Corticostriatal Circuits Research Articles

White matter disconnection and decreased functional connectivity between orbitofrontal cortex and the contralateral temporo-occipital cortex in adults with obsessive compulsive disorder

IntroductionObsessive compulsive disorder (OCD) affects 2-3% of the general population. The neurobiology of OCD has been linked to dysfunction of cortico-striatal circuits connecting the orbitofrontal (OFC) to the striatum. Recently, this loop has become an approved target for non-invasive neuromodulatory treatment of OCD.ObjectivesTo explore structural and functional connectivity of the OFC in OCD subjects and healthy controls.Methods14 OCD patients and 12 age/sex-matched controls underwent magnetic resonance imaging (MRI) (3T-Philips scanner) for diffusion tensor imaging (DTI) and resting state functional connectivity (rsFC). DTI images were brain extracted and corrected for movement and eddy currents. A diffusion tensor model was fitted to each voxel and used to generate Fractional Anisotropy (FA) maps. Voxel-wise statistical analysis of FA was performed using Tract-Based Spatial Statistics. RsFC images were preprocessed and seed-based correlation (SBC) analysis was performed using Data Processing Assistant for Resting-State fMRI.ResultsWe found decreased values of FA in the body of the Corpus Callosum bilaterally (MNI_coordinates: x= 16, y= -16, z= 33 and x= -19, y= -16, z= 42) and left superior longitudinal fasciculus in OCD patients (fig 1, left), as well as decreased rsFC of the right superior orbitofrontal seed with the left inferior frontal gyrus and left middle occipital gyrus (fig 2, right).ConclusionsUsing an exploratory multimodal approach we found evidence of abnormal structural and functional long-range connectivity of the OFC in OCD. If confirmed in a larger sample these connectivity abnormalities could be explored as potential predictors of response to OFC-targeted non-invasive neuromodulatory interventions.DisclosureNo significant relationships.

Comorbidity and therapeutic response of body dysmorphic disorder (BDD) in autism spectrum disorder (ASD)

IntroductionAutism spectrum disorder (ASD) is a neurodevelopmental disorder with a biological basis overlapped with obsessive compulsive disorders and body dysmorphic disorder (BDD). The combination of pharmacological treatment and psychological interventions have been considered the gold-standardObjectivesOur main objective was to present the case of a patient with ASD and comorbid BDD. As a second objective, we reviewed recent works on the common neurobiological substrate and therapeutic options for both conditions.Methods(1)Clinical case: Patient with ASD and BDD, treated with fluoxetine 60 mg/day and aripiprazole 30 mg/day. (2)Non-systematic narrative review focused on neurobiological substrate and treatment of ASD and BDD. The electronic search was performed by the PubMed database (1990-2020) using the following key terms: “autism spectrum disorder”, “body dysmorphic disorder”, “dysmorphophobia”, “neurobiology”, “pharmacological treatment”, “psychological treatment” and “treatment”.ResultsOur patient is a 31-year-old single male fulfilling DSM-5 criteria for ASD, diagnosed in childhood, and BDD. He received pharmacological treatment and CBT. He also verbalized having been concerned with his lips and mouth for the last 10 years. This discomfort leads to passive ideas of death. Review: All articles (n=4) supported the use of selective serotonin reuptake inhibitors (SSRIs) and CBT in this comorbidity. None of them reported the use of antipsychotics. Oone article described the use of Repetitive transcranial magnetic stimulation (rTMS) and oxytocin.ConclusionsASD and BDD share the basis of corticostriatal circuits. ISRS and CBT may be effective in treatment. Other options (oxytocin or rTMS) should be further investigated. Examining this comorbidity could be useful for discovering possible endophenotypes.

Resting-state functional connectivity of the ventral tegmental area and negative symptom domains in subjects with schizophrenia

IntroductionNegative symptoms (NS) represent a core aspect of schizophrenia with a huge impact on real life functioning. Dysfunctions within the dopaminergic cortico-striatal circuits have been documented in subjects with schizophrenia (SCZ) and hypothesized as possible neurobiological mechanisms underlying some domains of NS.ObjectivesWe investigated relationships between the resting-state functional connectivity (RS-FC) of the ventro-tegmental area (VTA) and NS.MethodsResting-state fMRI data were recorded in 35 SCZ, recruited within the Italian Network for Research on Psychoses. We performed partial correlations between RS-FC and NS (evaluated with the Brief Negative Symptom Scale) controlling for possible sources of secondary negative symptoms.ResultsWe found that the experiential domain correlated with the RS-FC of the VTA with the left ventro-lateral prefrontal cortex (lVLPFC) (r=0.372, p=0.039), while the Expressive deficit domain correlated with the RS-FC of the VTA with the left dorso-lateral prefrontal cortex (lDLPFC) (r= 0.470, p .008). Looking at subdomains, only the avolition (r= 0.418, p=0.019) and the blunted affect (r= 0.465, p=.008) showed the same correlations of the domains to which they belong.ConclusionsAccording to our findings, separate dysfunctional neuronal circuits could underpin distinct negative symptom subdomains. A better understanding of neurobiological dysfunctions underlying NS could help to design new treatments, targeting different NS subdomains.

Unraveling the Temporal Dynamics of Reward Signals in Music-Induced Pleasure with TMS.

Music's ability to induce feelings of pleasure has been the subject of intense neuroscientific research lately. Prior neuroimaging studies have shown that music-induced pleasure engages cortico-striatal circuits related to the anticipation and receipt of biologically relevant rewards/incentives, but these reports are necessarily correlational. Here, we studied both the causal role of this circuitry and its temporal dynamics by applying transcranial magnetic stimulation (TMS) over the left dorsolateral PFC combined with fMRI in 17 male and female participants. Behaviorally, we found that, in accord with previous findings, excitation of fronto-striatal pathways enhanced subjective reports of music-induced pleasure and motivation, whereas inhibition of the same circuitry led to the reduction of both. fMRI activity patterns indicated that these behavioral changes were driven by bidirectional TMS-induced alteration of fronto-striatal function. Specifically, changes in activity in the NAcc predicted modulation of both hedonic and motivational responses, with a dissociation between pre-experiential versus experiential components of musical reward. In addition, TMS-induced changes in the fMRI functional connectivity between the NAcc and frontal and auditory cortices predicted the degree of modulation of hedonic responses. These results indicate that the engagement of cortico-striatal pathways and the NAcc, in particular, is indispensable to experience rewarding feelings from music.SIGNIFICANCE STATEMENT Neuroimaging studies have shown that music-induced pleasure engages cortico-striatal circuits involved in the processing of biologically relevant rewards. Yet, these reports are necessarily correlational. Here, we studied both the causal role of this circuitry and its temporal dynamics by combining brain stimulation over the frontal cortex with functional imaging. Behaviorally, we found that excitation and inhibition of fronto-striatal pathways enhanced and disrupted, respectively, subjective reports of music-induced pleasure and motivation. These changes were associated with changes in NAcc activity and NAcc coupling with frontal and auditory cortices, dissociating between pre-experimental versus experiential components of musical reward. These results indicate that the engagement of cortico-striatal pathways, and the NAcc in particular, is indispensable to experience rewarding feeling from music.

Altered activation and functional connectivity in individuals with social anhedonia when envisioning positive future episodes.

Anticipatory pleasure deficits are closely correlated with negative symptoms in schizophrenia, and may be found in both clinical and subclinical populations along the psychosis continuum. Prospection, which is an important component of anticipatory pleasure, is impaired in individuals with social anhedonia (SocAnh). In this study, we examined the neural correlates of envisioning positive future events in individuals with SocAnh. Forty-nine individuals with SocAnh and 33 matched controls were recruited to undergo functional MRI scanning, during which they were instructed to simulate positive or neutral future episodes according to cue words. Two stages of prospection were distinguished: construction and elaboration. Reduced activation at the caudate and the precuneus when prospecting positive (v. neutral) future events was observed in individuals with SocAnh. Furthermore, compared with controls, increased functional connectivity between the caudate and the inferior occipital gyrus during positive (v. neutral) prospection was found in individuals with SocAnh. Both groups exhibited a similar pattern of brain activation for the construction v. elaboration contrast, regardless of the emotional context. Our results provide further evidence on the neural mechanism of anticipatory pleasure deficits in subclinical individuals with SocAnh and suggest that altered cortico-striatal circuit may play a role in anticipatory pleasure deficits in these individuals.

AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain

The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.

A change of mind: Globus pallidus activity and effective connectivity during changes in choice selections.

The basal ganglia are a group of interconnected subcortical nuclei that plays a key role in multiple motor and cognitive processes, in a close interplay with several cortical regions. Two conflicting theories postulate that the basal ganglia pathways can either foster or suppress the cortico-striatal output or, alternatively, they can stabilize or destabilize the cortico-striatal circuit dynamics. These different approaches significantly impact the understanding of observable behaviours and cognitive processes in healthy, as well as clinical populations. We investigated the predictions of these models in healthy participants (N=28), using dynamic causal modeling of fMRI BOLD activity to estimate time- and context-dependent changes in the indirect pathway effective connectivity, in association with repetitions or changes of choice selections. We used two multi-option tasks that required the participants to adapt to uncontrollable environmental changes, by performing sequential choice selections, with and without value-based feedbacks. We found that, irrespective of the task, the trials that were characterized by changes in choice selections (switch trials) were associated with a neural response that mostly overlapped with a network commonly described for the encoding of uncertainty. More interestingly, dynamic causal modeling and family-wise model comparison identified with high likelihood a directed causal relation from the external to the internal part of the globus pallidus (i.e., the short indirect pathway in the basal ganglia), in association with the switch trials. This finding supports the hypothesis that the short indirect pathway in the basal ganglia drives instability in the network dynamics, resulting in changes in choice selection.

Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition

Overconsumption of food is a major health concern in the western world. Palatable food has been shown to alter the activity of neural circuits, and obesity has been linked to alterations in the connectivity between the hypothalamus and cortical regions involved in decision-making and reward processing, putatively modulating the incentive value of food. Outlining neurophysiological adaptations induced by dietary intake of high fat diets (HFD) is thus valuable to establish how the diet by itself may promote overeating. To this end, C57BL/6 mice were fed HFD rich in either saturated fatty acids (HFD-S) or polyunsaturated fatty acids (HFD-P), or a low-fat control diet (LFD) for four weeks. Food and energy intake were monitored and ex vivo electrophysiology was employed to assess neuroadaptations in lateral hypothalamus (LH) and corticostriatal circuits, previously associated with food intake. In addition, the effects of dietary saturated and polyunsaturated fatty acids on the gene expression of NMDA, AMPA and GABAA receptor subunits in the hypothalamus were investigated. Our data shows that mice fed HFD-P had increased daily food and energy intake compared with mice fed HFD-S or LFD. However, this increase in energy intake had no obesogenic effects. Electrophysiological recordings demonstrated that HFD-P had a selective effect on glutamatergic neurotransmission in the LH, which was concomitant with a change in mRNA expression of AMPA receptor subtypes Gria1, Gria3 and Gria4, with no effect on the mRNA expression of NMDA receptor subtypes or GABAA receptor subtypes. Furthermore, while synaptic output from corticostriatal subregions was not significantly modulated by diet, synaptic plasticity in the form of long-term depression (LTD) was impaired in the dorsomedial striatum of mice fed HFD-S. In conclusion, this study suggests that the composition of fatty acids in the diet not only affects weight gain, but may also modulate neuronal function and plasticity in brain regions involved in food intake.

Common neurofunctional dysregulations characterize obsessive-compulsive, substance use, and gaming disorders-An activation likelihood meta-analysis of functional imaging studies.

Compulsivity and loss of behavioral control represent core symptoms in obsessive-compulsive disorder (OCD), substance use disorder (SUD), and internet gaming disorder (IGD). Despite elaborated animal models suggesting that compulsivity is mediated by cortico-striatal circuits and a growing number of neuroimaging case-control studies, common neurofunctional alterations in these disorders have not been systematically examined. The present activation likelihood estimation (ALE) meta-analysis capitalized on previous functional magnetic resonance imaging (fMRI) studies to determine shared neurofunctional alterations among the three disorders. Task-based fMRI studies of individuals with SUD, OCD, or IGD were obtained. ALE was performed within each disorder. Next, contrast and conjunction meta-analyses were performed to determine differential and common alterations. Task-paradigm classes were group according to Research Domain Criteria (RDoC) domains to determine contributions of underlying behavioral domains. One hundred forty-four articles were included representing data from n=6897 individuals (SUD=2418, controls=2332; IGD=361, controls=360; OCD=715, controls=711) from case-control studies. Conjunction meta-analyses revealed shared alterations in the anterior insular cortex between OCD and SUDs. SUD exhibited additionally pronounced dorsal-striatal alterations compared with both, OCD and IGD. IGD shared frontal, particularly cingulate alterations with all SUDs, while IGD demonstrated pronounced temporal alterations compared with both, SUD and OCD. No robust overlap between IGD and OCD was observed. Across the disorders, neurofunctional alterations were mainly contributed by cognitive systems and positive valence RDoC domains. The present findings indicate that neurofunctional dysregulations in prefrontal regions engaged in regulatory-control represent shared neurofunctional alterations across substance and behavioral addictions, while shared neurofunctional dysregulations in the anterior insula may mediate compulsivity in substance addiction and OCD.

Motor Learning Selectively Strengthens Cortical and Striatal Synapses of Motor Engram Neurons

Learning and consolidation of new motor skills require adaptations of neuronal activity and connectivity in the motor cortex and striatum, two key motor regions of the brain. Yet, how neurons undergo synaptic changes and become recruited during motor learning to form a memory engram remains an open question. Here, we train mice on a single-pellet reaching motor learning task and use a genetic approach to identify and manipulate behavior-relevant neurons selectively in the primary motor cortex (M1). We find that the degree of reactivation of M1 engram neurons correlates strongly with motor performance. We further demonstrate that learning-induced dendritic spine reorganization specifically occurs in these M1 engram neurons. In addition, we find that motor learning leads to an increase in the number and strength of outputs from M1 engram neurons onto striatal spiny projection neurons (SPNs) and that these synapses form local clusters along SPN dendrites. These results identify a highly specific synaptic plasticity during the formation of long-lasting motor memory traces in the corticostriatal circuit.

Acute Ethanol Exposure Enhances Synaptic Plasticity in the Dorsal Striatum in Adult Male and Female Rats

Background:Acute (ex vivo) and chronic (in vivo) alcohol exposure induces neuroplastic changes in the dorsal striatum, a critical region implicated in instrumental learning.Objective:Sex differences are evident in alcohol reward and reinforcement, with female rats consuming higher amount of alcohol in operant paradigms compared to male rats. However, sex differences in the neuroplastic changes produced by acute alcohol in the dorsal striatum have been unexplored.Methods:Using electrophysiological recordings from dorsal striatal slices obtained from adult male and female rats, we investigated the effects of ex vivo ethanol exposure on synaptic transmission and synaptic plasticity. Ethanol (44 mM) enhanced basal synaptic transmission in both sexes. Ethanol also enhanced long-term potentiation in both sexes. Other measures of synaptic plasticity including paired-pulse ratio were unaltered by ethanol in both sexes.Results:The results suggest that alterations in synaptic plasticity induced by acute ethanol, at a concentration associated with intoxication, could play an important role in alcohol-induced experience-dependent modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions and formation of habits mediating alcohol seeking and taking.Conclusions:Taken together, understanding the mechanism(s) underlying alcohol induced changes in corticostriatal function may lead to the development of more effective therapeutic agents to reduce habitual drinking and seeking associated with alcohol use disorders.

Arbitration of Approach-Avoidance Conflict by Ventral Hippocampus

When environmental cues or stimuli that represent both rewarding and aversive outcomes are presented, complex computations must be made in order to determine whether approach or avoidance is the better behavioral strategy. In many neuropsychiatric illnesses these computations can be skewed. In some instances, circumstances that may normally warrant avoidance instead promote approach, thus producing compulsive-like behavioral strategies that are inflexible in response to new or conflicting information. Alternatively, high sensitivity to aversion or low sensitivity to reward can result in the failure to achieve goals and loss of resilience that characterizes depressive disorders. Increases in compulsive-like behavior have been found to be associated with disrupted signaling in regions that regulate response to conflicting stimuli, including the hippocampus. Classic behavioral inhibition theories of hippocampus function in anxiety suggest that the hippocampus blocks aberrant behavior in response to anxiety related cues or stimuli. The hippocampus may act to block approach in the face of conflicting stimuli. Dysregulations of hippocampal function, as may be present in neuropsychiatric disorders, may therefore promote aberrant approach behavior. The ventral hippocampus (vHPC) subregion is key for coordinating this approach/avoidance conflict resolution, likely through its participation with cortico-striatal and mesolimbic circuits. We revisit Gray's behavioral inhibition theory of HPC function, first posited in the 1980s, and interpret in the context of new knowledge on vHPC function gained through modern technology. Taken together with the extant, classical literature on hippocampal function, we propose that these new findings suggest that vHPC circuits balance behavioral response to conflicting stimuli in a manner that is both state- and context-dependent and, further, that disruption of specific vHPC circuits tips the balance in favor of biased approach or avoidance behavioral strategies.

Obsessive-Compulsive Symptoms Among Children in the Adolescent Brain and Cognitive Development Study: Clinical, Cognitive, and Brain Connectivity Correlates

BackgroundChildhood obsessive-compulsive symptoms (OCSs) are common and can be an early risk marker for obsessive-compulsive disorder. The Adolescent Brain and Cognitive Development (ABCD) Study provides a unique opportunity to characterize OCSs in a large normative sample of school-age children and to explore corticostriatal and task-control circuits implicated in pediatric obsessive-compulsive disorder. MethodsThe ABCD Study acquired data from 9- and 10-year-olds (N = 11,876). Linear mixed-effects models probed associations between OCSs (Child Behavior Checklist) and cognition (NIH Toolbox), brain structure (subcortical volume, cortical thickness), white matter (diffusion tensor imaging), and resting-state functional connectivity. ResultsOCS scores showed good psychometric properties and high prevalence, and they were related to familial/parental factors, including family conflict. Higher OCS scores related to better cognitive performance (β = .06, t9966.60 = 6.28, p < .001, ηp2= .01), particularly verbal, when controlling for attention-deficit/hyperactivity disorder, which related to worse performance. OCSs did not significantly relate to brain structure but did relate to lower superior corticostriatal tract fractional anisotropy (β = −.03, t = −3.07, p = .002, ηp2= .02). Higher OCS scores were related to altered functional connectivity, including weaker connectivity within the dorsal attention network (β = −.04, t7262.87 = −3.71, p < .001, ηp2= .002) and weaker dorsal attention–default mode anticorrelation (β = .04, t7251.95 = 3.94, p < .001, ηp2 = .002). Dorsal attention–default mode connectivity predicted OCS scores at 1 year (β = −.04, t2407.61 = −2.23, p = .03, ηp2 = .03). ConclusionsOCSs are common and may persist throughout childhood. Corticostriatal connectivity and attention network connectivity are likely mechanisms in the subclinical-to-clinical spectrum of OCSs. Understanding correlates and mechanisms of OCSs may elucidate their role in childhood psychiatric risk and suggest potential utility of neuroimaging, e.g., dorsal attention–default mode connectivity, for identifying children at increased risk for obsessive-compulsive disorder.

Childhood neglect is associated with corticostriatal circuit dysfunction in bipolar disorder adults

Bipolar disorder (BD) is characterized with cognitive impairment, which may be mediated by corticostriatal dysfunction. Here we examined whether history of childhood trauma, a risk factor for BD, was linked to corticostriatal dysfunction in BD patients. Furthermore, the possible associations between childhood trauma and cognitive impairment were examined. Thirty-eight BD participants who met the DSM-IV diagnostic criteria were enrolled. Childhood trauma was identified via the Childhood Trauma Questionnaire (CTQ). Participants completed the Wisconsin Card-Sorting Test (WCST). Resting-state functional magnetic resonance imaging (rsfMRI) was performed in participants using a 3T scanner. Bilateral caudate to whole-brain functional connectivity (FC) were analyzed, and childhood trauma was entered as a regressor of interest when controlling for age. Results showed the level of physical neglect was negatively correlated with left-caudate-seed FC to the frontoparietal network, including the right supramarginal gyrus, left inferior parietal lobule, right middle frontal gyrus, and right superior parietal lobule. The level of physical neglect was also negatively correlated with WCST performance. And the left-caudate-seed FCs to the frontoparietal network were positively correlated with WCST performance. Unequivocally, the specific impacts of physical neglect on brain connectivity and executive function in the BD population merit further investigation.

The basal ganglia corticostriatal loops and conditional learning.

Brief maneuvering of the literature as to the various roles attributed to the basal ganglia corticostriatal circuits in a variety of cognitive processes such as working memory, selective attention, and category learning has inspired us to investigate the interplay of the two major basal ganglia open-recurrent loops, namely, visual and executive loops specifically the possible involvement of their overlap in conditional learning. We propose that the interaction of the visual and executive loops reflected through their cortical overlap in the dorsolateral prefrontal cortex (DL-PFC), lateral orbitofrontal cortex (LO-PFC), and presupplementary motor area (SMA) plays an instrumental role preliminary first in forming associations between a series of correct responses following similar stimuli and then in shifting, abstracting, and generalizing conditioned responses. The premotor and supplementary motor areas have been shown essential to producing a sequence of movements while the SMA is engaged in monitoring complex movements. In light of the recent studies, we will suggest that the interaction of visual and executive loops could strengthen or weaken learned associations following different reward values. Furthermore, we speculate that the overlap of the visual and executive loops can account for the switching between the associative vs. rule-based category learning systems.

Cortical and striatal circuits together encode transitions in natural behavior.

In natural behavior, we fluidly change from one type of activity to another in a sequence of motor actions. Corticostriatal circuits are thought to have a particularly important role in the construction of action sequences, but neuronal coding of a sequential behavior consisting of different motor programs has not been investigated at the circuit level in corticostriatal networks, making the exact nature of this involvement elusive. Here, we show, by analyzing spontaneous self-grooming in rats, that neuronal modulation in motor cortex and dorsal striatum is strongly related to transitions between behaviors. Our data suggest that longer action sequences in rodent grooming behavior emerge from stepwise control of individual behavioral transitions, where future actions are encoded differently depending on current motor state. This state-dependent motor coding was found to differentiate between rare behavioral transitions and as opposed to more habitual sequencing of actions.

Cognitive and motor deficits in older adults with HIV infection: Comparison with normal ageing and Parkinson's disease.

Despite the life-extending success of antiretroviral pharmacotherapy in HIV infection (HIV), the prevalence of mild cognitive impairment in HIV remains high. Near-normal life expectancy invokes an emerging role for age-infection interaction and a potential synergy between immunosenescence and HIV-related health factors, increasing risk of cognitive and motor impairment associated with degradation in corticostriatal circuits. These neural systems are also compromised in Parkinson's disease (PD), which could help model the cognitive deficit pattern in HIV.This cross-sectional study examined three groups, age 45-79years: 42 HIV, 41 PD, and 37 control (CTRL) participants, tested at Stanford University Medical School and SRI International. Neuropsychological tests assessed executive function (EF), information processing speed (IPS), episodic memory (MEM), visuospatial processing (VSP), and upper motor (MOT) speed and dexterity. The HIV and PD deficit profiles were similar for EF, MEM, and VSP. Although only the PD group was impaired on MOT compared with CTRL, MOT scores were related to cognitive scores in HIV but not PD. Performance was not related to depressive symptoms, socioeconomic status, or CD4+ T-cell counts. The overlap of HIV-PD cognitive deficits implicates frontostriatal disruption in both conditions. The motor-cognitive score relation in HIV provides further support for the hypothesis that these processes share similar underlying mechanisms in HIV infection possibly expressed with or exacerbated by ageing.

M2 cortex-dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's disease.

Huntington's disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.

BEHAVIORAL AND NEUROBIOLOGICAL MECHANISMS OF PAVLOVIAN AND INSTRUMENTAL EXTINCTION LEARNING.

This article reviews the behavioral neuroscience of extinction, the phenomenon in which a behavior that has been acquired through Pavlovian or instrumental (operant) learning decreases in strength when the outcome that reinforced it is removed. Behavioral research indicates that neither Pavlovian nor operant extinction depends substantially on erasure of the original learning but instead depends on new inhibitory learning that is primarily expressed in the context in which it is learned, as exemplified by the renewal effect. Although the nature of the inhibition may differ in Pavlovian and operant extinction, in either case the decline in responding may depend on both generalization decrement and the correction of prediction error. At the neural level, Pavlovian extinction requires a tripartite neural circuit involving the amygdala, prefrontal cortex, and hippocampus. Synaptic plasticity in the amygdala is essential for extinction learning, and prefrontal cortical inhibition of amygdala neurons encoding fear memories is involved in extinction retrieval. Hippocampal-prefrontal circuits mediate fear relapse phenomena, including renewal. Instrumental extinction involves distinct ensembles in corticostriatal, striatopallidal, and striatohypothalamic circuits as well as their thalamic returns for inhibitory (extinction) and excitatory (renewal and other relapse phenomena) control over operant responding. The field has made significant progress in recent decades, although a fully integrated biobehavioral understanding still awaits.

SCH23390 Reduces Methamphetamine Self-Administration and Prevents Methamphetamine-Induced Striatal LTD.

Extended-access methamphetamine self-administration results in unregulated intake of the drug; however, the role of dorsal striatal dopamine D1-like receptors (D1Rs) in the reinforcing properties of methamphetamine under extended-access conditions is unclear. Acute (ex vivo) and chronic (in vivo) methamphetamine exposure induces neuroplastic changes in the dorsal striatum, a critical region implicated in instrumental learning. For example, methamphetamine exposure alters high-frequency stimulation (HFS)-induced long-term depression in the dorsal striatum; however, the effect of methamphetamine on HFS-induced long-term potentiation (LTP) in the dorsal striatum is unknown. In the current study, dorsal striatal infusion of SCH23390, a D1R antagonist, prior to extended-access methamphetamine self-administration reduced methamphetamine addiction-like behavior. Reduced behavior was associated with reduced expression of PSD-95 in the dorsal striatum. Electrophysiological findings demonstrate that superfusion of methamphetamine reduced basal synaptic transmission and HFS-induced LTP in dorsal striatal slices, and SCH23390 prevented this effect. These results suggest that alterations in synaptic transmission and synaptic plasticity induced by acute methamphetamine via D1Rs could assist with methamphetamine-induced modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions and formation of habits, mediating escalation of methamphetamine self-administration and methamphetamine addiction-like behavior.