Corticostriatal Pathway Research Articles

Distinct Cell- and Layer-Specific Expression Patterns and Independent Regulation of Kv2 Channel Subtypes in Cortical Pyramidal Neurons.

Neurons within the neocortex are arranged in a laminar architecture and contribute to the input, processing, and/or output of sensory and motor signals in a cell- and layer-specific manner. Neurons of different cortical layers express diverse populations of ion channels and possess distinct intrinsic membrane properties. Here, we show that the Kv2 family members Kv2.1 and Kv2.2 are expressed in distinct cortical layers and pyramidal cell types associated with specific corticostriatal pathways. We find that Kv2.1 and Kv2.2 exhibit distinct responses to acute phosphorylation-dependent regulation in brain neurons in situ and in heterologous cells in vitro. These results identify a molecular mechanism that contributes to heterogeneity in cortical neuron ion channel function and regulation.

Preserved priming effect in individuals with schizophrenia: cues towards rehabilitation

Introduction. Individuals with schizophrenia and affective disorders show relatively intact implicit memory as compared to declarative memory. Implicit memory is usually assessed with skill learning and priming tasks. Whereas priming is thought to involve storage changes in the posterior neocortex, skill learning is thought to rely more on the corticostriatal pathway. Since frontostriatal and frontotemporal dysfunctions are, respectively, found in schizophrenia and affective disorders, we hypothesised that individuals with schizophrenia and first-episode psychosis would exhibit disturbances in skill learning, but not priming.Methods. Thirty-five patients (11 first-episode psychosis; 11 schizophrenia; 13 affective disorders) and 10 controls completed a procedural learning and priming task. Participants had to identify fragmented images throughout five training sessions. The improvement of the threshold at which the images could be identified between the first and last session was used as an index of procedural learning. In a final session, the identification thresholds for old and new images were compared to assess the priming effect.Results. Whereas individuals with schizophrenia and first-episode psychosis showed impaired skill learning, the priming effect was similar in all groups.Conclusion. Even though some aspects of learning and memory are affected in schizophrenia, our results suggest that the posterior cortical pathway remains efficient at modulating the priming effect. This intact ability could be used to guide the elaboration of new rehabilitation programmes.

Examining procedural learning and corticostriatal pathways for individual differences in language: testing endophenotypes of DRD2/ANKK1

ABSTRACTThe aim was to explore whether genetic variation in the dopaminergic system is associated with procedural learning and the corticostriatal pathways in individuals with developmental language impairment (DLI). We viewed these two systems as endophenotypes and hypothesised that they would be more sensitive indicators of genetic effects than the language phenotype itself. Thus, we genotyped two single nucleotide polymorphisms in DRD2/ANKK1, and tested for their associations to the language phenotype and the endophenotypes. Results showed that individuals with DLI revealed poor procedural learning abilities and abnormal structures of the basal ganglia. Genetic variation in DRD2/ANKK1 was associated with procedural learning and microstructural differences of the caudate nucleus. The association of the language phenotype with DRD2/ANKK1 polymorphisms was non-significant, but the language phenotype was significantly associated with the endophenotypes. We suggest procedural learning and the corticostriatal pathways as effective endophenotypes to aid molecular genetic studies searching for genes predisposing to DLI.

Three-Dimensional Histology Volume Reconstruction of Axonal Tract Tracing Data: Exploring Topographical Organization in Subcortical Projections from Rat Barrel Cortex.

Topographical organization is a hallmark of the mammalian brain, and the spatial organization of axonal connections in different brain regions provides a structural framework accommodating specific patterns of neural activity. The presence, amount, and spatial distribution of axonal connections are typically studied in tract tracing experiments in which axons or neurons are labeled and examined in histological sections. Three-dimensional (3-D) reconstruction techniques are used to achieve more complete visualization and improved understanding of complex topographical relationships. 3-D reconstruction approaches based on manually or semi-automatically recorded spatial points representing axonal labeling have been successfully applied for investigation of smaller brain regions, but are not practically feasible for whole-brain analysis of multiple regions. We here reconstruct serial histological images from four whole brains (originally acquired for conventional microscopic analysis) into volumetric images that are spatially registered to a 3-D atlas template. The aims were firstly to evaluate the quality of the 3-D reconstructions and the usefulness of the approach, and secondly to investigate axonal projection patterns and topographical organization in rat corticostriatal and corticothalamic pathways. We demonstrate that even with the limitations of the original routine histological material, the 3-D reconstructed volumetric images allow efficient visualization of tracer injection sites and axonal labeling, facilitating detection of spatial distributions and across-case comparisons. Our results further show that clusters of S1 corticostriatal and corticothalamic projections are distributed within narrow, elongated or spherical subspaces extending across the entire striatum / thalamus. We conclude that histology volume reconstructions facilitate mapping of spatial distribution patterns and topographical organization. The reconstructed image volumes are shared via the Rodent Brain Workbench (www.rbwb.org).

NEURAL CORRELATES OF WAITING IMPULSIVITY: A DIMENSIONAL APPROACH TO ALCOHOL MISUSE

ObjectiveWhy do we “jump the gun”, speak out of turn, or run a red light? Waiting and stopping are fundamental mechanisms of behavioural control. Here we assess waiting impulsivity, or...

P2. Altered task switching as a marker for dysfunctional cortico-striatal pathways in ADHD

Introduction Impulsivity is one of the core symptoms of Attention-Deficit-Hyperactivity-Disorder (ADHD). However, the neural mechanisms underlying impulsivity remain poorly understood. Recent studies from our own lab have shown altered cortico-striatal functionality in healthy controls carrying long or short alleles of the NOS1ex1f-VNTR, a polymorphism associated with heightened impulsivity and ADHD. The study used a switching task to examine striatal functioning of the prefrontal cortex in those controls, which presumably is modulated by differential functionality of NOS1ex1f-VNTR, which in humans is mainly expressed in the striatum. The short allele of this polymorphism leads to a decrease in the expression of NO-Synthase. This switching task is known to be disturbed in Parkinson’s patients, a disorder affecting the striatum. Other studies also suggest a link between ADHD and altered cortico-striatal pathways, presuming that this dysfunctional cortico-striatal connection may be responsible for many of the symptoms of ADHD. Methods 19 patients with ADHD with no medication or a medication washout of at least 24 h and 20 healthy controls were given a set switching task. While performing that task, prefrontal brain activity was measured using near-infrared spectroscopy. Results Behavioral results showed a heightened error rate and reaction time for the ADHD group, as compared with the control group. However, this effect was not modulated by a varying difficulty for the switching tasks. Brain activation show a robust dorsolateral prefrontal activation pattern for the control group, switch trials activated the dorsolateral prefrontal cortex (dlPFC) more than the no-switch trials. ADHD subjects activated the dlPFC significantly less than did the control group, surprisingly, no modulation by the switching task could be found. Our hypothesis that the activation pattern of the ADHD group could hint at a dysfunctional mechanism in the fronto-striatal-frontal loop, hypothesized to be active in switching set, could not be validated. Whats more, an overall hypoactivation of the prefrontal cortex could be observed in patients with ADHD. Apparently their disease load is so high that patients were slower than controls even in the easy no switch condition. It is possible that the dysfunction in the striatum is so severe that patients overall prefrontal activation is suffering. However, with fNIRS it is not possible to disentangle the underlying mechanisms in subcortical areas, not even by means of measuring related prefrontal activity. Further studies using other imaging methods are needed to research the question of dysfunctional cortico-striatal loops in ADHD patients.

Editorial: structural plasticity induced by drugs of abuse.

The roots of addiction are often attributed to the ability of repeated drug use to compromise proper functioning of the central nervous system. Drug-induced functional changes in the brain occur on many levels, including altered expression of specific genes via genomic and epigenetic mechanisms, induction of synaptic plasticity and other cellular adaptations, and volumetric changes in discrete brain regions (Luscher and Malenka, 2011). These alterations can be drug class-specific and occur in both neuronal and non-neuronal cell populations. Drug-induced plasticity, or “rewiring” of the brain contributes to the development, maintenance, and persistence of the addicted state (Kalivas and O'Brien, 2008). The goal of this Research Topic is to assimilate recent findings related to plasticity and structural alterations produced by drug of abuse in neurons, glia, and other cell types of the brain. The mesolimbic dopamine system, originating in the ventral tegmental area (VTA) of the midbrain and projecting rostrally to the nucleus accumbens (NAc) and prefrontal cortex (PFC), mediates the acute reinforcing and incentive salience of abused drugs, as well as their aversive properties. As reviewed by Vashchinkina et al. (2014) mesolimbic dopamine neurons are highly regulated by intrinsic and extrinsic inhibitory GABAergic neurons. Vashchinkina et al. (2014) hypothesize that abused drugs induce structural and functional mesolimbic adaptations differentially via endogenous (e.g., THIP and neurosteroids) vs. exogenous (e.g., benzodiazepines and alcohol) modulators of GABAA receptors, as well as via synaptic vs. extrasynaptic GABAA receptors in the VTA. Collo et al. (2014) review evidence that drug-induced plasticity in mesolimbic dopaminergic neurons is mediated by common dopamine and brain-derived neurotrophic factor (BDNF) signaling pathways, specifically those recruiting MEK-ERK1/2, and PI3K-Akt-mTOR. Cadet and Bisagno (2014) review evidence for substantial plasticity in non-neuronal cell types in brain reward circuitry, including changes in astrocytic glutamate transporter expression, increases in pro-inflammatory cytokine production by microglia, and dysregulated oligodendrocytic myelin production. This latter topic is further elaborated on by Somkuwar et al. (2014) in their review of the proteoglycan neuron-glial antigen 2 (NG2), its expression by oligodendrocyte progenitor cells in the brain reward circuitry, and its interaction with stress-related neuromodulators. In addition, Bajo et al. (2015) provide evidence that interleukin-1β alters both basal and ethanol-facilitated GABAergic transmission in the central nucleus of the amygdala, part of the extended amygdala circuitry which is implicated in ethanol's central effects. Drugs of abuse also alter the dynamics and microstructure of both dendrites and dendritic spines, which can be interpreted as cellular (mal)adaptations that reinforce the addiction cycle (Luscher and Malenka, 2011; Gipson et al., 2014). DePoy et al. (2014) show that repeated exposure of early adolescent mice to cocaine produces lasting reductions in orbitofrontal cortex dendritic arbor length and complexity and as well as impaired reversal learning. In addition, these investigators show that while mice carrying a heterozygous deletion of the actin cytoskeleton stabilizing protein p190RhoGAP exhibit enhanced vulnerability to cocaine-induced hyperlocomotion, orbitofrontal dendritic complexity in cocaine-naive mice is intact. These findings suggest that orbitofrontal dendrite structure is impacted by repeated cocaine during adolescence, but pre-existing structural dendritic deficiencies do not account for increased behavioral sensitivity to this drug. Glutamate is the predominant excitatory amino acid in the central nervous system and mediates both normal and maladaptive cellular plasticity. Several articles in this Research Topic provide novel findings on the role of glutamate in addictive processes. Weiland et al. (2015) demonstrate that antibiotics with the glutamate and GABA modulating properties (ceftriaxone and cefazolin, respectively) attenuate cue-primed reinstatement of alcohol-seeking. Griffin et al. (2015) demonstrate that chronic intermittent ethanol exposure results in increased extracellular levels of glutamate in the NAc in ethanol-dependent mice, but these effects are not a result of locally dysregulated sodium-dependent and independent glutamate transporter function, suggesting that extrinsic corticostriatal glutamatergic pathways may contribute to this hyperglutamatergic state. Finally, McGuier et al. (2015) show that deletion of the excitatory postsynaptic scaffolding protein Homer2 is associated with an increased density of long, thin dendritic spines in NAc core medium spiny neurons, yet unexpectedly these structural modifications are not modified by repeated alcohol exposure. Together, this body of work indicates complex interactions between drugs of abuse, endogenous neuromodulators and their signaling targets, and the mechanisms underlying the functional and structural plasticity in the brain. Research into this complexity is only in its infancy, and needs to be pursued at multiple levels in order to better understand and treat addictive disorders.

The impact of Parkinson’s disease and subthalamic deep brain stimulation on reward processing

BackgroundDue to its position in cortico-subthalamic and cortico-striatal pathways, the subthalamic nucleus (STN) is considered to play a crucial role not only in motor, but also in cognitive and motivational functions. In the present study we aimed to characterize how different aspects of reward processing are affected by disease and deep brain stimulation of the STN (DBS-STN) in patients with idiopathic Parkinson’s disease (PD). MethodsWe compared 33 PD patients treated with DBS-STN under best medical treatment (DBS-on, medication-on) to 33 PD patients without DBS, but optimized pharmacological treatment and 34 age-matched healthy controls. We then investigated DBS-STN effects using a postoperative stimulation-on/ -off design. The task set included a delay discounting task, a task to assess changes in incentive salience attribution, and the Iowa Gambling Task. ResultsThe presence of PD was associated with increased incentive salience attribution and devaluation of delayed rewards. Acute DBS-STN increased risky choices in the Iowa Gambling Task under DBS-on condition, but did not further affect incentive salience attribution or the evaluation of delayed rewards. ConclusionFindings indicate that acute DBS-STN affects specific aspects of reward processing, including the weighting of gains and losses, while larger-scale effects of disease or medication are predominant in others reward-related functions.

Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models

Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A2A receptors (A2AR), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A2AR inactivation to prevent cognitive deficits in early HD, we cross-bred A2AR knockout (KO) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2–CAG120–A2AR KO and R6/2–CAG240–A2AR KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A2AR prevented working memory deficits induced by R6/2–CAG120 at post-natal week 6 and by R6/2–CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A2AR antagonist KW6002 selectively reverted working memory deficits in R6/2–CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A2AR did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A2AR blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2–CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A2AR provides a proof-of-principle for A2AR as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation.

Corticostriatal BDNF and alcohol addiction

Growth factors, long studied for their involvement in neuronal development and plasticity, also regulate responses to drugs of abuse, including alcohol. This review details the intricate interaction between the Brain-Derived Neurotrophic Factor (BDNF) and alcohol, and provides evidence to suggest that corticostriatal BDNF signaling acts to keep alcohol drinking in moderation. Specifically, we describe studies in rodent models suggesting that moderate consumption of alcohol increases BDNF levels in the dorsal striatum, which in turn act to suppress alcohol intake by activating a Mitogen-Activated Protein Kinase (MAPK)-dependent genomic mechanism. We further provide data to suggest that alcohol intake levels escalate when the endogenous corticostriatal BDNF pathway becomes dysregulated. Finally, we summarize recent studies suggesting that specific microRNAs targeting BDNF mRNA in the medial prefrontal cortex (mPFC) regulate the breakdown of the protective corticostriatal BDNF pathway.This article is part of a Special Issue entitled SI:Addiction circuits.

The cognitive thalamus

The thalamus, once viewed as passively relaying sensory information to the cerebral cortex, is becoming increasingly acknowledged as actively regulating the information transmitted to cortical areas. There are a number of reasons for this change. First, evidence suggests that first-order thalamic areas, like the lateral geniculate nucleus, ventral division of the medial geniculate nucleus, and the ventral posterior nuclei, can modulate neural processing along the sensory pathways to the cortex according to behavioral context (O'Connor et al., 2002; McAlonan et al., 2008). Second, much of the thalamus receives relatively little input from the sensory periphery, instead receiving its major driving input from the cortex. This higher-order thalamus forms pathways between cortical areas, which can strongly influence cortical activity (Theyel et al., 2010; Purushothaman et al., 2012; Saalmann et al., 2012). Third, lesions to higher-order thalamic areas, such as the pulvinar and mediodorsal nucleus, can produce severe attention and memory deficits (Saalmann and Kastner, 2011; Baxter, 2013; Bradfield et al., 2013; Jankowski et al., 2013; Mitchell and Chakraborty, 2013), suggesting an important role for the thalamus in cognition. In this Research Topic, we bring together neuroscientists who study different parts of the thalamus, particularly the higher-order thalamic nuclei, to highlight thalamic contributions to learning (Bradfield et al., 2013; Habib et al., 2013), memory processes (Baxter, 2013; Funahashi, 2013; Jankowski et al., 2013; Mitchell and Chakraborty, 2013; Saalmann, 2014), set-shifting (Bradfield et al., 2013; Minamimoto et al., 2014; Saalmann, 2014), language (Klostermann et al., 2013), as well as movement monitoring and control (Ostendorf et al., 2013; Prevosto and Sommer, 2013; Minamimoto et al., 2014). These studies incorporate a range of methods, from molecular to systems-level approaches, and connect rodent, non-human primate and human data, for a better understanding of human cognition. The first three articles focus on movement monitoring and motor control. Based on lesion data from clinical subjects, Ostendorf et al. (2013) show that the central thalamus makes an important contribution to predicting the perceptual consequences of eye movements. Focusing on cerebello-cortical pathways incorporating the central and ventral lateral thalamus, Prevosto and Sommer (2013) review evidence for thalamic modulation of movement processing based on cognitive requirements. Encompassing a number of thalamic nuclei, including the pulvinar, mediodorsal and ventral intermediate nuclei, Klostermann et al. (2013) discuss contributions of the thalamus and basal ganglia to language perception and production. The Research Topic continues on the theme of behavioral flexibility. Minamimoto et al. (2014) show that that the macaque centromedian nucleus, in the intralaminar thalamus, plays a role in counteracting behavioral biases, which contributes to flexible behavior via interactions with the basal ganglia. Bradfield et al. (2013) review evidence from rodent studies that another intralaminar thalamic nucleus, the parafascicular thalamus, also contributes to behavioral flexibility, whereas the mediodorsal thalamic nucleus plays a key role in acquiring goal-directed behavior. Next, the focus shifts to memory processes. Jankowski et al. (2013) review contributions of the anterior thalamus, and its interactions with the hippocampus and cortex, to memory processing and spatial navigation in rodents. This includes evidence for oscillatory activity at theta frequencies in the anterior thalamus. Habib et al. (2013) investigate memory processes in the auditory thalamus, showing differential molecular events underlying safety learning and fear conditioning. Finally, there are four reviews highlighting different functions of the large mediodorsal thalamic nucleus and its interactions with the prefrontal cortex in primates. Mitchell and Chakraborty (2013) discuss the effects of lesions of the mediodorsal thalamus, supporting its role in memory and other cognitive processes. Baxter (2013) argues that the mediodorsal thalamus regulates plasticity within prefrontal cortex as well as the flexibility of prefrontal-dependent operations. Funahashi (2013) reviews contributions of the mediodorsal thalamus to spatial working memory, including how interaction between the thalamus and prefrontal cortex can enable sensory-to-motor transformations of maintained information. To conclude, Saalmann (2014) proposes that the mediodorsal thalamus regulates synchrony between neurons in prefrontal cortex and, consequently, their information exchange according to cognitive control demands. This Research Topic highlights the key contributions of the thalamus to neural processing in cortico-cortical, hippocampo-cortical, cortico-striatal and cerebello-cortical pathways. Although the underlying mechanisms of thalamic influence on these pathways remain to be clarified, there is growing evidence that the thalamus plays a key role in dynamically routing information across the brain (Saalmann et al., 2012; Xu and Sudhof, 2013). Such a role may involve flexibly synchronizing ensembles of neurons, thereby configuring brain networks for the current behavioral context. Taken together, the articles in this Research Topic show that thalamic interactions with cortical and subcortical areas are integral to behavioral flexibility, memory processes and cognition in general.

Converging structural and functional connectivity of orbitofrontal, dorsolateral prefrontal, and posterior parietal cortex in the human striatum.

Modification of spatial attention via reinforcement learning (Lee and Shomstein, 2013) requires the integration of reward, attention, and executive processes. Corticostriatal pathways are an ideal neural substrate for this integration because these projections exhibit a globally parallel (Alexander et al., 1986), but locally overlapping (Haber, 2003), topographical organization. Here we explore whether there are unique striatal regions that exhibit convergent anatomical connections from orbitofrontal cortex, dorsolateral prefrontal cortex, and posterior parietal cortex. Deterministic fiber tractography on diffusion spectrum imaging data from neurologically healthy adults (N = 60) was used to map frontostriatal and parietostriatal projections. In general, projections from cortex were organized according to both a medial-lateral and a rostral-caudal gradient along the striatal nuclei. Within rostral aspects of the striatum, we identified two bilateral convergence zones (one in the caudate nucleus and another in the putamen) that consisted of voxels with unique projections from orbitofrontal cortex, dorsolateral prefrontal cortex, and parietal regions. The distributed cortical connectivity of these striatal convergence zones was confirmed with follow-up functional connectivity analysis from resting state fMRI data, in which a high percentage of structurally connected voxels also showed significant functional connectivity. The specificity of this convergent architecture to these regions of the rostral striatum was validated against control analysis of connectivity within the motor putamen. These results delineate a neurologically plausible network of converging corticostriatal projections that may support the integration of reward, executive control, and spatial attention that occurs during spatial reinforcement learning.

Role of the indirect pathway of the basal ganglia in perceptual decision making.

The basal ganglia (BG) play an important role in motor control, reinforcement learning, and perceptual decision making. Modeling and experimental evidence suggest that, in a speed-accuracy tradeoff, the corticostriatal pathway can adaptively adjust a decision threshold (the amount of information needed to make a choice). In this study, we go beyond the focus of previous works on the direct and hyperdirect pathways to examine the contribution of the indirect pathway of the BG system to decision making in a biophysically based spiking network model. We find that the mechanism of adjusting the decision threshold by plasticity of the corticostriatal connections is effective, provided that the indirect pathway counterbalances the direct pathway in their projections to the output nucleus. Furthermore, in our model, changes within basal ganglia connections similar to those that arise in parkinsonism give rise to strong beta oscillations. Specifically, beta oscillations are produced by an abnormal enhancement of the interactions between the subthalamic nucleus (STN) and the external segment of globus pallidus (GPe) in the indirect pathway, with an oscillation frequency that depends on the excitatory cortical input to the STN and the inhibitory input to the GPe from the striatum. In a parkinsonian state characterized by pronounced beta oscillations, the mean reaction time and range of threshold variation (a measure of behavioral flexibility) are significantly reduced compared with the normal state. Our work thus reveals a specific circuit mechanism for impairments of perceptual decision making associated with Parkinson's disease.

Social network diversity and white matter microstructural integrity in humans.

Diverse aspects of physical, affective and cognitive health relate to social integration, reflecting engagement in social activities and identification with diverse roles within a social network. However, the mechanisms by which social integration interacts with the brain are unclear. In healthy adults (N = 155), we tested the links between social integration and measures of white matter microstructure using diffusion tensor imaging. Across the brain, there was a predominantly positive association between a measure of white matter integrity, fractional anisotropy (FA), and social network diversity. This association was particularly strong in a region near the anterior corpus callosum and driven by a negative association with the radial component of the diffusion signal. This callosal region contained projections between bilateral prefrontal cortices, as well as cingulum and corticostriatal pathways. FA within this region was weakly associated with circulating levels of the inflammatory cytokine interleukin-6 (IL-6), but IL-6 did not mediate the social network and FA relationship. Finally, variation in FA indirectly mediated the relationship between social network diversity and intrinsic functional connectivity of medial corticostriatal pathways. These findings suggest that social integration relates to myelin integrity in humans, which may help explain the diverse aspects of health affected by social networks.

Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes

The extent to which we learn from positive and negative outcomes of decisions is modulated by the neurotransmitter dopamine. Dopamine neurons burst fire in response to unexpected rewards and pause following negative outcomes. This dual signaling mechanism is hypothesized to drive both approach and avoidance behavior. Here we test a prediction deriving from a computational reinforcement learning model, in which approach is mediated via activation of the direct cortico-striatal pathway due to striatal D1 receptor stimulation, while avoidance occurs via disinhibition of indirect pathway striatal neurons secondary to a reduction of D2 receptor stimulation. Using positron emission tomography with two separate radioligands, we demonstrate that individual differences in human approach and avoidance learning are predicted by variability in striatal D1 and D2 receptor binding, respectively. Moreover, transient dopamine precursor depletion improved learning from negative outcomes. These findings support a bidirectional modulatory role for striatal dopamine in reward and avoidance learning via segregated D1 and D2 cortico-striatal pathways.

Postnatal Administration of Allopregnanolone Modifies Glutamate Release but Not BDNF Content in Striatum Samples of Rats Prenatally Exposed to Ethanol

Ethanol consumption during pregnancy may induce profound changes in fetal CNS development. We postulate that some of the effects of ethanol on striatal glutamatergic transmission and neurotrophin expression could be modulated by allopregnanolone, a neurosteroid modulator of GABAA receptor activity. We describe the acute pharmacological effect of allopregnanolone (65 μg/kg, s.c.) administered to juvenile male rats (day 21 of age) on the corticostriatal glutamatergic pathway, in both control and prenatally ethanol-exposed rats (two ip injections of 2.9 g/kg in 24% v/v saline solution on gestational day 8). Prenatal ethanol administration decreased the K+-induced release of glutamate regarding the control group. Interestingly, this effect was reverted by allopregnanolone. Regarding BDNF, allopregnanolone decreases the content of this neurotrophic factor in the striatum of control groups. However, both ethanol alone and ethanol plus allopregnanolone treated animals did not show any change regarding control values. We suggest that prenatal ethanol exposure may produce an alteration of GABAA receptors which blocks the GABA agonist-like effect of allopregnanolone on rapid glutamate release, thus disturbing normal neural transmission. Furthermore, the reciprocal interactions found between GABAergic neurosteroids and BDNF could underlie mechanisms operating during the neuronal plasticity of fetal development.

Resting activity in visual and corticostriatal pathways in Parkinson's disease with hallucinations

Visual hallucinations are an important non-motor complication of Parkinson's disease (PD) and carry a negative prognosis. Their biological basis is uncertain, but may relate to the activity of resting state networks in brain. We therefore aimed to investigate functional activity of brain in patients with visual hallucinations (PDVH) in resting state compared to patients without hallucinations (PDnonVH) and a healthy control group (HC). Resting state functional MRI was acquired and the primary analysis compared the amplitude of low-frequency fluctuations (ALFF) across groups. This informed a secondary analysis, in the PD groups only, comparing functional connectivity between a 'seed' region in the occipital lobe and the rest of the brain. Individuals with PDVH showed lower ALFF in bilateral lingual gyrus and cuneus and greater ALFF in temporo-parietal regions, medial temporal gyrus and cerebellum than PDnonVH and HC. PDnonVH also had lower ALFF in occipitoparietal region and greater ALFF in medial temporal gyrus, temporo-parietal and cerebellum regions than HC. Functional connectivity analysis revealed that, although both PD groups had lower occipital functional connectivity relative to the HC group, occipital - corticostriatal connectivity was significantly higher in those with PDVH compared with PDnonVH. Our study reveals widespread hemodynamic alterations in PD. However, within a functionally abnormal occipital lobe, those with PDVH have even lower ALFF than non-hallucinators, but have higher occipital functional connectivity with cortical-striatal regions. These findings suggest disruption of pathways underpinning both primary visual perceptual and intrinsic visual integration may contribute to visual hallucinations in PD.

Altered structural connectivity of cortico-striato-pallido-thalamic networks in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a childhood-onset syndrome characterized by the presence and persistence of motor and vocal tics. A dysfunction of cortico-striato-pallido-thalamo-cortical networks in this syndrome has been supported by convergent data from neuro-pathological, electrophysiological as well as structural and functional neuroimaging studies. Here, we addressed the question of structural integration of cortico-striato-pallido-thalamo-cortical networks in Gilles de la Tourette syndrome. We specifically tested the hypothesis that deviant brain development in Gilles de la Tourette syndrome could affect structural connectivity within the input and output basal ganglia structures and thalamus. To this aim, we acquired data on 49 adult patients and 28 gender and age-matched control subjects on a 3 T magnetic resonance imaging scanner. We used and further implemented streamline probabilistic tractography algorithms that allowed us to quantify the structural integration of cortico-striato-pallido-thalamo-cortical networks. To further investigate the microstructure of white matter in patients with Gilles de la Tourette syndrome, we also evaluated fractional anisotropy and radial diffusivity in these pathways, which are both sensitive to axonal package and to myelin ensheathment. In patients with Gilles de la Tourette syndrome compared to control subjects, we found white matter abnormalities in neuronal pathways connecting the cerebral cortex, the basal ganglia and the thalamus. Specifically, striatum and thalamus had abnormally enhanced structural connectivity with primary motor and sensory cortices, as well as paracentral lobule, supplementary motor area and parietal cortices. This enhanced connectivity of motor cortex positively correlated with severity of tics measured by the Yale Global Tics Severity Scale and was not influenced by current medication status, age or gender of patients. Independently of the severity of tics, lateral and medial orbito-frontal cortex, inferior frontal, temporo-parietal junction, medial temporal and frontal pole also had enhanced structural connectivity with the striatum and thalamus in patients with Gilles de la Tourette syndrome. In addition, the cortico-striatal pathways were characterized by elevated fractional anisotropy and diminished radial diffusivity, suggesting microstructural axonal abnormalities of white matter in Gilles de la Tourette syndrome. These changes were more prominent in females with Gilles de la Tourette syndrome compared to males and were not related to the current medication status. Taken together, our data showed widespread structural abnormalities in cortico-striato-pallido-thalamic white matter pathways in patients with Gilles de la Tourette, which likely result from abnormal brain development in this syndrome.

Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats

It is well known that nitric oxide (NO) interacts with dopamine (DA) within the striatal circuitry. The anti-dyskinetic properties of NO synthase (NOS) inhibitors demonstrate the importance of NO in L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). Here, we investigated the ability of a daily co-treatment of the preferential neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI, 30 mg/kg), with l-DOPA (30 mg/kg) to counteract LID in unilaterally 6-OHDA-lesioned rats. We analyzed striatal nNOS-expressing interneurons, DA and 5-HT neurochemistry in the striatum and alterations of the Fos-B/ΔFosB expression in the corticostriatal, nigrostriatal and mesolimbic pathways. Prolonged administration of 7-NI inhibited the manifestation of chronic l-DOPA treatment-induced abnormal involuntary movements (AIMs). LID was associated with an up-regulation in the number of nNOS-expressing interneurons in the lateral but not medial striatum. nNOS inhibition reduced the number of nNOS-expressing interneurons. The anti-dyskinetic effects of 7-NI correlated with a reduction in DA and 5-HT turnover in the striatum. At postsynaptic striatal sites, 7-NI prevented l-DOPA-induced Fos-B/ΔFosB up-regulation in the motor cortex, nucleus accumbens and striatum. Finally, 7-NI blocked Fos-B/ΔFosB expression in nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive interneurons in the striatum. These results provide further evidence of the molecular mechanisms by which NOS-inhibiting compounds attenuate LID. The involvement of NO with DA and 5-HT neurochemistry may contribute to the understanding of this new, non-dopaminergic therapy for the management of LID.

E26 Abnormal Functional Connectivity in Huntington's Disease During a Sequential Motor Task

<h3>Introduction</h3> Huntington’s disease (HD) is a neurodegenerative disorder that induces striatal and cortical neuronal dysfunction and loss which main symptom is motor impairment. Goals to study whether this motor impairment is accompanied by changes in brain activity and functional connectivity. <h3>Methods</h3> Fifteen early stage HD patients with a UHDRS motor score &gt; 5 (9 men, mean age = 48 ± 8.9, mean TFC = 11.7 ± 1.17) and 15 controls (9 men, mean age = 46.6 ± 8.1) matched in age, gender and educational background underwent 3T structural and functional MRI scanning while they performed a sequential tapping task with their right or left hand in alternated blocks. <h3>Results</h3> Compared to rest blocks, active tapping activated the contralateral primary motor, premotor and supplementary motor areas, thalamus and cerebellum in both patients and controls. However, in the right hand condition, patients deactivated the right putamen to a greater extent than controls, which suggests that patients need a greater inhibition of the ipsilateral putamen in order to suppress the movement of the opposite hand. Furthermore, HD patients showed less activation in the right putamen during the left hand condition compared to controls. These effects could be ascribed to the general imbalance in the Go and No-Go cortico-striatal pathways that is believed to occur in HD. The left precentral gyrus, was selected as a seed region for a whole brain functional connectivity analysis. Compared with controls, right precentral gyrus, right SMA and right putamen were more connected (negatively) to the left precentral gyrus in patients. This indicates that not only the right putamen, but all the right motor circuit undergoes a greater deactivation in HD patients when they move their left hand. In addition, the negative functional connectivity between the left precentral gyrus and the right putamen showed a positive correlation with the motor-UHDRS score and the TFC score. <h3>Conclusions</h3> These results indicate that HD patients need to inhibit the contralateral motor circuit of the moving hand to compensate for the hyperactivation of the dopaminergic system that underlies their motor symptoms. This effect is specific to the right hemisphere, showing an asymmetry of the motor circuit dysfunction.