivity (FC) of the brain circuits for goal-directed or habitual behavior has not been clearly reported in tobacco-dependent groups. Smoking is one of the factors in the formation of atherosclerosis. Studies have shown that the thickness of carotid intima-media (cIMT) is associated with attention-executive-psychomotor functioning. Therefore, we hypothesized whether cIMT in tobacco-dependent individuals is associated with changes in the FC of the dual-system network. A total of 29 male tobacco-dependent subjects (tobacco-dependent group) (mean age: 64.20 years, standard deviation [SD]: 4.81 years) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Exactly 28 male nonsmokers (control group) (mean age: 61.95 years, SD: 5.52 years) were also recruited to undergo rs-fMRI. We used the dorsolateral striatum (putamen) and dorsomedial striatum (caudate) as regions of interest for whole-brain resting-state connectivity to construct habitual and goal-directed brain networks, respectively. In addition, all participants were evaluated by carotid artery ultrasound to obtain the cIMT values. Then, we compared the dual-system brain networks between the tobacco dependence and control groups and the relationship between cIMT and imbalance of dual-system brain networks in tobacco dependence. The results showed a reduction in the connection between the caudate and precuneus and an increased connection between the putamen and prefrontal cortex; and supplementary motor area. The bilateral connectivity between the caudate and inferior frontal gyrus showed a significant negative correlation with the cIMT, and no positive correlation was observed with cIMT in the brain region that connects to the caudate. However, for the putamen, increased connectivity with the inferior temporal and medial frontal gyri was strongly associated with a high cIMT. The results indicate that the formation of tobacco dependence behavior is related to changes in the dual-system brain network. Carotid sclerosis is associated with the weakening of the goal-directed network and enhancement of the habit network in tobacco dependence. This finding suggests that tobacco dependence behavior and clinical vascular diseases are related to changes in brain functional networks.

Identifying Neural Signatures of Dopamine Signaling with Machine Learning.

The emergence of new tools to image neurotransmitters, neuromodulators, and neuropeptides has transformed our understanding of the role of neurochemistry in brain development and cognition, yet analysis of this new dimension of neurobiological information remains challenging. Here, we image dopamine modulation in striatal brain tissue slices with near-infrared catecholamine nanosensors (nIRCat) and implement machine learning to determine which features of dopamine modulation are unique to changes in stimulation strength, and to different neuroanatomical regions. We trained a support vector machine and a random forest classifier to decide whether the recordings were made from the dorsolateral striatum (DLS) versus the dorsomedial striatum (DMS) and find that machine learning is able to accurately distinguish dopamine release that occurs in DLS from that occurring in DMS in a manner unachievable with canonical statistical analysis. Furthermore, our analysis determines that dopamine modulatory signals including the number of unique dopamine release sites and peak dopamine released per stimulation event are most predictive of neuroanatomy. This is in light of integrated neuromodulator amount being the conventional metric used to monitor neuromodulation in animal studies. Lastly, our study finds that machine learning discrimination of different stimulation strengths or neuroanatomical regions is only possible in adult animals, suggesting a high degree of variability in dopamine modulatory kinetics during animal development. Our study highlights that machine learning could become a broadly utilized tool to differentiate between neuroanatomical regions or between neurotypical and disease states, with features not detectable by conventional statistical analysis.

Neuronal Representation of a Working Memory-Based Decision Strategy in the Motor and Prefrontal Cortico-Basal Ganglia Loops.

While animal and human decision strategies are typically explained by model-free and model-based reinforcement learning (RL), their choice sequences often follow simple procedures based on working memory (WM) of past actions and rewards. Here, we address how working memory-based choice strategies, such as win-stay-lose-switch (WSLS), are represented in the prefrontal and motor cortico-basal ganglia loops by simultaneous recording of neuronal activities in the dorsomedial striatum (DMS), the dorsolateral striatum (DLS), the medial prefrontal cortex (mPFC), and the primary motor cortex (M1). In order to compare neuronal representations when rats employ working memory-based strategies, we developed a new task paradigm, a continuous/intermittent choice task, consisting of choice and no-choice trials. While the continuous condition (CC) consisted of only choice trials, in the intermittent condition (IC), a no-choice trial was inserted after each choice trial to disrupt working memory of the previous choice and reward. Behaviors in CC showed high proportions of win-stay and lose-switch choices, which could be regarded as "a noisy WSLS strategy." Poisson regression of neural spikes revealed encoding specifically in CC of the previous action and reward before action choice and prospective coding of WSLS action during action execution. A striking finding was that the DLS and M1 in the motor cortico-basal ganglia loop carry substantial WM information about previous choices, rewards, and their interactions, in addition to current action coding.

Differential Development of Dendritic Spines in Striatal Projection Neurons of Direct and Indirect Pathways in the Caudoputamen and Nucleus Accumbens.

Synaptic modification in postnatal development is essential for the maturation of neural networks. Developmental maturation of excitatory synapses occurs at the loci of dendritic spines that are dynamically regulated by growth and pruning. Striatal spiny projection neurons (SPNs) receive excitatory input from the cerebral cortex and thalamus. SPNs of the striatonigral direct pathway (dSPNs) and SPNs of the striatopallidal indirect pathway (iSPNs) have different developmental roots and functions. The spatial and temporal dynamics of dendritic spine maturation of these two types of SPNs remain elusive. Here, we delineate the developmental trajectories of dendritic spines of dSPNs and iSPNs in the caudoputamen and nucleus accumbens (NAc). We labeled dendritic spines of SPNs by microinjecting Cre-dependent AAV-eYFP viruses into newborn Drd1-Cre or Adora2a-Cre mice, and analyzed spinogenesis at three levels, including different SPN cell types, subregions and postnatal times. In the dorsolateral striatum, spine pruning of dSPNs and iSPNs occurred at postnatal day (P)30-P50. In the dorsomedial striatum, the spine density of both dSPNs and iSPNs reached its peak between P30 and P50, and spine pruning occurred after P30 and P50, respectively, for dSPNs and iSPNs. In the NAc shell, spines of dSPNs and iSPNs were pruned after P21-P30, but no significant pruning was observed in iSPNs of lateral NAc shell. In the NAc core, the spine density of dSPNs and iSPNs reached its peak at P21 and P30, respectively, and subsequently declined. Collectively, the developmental maturation of dendritic spines in dSPNs and iSPNs follows distinct spatiotemporal trajectories in the dorsal and ventral striatum.

0039 Investigating the role of striatal dopamine in sleep and narcolepsy-cataplexy

Abstract Introduction Dopamine release in the striatum is known to govern reward, motor, and sleep behaviors. There also exists a link between pharmacological manipulation of dopamine receptors and cataplexy occurrence, yet the precise spatial and temporal dynamics of dopamine release in relation to cataplexy onset are not understood. In the present study, we evaluate dopamine release dynamics in orexin knockout (OX KO) mice during cataplexy and physiological behaviors. Methods OX KO mice were implanted with EEG/EMG electrodes, and dLight1.1 was expressed in the nucleus accumbens core (NAcc), shell (NAcSh), and dorsolateral striatum (DLS) to perform in vivo fiber photometry of dopamine release in freely-moving animals. In NAcc and NAcSh mice, ChrimsonR was retrogradely expressed in the ventral tegmental area (VTA), to allow for precise optogenetic control of midbrain dopamine projections to different regions of the striatum. We also expressed dLight1.1 in the NAcc of wildtype (WT) mice as a control. Three different stimulation parameters were used in independent recordings: phasic 20 Hz stimulation, phasic 10-40 Hz variable stimulation, and tonic 2 Hz stimulation. Results First, we show that while dopamine release in response to rewarding behaviors is muted in OX KO animals, there is no difference in dopamine release across sleep state transitions between OX KO and WT animals. Second, we demonstrate that there is a striking increase in dopamine release in both the NAcc and NAcSh, but not in the DLS, at the onset of cataplexy. This increase occurs independently of the behaviors that the animals were engaged in immediately prior to cataplexy, suggesting that the increase is characteristic of all cataplexy episodes. Finally, we find that while high frequency phasic stimulation did not affect cataplexy frequency, low frequency, tonic stimulation reduced both cataplexy and REM occurrence. Conclusion We show that there are differences in dopamine release in response to rewarding events, but not changes in sleep states, in OX KO and WT animals. We also identify dopamine release in the ventral striatum as a key node in cataplexy regulation, which helps to further our understanding of the limbic circuitry that underlies narcolepsy symptoms. Support (if any) University of Michigan Gilmore Award and Rackham Graduate Research Award.

Chronic alcohol consumption shifts learning strategies and synaptic plasticity from hippocampus to striatum-dependent pathways.

The hippocampus and striatum have dissociable roles in memory and are necessary for spatial and procedural/cued learning, respectively. Emotionally charged, stressful events promote the use of striatal- over hippocampus-dependent learning through the activation of the amygdala. An emerging hypothesis suggests that chronic consumption of addictive drugs similarly disrupt spatial/declarative memory while facilitating striatum-dependent associative learning. This cognitive imbalance could contribute to maintain addictive behaviors and increase the risk of relapse. We first examined, in C57BL/6 J male mice, whether chronic alcohol consumption (CAC) and alcohol withdrawal (AW) might modulate the respective use of spatial vs. single cue-based learning strategies, using a competition protocol in the Barnes maze task. We then performed in vivo electrophysiological studies in freely moving mice to assess learning-induced synaptic plasticity in both the basolateral amygdala (BLA) to dorsal hippocampus (dCA1) and BLA to dorsolateral striatum (DLS) pathways. We found that both CAC and early AW promote the use of cue-dependent learning strategies, and potentiate plasticity in the BLA → DLS pathway while reducing the use of spatial memory and depressing BLA → dCA1 neurotransmission. These results support the view that CAC disrupt normal hippocampo-striatal interactions, and suggest that targeting this cognitive imbalance through spatial/declarative task training could be of great help to maintain protracted abstinence in alcoholic patients.

Gestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function.

Fetal alcohol exposure has deleterious consequences on the motor skills of patients affected by Fetal Alcohol Spectrum Disorder (FASD) and in pre-clinical models of gestational ethanol exposure (GEE). Deficits in striatal cholinergic interneurons (CINs) and dopamine function impair action learning and execution, yet the effects of GEE on acetylcholine (ACh) and striatal dopamine release remain unexplored. Here, we report that alcohol exposure during the first ten postnatal days (GEEP0-P10), which mimics ethanol consumption during the last gestational trimester in humans, induces sex-specific anatomical and motor skill deficits in female mice during adulthood. Consistent with these behavioral impairments, we observed increased stimulus evoked-dopamine levels in the dorsolateral striatum (DLS) of GEEP0-P10 female, but not male, mice. Further experiments revealed sex-specific deficits in β2-containing nicotinic ACh receptor (nAChR)-modulation of electrically evoked dopamine release. Moreover, we found a reduced decay of ACh transients and a decreased excitability of striatal CINs in DLS of GEEP0-P10 females, indicating striatal CIN dysfunctions. Finally, the administration of varenicline, a β2-containing nAChR partial agonist, and chemogenetic-mediated increase in CIN activity improved motor performance in adult GEEP0-P10 females. Altogether, these data shed new light on GEE-induced striatal deficits and establish potential pharmacological and circuit-specific interventions to ameliorate motor symptoms of FASD.

Glutamate dynamics in the dorsolateral striatum of rats with goal-directed and habitual cocaine-seeking behavior.

The shift from drug abuse to addiction is considered to arise from the transition between goal-directed and habitual control over drug behavior. Habitual responding for appetitive and skill-based behaviors is mediated by potentiated glutamate signaling in the dorsolateral striatum (DLS), but the state of the DLS glutamate system in the context of habitual drug-behavior remains undefined. Evidence from the nucleus accumbens of cocaine-experienced rats suggests that decreased transporter-mediated glutamate clearance and enhanced synaptic glutamate release contribute to the potentiated glutamate signaling that underlies the enduring vulnerability to relapse. Preliminary evidence from the dorsal striatum of cocaine-experienced rats suggests that this region exhibits similar alterations to glutamate clearance and release, but it is not known whether these glutamate dynamics are associated with goal-directed or habitual control over cocaine-seeking behavior. Therefore, we trained rats to self-administer cocaine in a chained cocaine-seeking and -taking paradigm, which yielded goal-directed, intermediate, and habitual cocaine-seeking rats. We then assessed glutamate clearance and release dynamics in the DLS of these rats using two different methods: synaptic transporter current (STC) recordings of patch-clamped astrocytes and the intensity-based glutamate sensing fluorescent reporter (iGluSnFr). While we observed a decreased rate of glutamate clearance in STCs evoked with single-pulse stimulation in cocaine-experienced rats, we did not observe any cocaine-induced differences in glutamate clearance rates from STCs evoked with high frequency stimulation (HFS) or iGluSnFr responses evoked with either double-pulse stimulation or HFS. Furthermore, GLT-1 protein expression in the DLS was unchanged in cocaine-experienced rats, regardless of their mode of control over cocaine-seeking behavior. Lastly, there were no differences in metrics of glutamate release between cocaine-experienced rats and yoked-saline controls in either assay. Together, these results suggest that glutamate clearance and release dynamics in the DLS are largely unaltered by a history of cocaine self-administration on this established cocaine seeking-taking paradigm, regardless of whether the control over the cocaine seeking behavior was habitual or goal directed.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.