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1.  Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease 
Antioxidants & Redox Signaling  2013;19(17):2115-2128.
Abstract
Significance: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA–glutamate interaction could lead to new therapeutic strategies for HD. Recent Advances: Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum. Critical Issues: Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role. Future Directions: Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA. Antioxid. Redox Signal. 19, 2115–2128.
doi:10.1089/ars.2013.5387
PMCID: PMC3869431  PMID: 23642110
2.  Role of the major glutamate transporter GLT1 in nucleus accumbens core vs. shell in cue-induced cocaine seeking behavior 
Relapse to cocaine-seeking behavior requires an increase in nucleus accumbens (NAc) core glutamate transmission. Decreased expression of glutamate type I transporter (GLT1), which is responsible for >90% of glutamate clearance, occurs in the core of rats withdrawn from cocaine self-administration, while treatment with ceftriaxone, a beta-lactam antibiotic previously shown to increase GLT1 expression and function in rodents, up-regulates GLT1 and attenuates cue-induced cocaine reinstatement. Here, we tested the effects of increasing GLT1 expression on cue-induced cocaine seeking in rats exposed to either limited (2 h/d) or extended (6 h/d) cocaine access followed by short (2 d) or long (45 d) withdrawal periods. Treatment with ceftriaxone (200 mg/kg, ip), up-regulated core GLT1 expression and attenuated cue-induced cocaine-seeking behavior only in rats exposed to long withdrawal periods, with a greater effect in the extended access condition. Pearson's correlation revealed GLT1 expression in core to be inversely correlated with cue-induced cocaine-seeking behavior. To localize the effects of GLT1 up-regulation within NAc, we tested the hypothesis that blockade of GLT1 in NAc core, but not shell, would reverse the ceftriaxone-mediated effect. Rats withdrawn from cocaine self-administration were treated with the same dose of ceftriaxone followed by intra-core or intra-shell infusions of one of two GLT1 blockers, dihydrokainic acid (500 μM) or DL-threo-beta-benzyloxyaspartate (250 μM), or saline. Our results reveal that the ceftriaxone-mediated attenuation of cue-induced cocaine reinstatement is reversed by GLT1 blockade in core, but not shell, and further implicate core GLT1 as a potential therapeutic target for cocaine relapse.
doi:10.1523/JNEUROSCI.3278-12.2013
PMCID: PMC3694387  PMID: 23719800
3.  Differential effects of cocaine access and withdrawal on GLT1 expression in rat nucleus accumbens core and shell 
Neuroscience  2012;210:333-339.
Cocaine addiction is characterized by compulsive drug seeking, including relapse after a period of withdrawal. The relapse response requires increased glutamate transmission in the nucleus accumbens (NAc). Consistent with this view, GLT1, the transporter responsible for >90% of glutamate uptake, is down-regulated in NAc after several days of withdrawal in rats previously trained to self-administer cocaine under limited access conditions (1–2 hr/day). Human addiction, however, appears to be better modeled by extending daily drug access (6–8 hr/day) and introducing long periods of withdrawal. Here, we determined the combined effects of manipulating cocaine access and withdrawal on GLT1 expression in NAc core and shell. Rats were trained to self-administer cocaine (0.25 mg per intravenous infusion) in daily limited or extended access sessions for 11 days followed by a period of short (1 day) or long (40–45 days) withdrawal. We found that although cocaine withdrawal decreases GLT1 expression in both core and shell, only in core is GLT1 down-regulation sensitive to both access and withdrawal. In fact, after long withdrawal, GLT1 in core is down-regulated more than in shell in either the limited or extended access condition. Thus, glutamate regulation in core appears to be a critical factor in the drug-seeking behavior that follows relatively long periods of cocaine withdrawal.
doi:10.1016/j.neuroscience.2012.02.049
PMCID: PMC3358423  PMID: 22433294
cocaine; GLT1; nucleus accumbens; self-administration; withdrawal; glutamate
4.  Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington's disease 
Journal of Neurochemistry  2012;121(4):629-638.
A corticostriatal-dependent deficit in the release of ascorbate (AA), an antioxidant vitamin and neuromodulator, occurs concurrently in striatum with dysfunctional GLT1-dependent uptake of glutamate in the R6/2 mouse model of Huntington's disease (HD), an autosomal dominant condition characterized by overt corticostriatal dysfunction. To determine if deficient striatal AA release into extracellular fluid is related to altered GLT1 activity in HD, symptomatic R6/2 mice between 6 and 9 weeks of age and age-matched wild-type (WT) mice received single daily injections of 200 mg/kg ceftriaxone, a β-lactam antibiotic that elevates the functional expression of GLT1, or saline vehicle for 5 consecutive days. On the following day, in vivo voltammetry was coupled with corticostriatal afferent stimulation to monitor evoked release of AA into striatum. In saline-treated mice, we found a marked decrease in evoked extracellular AA in striatum of R6/2 relative to WT. Ceftriaxone, in contrast, restored striatal AA in R6/2 mice to WT levels. In addition, intra-striatal infusion of either the GLT1 inhibitor dihydrokainic acid (DHK) or DL-threo-beta-benzyloxyaspartate (TBOA) blocked evoked striatal AA release. Collectively, our results provide compelling evidence for a link between GLT1 activation and release of AA into the striatal extracellular fluid, and suggest that dysfunction of this system is a key component of HD pathophysiology.
doi:10.1111/j.1471-4159.2012.07691.x
PMCID: PMC3325322  PMID: 22332910
Huntington's disease; ceftriaxone; ascorbate; glutamate uptake; striatum
5.  Abnormal Burst Patterns of Single Neurons Recorded in the Substantia Nigra Reticulata of Behaving 140 CAG Huntington’s Disease Mice 
Neuroscience Letters  2012;512(1):1-5.
Huntington’s disease (HD) is an inherited neurodegenerative disorder that causes neurological pathology in the basal ganglia and related circuitry. A key site of HD pathology is striatum, the principal basal ganglia input structure; striatal pathology likely changes basal ganglia output but no existing studies address this issue. In this report, we characterize single-neuron activity in the substantia nigra reticulata (SNr) of awake, freely-behaving 140 CAG knock-in (KI) mice at 16 to 40 weeks. KI mice are a well characterized model of adult HD and are mildly symptomatic in this age range. As the primary basal ganglia output nucleus in rodents, the SNr receives direct innervation from striatum, as well as indirect influence via polysynaptic inputs. We analyzed 32 single neurons recorded from KI animals and 44 from wild-type (WT) controls. We found increased burst rates, without a concordant change in spike discharge rate, in KI animals relative to WTs. Furthermore, although metrics of burst structure, such as the inter-spike interval in bursts, do not differ between groups, burst rate increases with age in KI, but not WT, animals. Our findings suggest that altered basal ganglia output is a physiological feature of early HD pathology.
doi:10.1016/j.neulet.2011.12.040
PMCID: PMC3285379  PMID: 22327034
Huntington’s disease; knock-in mice; basal ganglia; substantia nigra reticulata; spike burst
6.  Role of cerebral cortex in the neuropathology of Huntington's disease 
An expansion of glutamine repeats in the N-terminal domain of the huntingtin protein leads to Huntington's disease (HD), a neurodegenerative condition characterized by the presence of involuntary movements, dementia, and psychiatric disturbances. Evaluation of postmortem HD tissue indicates that the most prominent cell loss occurs in cerebral cortex and striatum, forebrain regions in which cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs) are the most affected. Subsequent evidence obtained from HD patients and especially from transgenic mouse models of HD indicates that long before neuronal death, patterns of communication between CPNs and MSNs become dysfunctional. In fact, electrophysiological signaling in transgenic HD mice is altered even before the appearance of the HD behavioral phenotype, suggesting that dysfunctional cortical input to the striatum sets the stage for the emergence of HD neurological signs. Striatal MSNs, moreover, project back to cortex via multi-synaptic connections, allowing for even further disruptions in cortical processing. An effective therapeutic strategy for HD, therefore, may lie in understanding the synaptic mechanisms by which it dysregulates the corticostriatal system. Here, we review literature evaluating the molecular, morphological, and physiological alterations in the cerebral cortex, a key component of brain circuitry controlling motor behavior, as they occur in both patients and transgenic HD models.
doi:10.3389/fncir.2013.00019
PMCID: PMC3575072  PMID: 23423362
basal ganglia; glutamate transmission; huntingtin; neuronal processing
7.  Behavior Modulates Effective Connectivity between Cortex and Striatum 
PLoS ONE  2014;9(3):e89443.
It has been notoriously difficult to understand interactions in the basal ganglia because of multiple recurrent loops. Another complication is that activity there is strongly dependent on behavior, suggesting that directional interactions, or effective connections, can dynamically change. A simplifying approach would be to examine just the direct, monosynaptic projections from cortex to striatum and contrast this with the polysynaptic feedback connections from striatum to cortex. Previous work by others on effective connectivity in this pathway indicated that activity in cortex could be used to predict activity in striatum, but that striatal activity could not predict cortical activity. However, this work was conducted in anesthetized or seizing animals, making it impossible to know how free behavior might influence effective connectivity. To address this issue, we applied Granger causality to local field potential signals from cortex and striatum in freely behaving rats. Consistent with previous results, we found that effective connectivity was largely unidirectional, from cortex to striatum, during anesthetized and resting states. Interestingly, we found that effective connectivity became bidirectional during free behaviors. These results are the first to our knowledge to show that striatal influence on cortex can be as strong as cortical influence on striatum. In addition, these findings highlight how behavioral states can affect basal ganglia interactions. Finally, we suggest that this approach may be useful for studies of Parkinson's or Huntington's diseases, in which effective connectivity may change during movement.
doi:10.1371/journal.pone.0089443
PMCID: PMC3949668  PMID: 24618981
8.  Reduced expression of conditioned fear in the R6/2 mouse model of Huntington’s disease is related to abnormal activity in prelimbic cortex 
Neurobiology of disease  2011;43(2):379-387.
Prefrontal cortex (PFC) dysfunction is common in patients with Huntington’s disease (HD), a dominantly inherited neurological disorder, and has been linked to cognitive disruption. We previously reported alterations in neuronal firing patterns recorded from PFC of the R6/2 mouse model of HD. To determine if PFC dysfunction results in behavioral impairments, we evaluated performance of wild-type (WT) and R6/2 mice in a fear conditioning and extinction behavioral task. Fear conditioning and extinction retrieval were similar in both genotypes, but R6/2s exhibited less fear during extinction by freezing less than WTs. A fear reinstatement test after extinction retrieval indicated that faster extinction was not due to poor memory for conditioning. During initial extinction and extinction retrieval training, neuronal activity was recorded from prelimbic (PL) cortex, a subregion of PFC known to be important for fear expression. In WTs, a large number of neurons were activated by the conditioned stimulus during initial extinction and this activation was significantly impaired in R6/2s. Notably, there was no genotype difference in PFC activity during extinction retrieval. Thus, altered extinction is likely a result of reduced fear expression due to impairments in PL activation. Collectively, our results suggest that PFC dysfunction may play a key role in R6/2 cognitive impairments.
doi:10.1016/j.nbd.2011.04.009
PMCID: PMC3114205  PMID: 21515374
fear extinction; Huntington’s disease; prefrontal cortex; electrophysiology; R6/2
9.  Experience-dependent changes in neuronal processing in the nucleus accumbens shell in a discriminative learning task in differentially housed rats 
Brain research  2011;1390:90-98.
Environmental enrichment is associated with enhanced learning of complex tasks, attenuated seeking of natural and drug rewards, and altered function of the nucleus accumbens (NAcc), a brain region involved in goal-directed behavior. For example, during acquisition of a discriminative learning task, neurons in the NAcc core subregion are more responsive to discrete, goal-directed movements in rats raised in an enriched condition (EC) relative to an isolated condition (IC), but as learning materialized, this enhanced responsiveness shifts to the cues that predict these movements. Here, we report that these results do not extend to NAcc shell: neuronal responses in this subregion are similar in EC and IC rats during goal-directed movement and the presentation of associative cues both during and after task acquisition. With experience in this task, however, the overall proportion of task-related neuronal responses in NAcc shell decreases. The response pattern of shell neurons is also sensitive to the presence of contextual cues: shell neuronal firing reveals a significant shift from a predominant excitatory to a predominant inhibitory profile in probe trials when the cue that predicts sucrose availability is absent. Collectively, these data suggest that NAcc shell neurons encode cues associated with natural reward, are less responsive during appetitive behavior in familiar conditions, and are insensitive to appetitive learning differences expressed in rats reared in different environmental conditions.
doi:10.1016/j.brainres.2011.03.023
PMCID: PMC3085613  PMID: 21420938
Nucleus accumbens; Environmental enrichment; Social isolation; Single-unit activity; Appetitive conditioning
10.  Neural correlates of unpredictability in behavioral patterns of wild-type and R6/2 mice 
This paper expands on recent findings that link dynamic patterns of striatal activity with patterns of movement and exploration in wild-type and transgenic mice (R6/2) that model Huntington disease (HD), a fatally inherited neurological condition. Here, with HD as a backdrop, we further develop the concept of entropy conservation in brain and behavior. In particular, we propose that entropy conservation could serve as a rule that guides the process of redistributing brain activity dynamics in order to alter behavior, allowing the adaptation to an ever-changing external environment. This concept is further linked to recent neuroimaging studies in human aging, building a new bridge between our recent findings of entropy conservation and the extant literature.
doi:10.4161/cib.19782
PMCID: PMC3419109  PMID: 22896787
aging; neuroimaging; entropy; Huntington disease; striatum; behavioral neuroscience
11.  Electrophysiological and Structural Alterations in Striatum Associated with Behavioral Sensitization to (±)3,4-Methylenedioxymethamphetamine (Ecstasy) in Rats: Role of Drug Context 
Neuroscience  2010;171(3):794-811.
We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) results in long-lasting neurobehavioral changes, and further, the ability of contextual cues to modulate these changes. We focused on dorsal striatum, a brain region implicated in the formation of persistent drug-related habits. Rats were transported to a novel recording chamber and treated with once-daily injections (sc) of (±)-MDMA (5.0 mg/kg) or saline for 5 days, followed by a challenge injection 14 days later either in the same (Experiment 1) or different context (Experiment 2). Chronically implanted micro-wire bundles were used to record from populations of striatal neurons on days 1, 5, and challenge. Twenty-four h after the last injection, brains were removed and processed using a modified Golgi method to assess changes in neuronal morphology. A sensitized locomotor response was observed following MDMA challenge in 11 of 12 rats in Experiment 1 (same context), whereas only 58% of rats (7 of 12) displayed sensitization in Experiment 2 (different context). Furthermore, several alterations in striatal electrophysiology were apparent on challenge day, but only in rats that displayed sensitization. Conversely, structural changes in striatal medium spiny neurons, such as increases in spine density, were observed in MDMA-treated rats regardless of whether they displayed behavioral sensitization. Thus, it appears that reorganization of synaptic connectivity in dorsal striatum may contribute to long-lasting drug-induced behavioral alterations, but that these behavioral alterations are subject to modification depending on individual differences and the context surrounding drug administration.
doi:10.1016/j.neuroscience.2010.09.041
PMCID: PMC2987517  PMID: 20875842
DENDRITIC SPINES; ELECTROPHYSIOLOGY; MDMA; MORPHOLOGY; STRIATUM; SENSITIZATION
12.  Dysregulated Striatal Neuronal Processing and Impaired Motor Behavior in Mice Lacking Huntingtin Interacting Protein 14 (HIP14) 
PLoS ONE  2013;8(12):e84537.
Palmitoyl acyl transferases (PATs) play a critical role in protein trafficking and function. Huntingtin interacting protein 14 (HIP14) is a PAT that acts on proteins associated with neuronal transmission, suggesting that deficient protein palmitoylation by HIP14, which occurs in the YAC128 model of Huntington’s disease (HD), might have deleterious effects on neurobehavioral processing. HIP14 knockout mice show biochemical and neuropathological changes in the striatum, a forebrain region affected by HD that guides behavioral choice and motor flexibility. Thus, we evaluated the performance of these mice in two tests of motor ability: nest-building and plus maze turning behavior. Relative to wild-type controls, HIP14 knockout mice show impaired nest building and decreased turning in the plus maze. When we recorded the activity of striatal neurons during plus-maze performance, we found faster firing rates and dysregulated spike bursting in HIP14 knockouts compared to wild-type. There was also less correlated firing between simultaneously recorded neuronal pairs in the HIP14 knockouts. Overall, our results indicate that HIP14 is critically involved in behavioral modulation of striatal processing. In the absence of HIP14, striatal neurons become dysfunctional, leading to impaired motor behavior.
doi:10.1371/journal.pone.0084537
PMCID: PMC3871627  PMID: 24376823
13.  Altered Neuronal Dynamics in the Striatum on the Behavior of Huntingtin Interacting Protein 14 (HIP14) Knockout Mice 
Brain Sciences  2013;3(4):1588-1596.
Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, impairs information processing in the striatum, which, as part of the basal ganglia, modulates motor output. Growing evidence suggests that huntingtin interacting protein 14 (HIP14) contributes to HD neuropathology. Here, we recorded local field potentials (LFPs) in the striatum as HIP14 knockout mice and wild-type controls freely navigated a plus-shaped maze. Upon entering the choice point of the maze, HIP14 knockouts tend to continue in a straight line, turning left or right significantly less often than wild-types, a sign of motor inflexibility that also occurs in HD mice. Striatal LFP activity anticipates this difference. In wild-types, the power spectral density pattern associated with entry into the choice point differs significantly from the pattern immediately before entry, especially at low frequencies (≤13 Hz), whereas HIP14 knockouts show no change in LFP activity as they enter the choice point. The lack of change in striatal activity may explain the turning deficit in the plus maze. Our results suggest that HIP14 plays a critical role in the aberrant behavioral modulation of striatal neuronal activity underlying motor inflexibility, including the motor signs of HD.
doi:10.3390/brainsci3041588
PMCID: PMC4061888  PMID: 24961622
Huntington’s disease; huntingtin interacting protein 14; striatum; local field potentials; motor inflexibility; plus maze; palmitoylation
14.  Dysregulated Neuronal Activity Patterns Implicate Corticostriatal Circuit Dysfunction in Multiple Rodent Models of Huntington's Disease 
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that targets the corticostriatal system and results in progressive deterioration of cognitive, emotional, and motor skills. Although cortical and striatal neurons are widely studied in animal models of HD, there is little information on neuronal function during expression of the HD behavioral phenotype. To address this knowledge gap, we used chronically implanted micro-wire bundles to record extracellular spikes and local field potentials (LFPs) in truncated (R6/1 and R6/2) and full-length (knock-in, KI) mouse models as well as in transgenic HD rats (tgHD rats) behaving in an open-field arena. Spike activity was recorded in the striatum of all models and in prefrontal cortex (PFC) of R6/2 and KI mice, and in primary motor cortex (M1) of R6/2 mice. We also recorded LFP activity in R6/2 striatum. All HD models exhibited altered neuronal activity relative to wild-type (WT) controls. Although there was no consistent effect on firing rate across models and brain areas, burst firing was reduced in striatum, PFC, and M1 of R6/2 mice, and in striatum of KI mice. Consistent with a decline in bursting, the inter-spike-interval coefficient of variation was reduced in all regions of all models, except PFC of KI mice and striatum of tgHD rats. Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s. Preliminary analysis of striatal LFPs revealed aberrant behavior-related oscillations in the delta to theta range and in gamma activity. Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype. Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.
doi:10.3389/fnsys.2011.00026
PMCID: PMC3100808  PMID: 21629717
mouse models of Huntington's disease; behavioral electrophysiology; striatal local field potentials; spike synchrony; bursting
15.  Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington’s disease 
Brain research  2009;1290:111-120.
A behavior-related deficit in the release of ascorbate (AA), an antioxidant vitamin, occurs in the striatum of R6/2 mice expressing the human mutation for Huntington’s disease (HD), a dominantly inherited condition characterized by striatal dysfunction. To determine the role of corticostriatal fibers in AA release, we combined slow-scan voltammetry with electrical stimulation of cortical afferents to measure evoked fluctuations in extracellular AA in wild-type (WT) and R6/2 striatum. Although cortical stimulation evoked a rapid increase in AA release in both groups, the R6/2 response had a significantly shorter duration and smaller magnitude than WT. To determine if corticostriatal dysfunction also underlies the behavior-related AA deficit in R6/2s, we measured striatal AA release in separate groups of mice treated with d-amphetamine (5 mg/kg), a psychomotor stimulant known to release AA from corticostriatal terminals independently of dopamine. Relative to WT, both AA release and behavioral activation were diminished in R6/2 mice. Collectively, our results show that the corticostriatal pathway is directly involved in AA release and that this system is dysfunctional in HD. Moreover, because AA release requires glutamate uptake, a failure of striatal AA release in HD is consistent with an overactive glutamate system and diminished glutamate transport, both of which are thought to be central to HD pathogenesis.
doi:10.1016/j.brainres.2009.07.019
PMCID: PMC2745264  PMID: 19616518
ascorbate; cerebral cortex; Huntington’s disease; striatum; voltammetry
16.  Sensitizing Regimens of MDMA (Ecstasy) Elicit Enduring and Differential Structural Alterations in the Brain Motive Circuit of the Rat 
Neuroscience  2009;160(2):264-274.
Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received 2 daily injections of either 5.0 mg/kg (±)-MDMA or saline vehicle, ~6 hr apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.
doi:10.1016/j.neuroscience.2009.02.025
PMCID: PMC2669702  PMID: 19236907
DENDRITIC SPINES; MEDIAL PREFRONTAL CORTEX; MORPHOLOGY; NUCLEUS ACCUMBENS; SENSITIZATION
17.  Force-plate quantification of progressive behavioral deficits in the R6/2 mouse model of Huntington’s disease 
Behavioural brain research  2009;202(1):130-137.
The R6/2 mouse is a popular model of Huntington’s disease (HD) because of its rapid progression and measurable behavioral phenotype. Yet current behavioral phenotyping methods are usually univariate (e.g., latency to fall from a rotarod) and labor intensive. We used a force-plate actometer and specialized computer algorithms to partition the data into topographically specific behavioral categories that were sensitive to HD-like abnormalities. Seven R6/2 male mice and 7 wild type (WT) controls were placed in a 42 cm X 42 cm force-plate actometer for 20-min recording sessions at 6–7, 8–9, 10–11 and 12–13 weeks of age. Distance traveled, number of wall rears, and number of straight runs (traveling 175 mm or more in 1.5 s) were reduced in R6/2 relative to WT mice at all ages tested. Low mobility bouts (each defined as remaining continuously in a virtual circle of 15 mm radius for 5 s) were increased in R6/2 mice at 6–7 wk and beyond. Independent of body weight, force off-load during wall rears was reduced in R6/2 mice except at 6–7 wk. Power spectra of force variation during straight runs indicated an age-related progressive loss of rhythmicity in R6/2 compared to WT, suggesting gait dysrhythmia and dysmetria. Collectively, these data, which extend results obtained with other widely different behavioral phenotyping methods, document a multifaceted syndrome of motor abnormalities in R6/2 mice. We suggest, moreover, that the force-plate actometer offers a high-throughput tool for screening drugs that may affect symptom expression in R6/2 or other HD model mice.
doi:10.1016/j.bbr.2009.03.022
PMCID: PMC3711515  PMID: 19447289
18.  Environmental enrichment alters neuronal processing in the nucleus accumbens core during appetitive conditioning 
Brain research  2008;1259:59-67.
Although the core region of the nucleus accumbens (NAcc) has been implicated in motor control and the acquisition of appetitive learning, these processes are altered by environmental experience. To assess how environment influences neuronal processing in NAcc core, we recorded single-unit activity during acquisition of an appetitive learning task in which rats reared in an environmentally enriched condition (EC) learned the operant response (nosepoke into a lit hole) for sucrose reinforcement faster than rats reared in an isolated condition (IC). In the first training session, even before the emergence of learning differences, core neurons were more likely to respond (increase or decrease activity) during the operant and consummatory responses in EC than IC rats. By the third training session, when learning differences emerged, EC neurons continued to be more responsive than IC neurons, but in very different ways: the response shifted to the cues that signaled trial onset (1900 Hz tone and green LED) and reward availability (4500 Hz tone and yellow LED). Cue-related responding, moreover, was dominated by neuronal excitations. In contrast, post-acquisition recordings revealed no EC-IC differences. Collectively, these results suggest that core neurons are initially more responsive to discrete, goal-directed movements in EC rats, but as learning materializes, the neuronal response shifts to the cues that predict these movements. Thus, environmental experience alters core neuronal processing of both motor- and sensory-related events but at different stages over the course of learning.
doi:10.1016/j.brainres.2008.12.038
PMCID: PMC2656408  PMID: 19135429
nucleus accumbens; environmental enrichment; social isolation; single-unit activity; appetitive conditioning; goal-directed behavior
19.  Up-regulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats 
Relapse to cocaine-seeking behavior depends on increased glutamate transmission in key regions of the mesocorticolimbic motive circuit, including prefrontal cortex (PFC) and nucleus accumbens (NAcc). Because GLT1 is responsible for the uptake of ≥90% of extracellular glutamate, we tested the hypothesis that increased GLT1 expression attenuates cocaine relapse. Rats were trained to self-administer cocaine (0.125 mg per iv infusion) in a lever-pressing task in a daily two-hour session for 10–14 days followed by five days of extinction training. Immediately after each extinction session, rats received ceftriaxone (ip), a β-lactam antibiotic believed to increase GLT1 expression, or vehicle. On the following day, presentation of the cue (light and tone) previously associated with cocaine self-administration reinstated lever-pressing in rats treated with vehicle, whereas 100 or 200, but not 50 mg/kg ceftriaxone blocked this response. Immunoblotting confirmed that the ceftriaxone-induced blockade of cocaine relapse was associated with an increase in GLT1 expression in both PFC and NAcc. In separate groups of rats, 200 mg/kg ceftriaxone failed to block cue-induced food seeking, arguing against a ceftriaxone-induced effect unique to extinction training or lever pressing. Our results suggest that glutamate plays a key role in cue-induced relapse to cocaine-seeking behavior, implicating GLT1 as a potential therapeutic target for cocaine addiction.
doi:10.1523/JNEUROSCI.1746-09.2009
PMCID: PMC2737464  PMID: 19625514
ceftriaxone; cocaine; GLT1; glutamate; prefrontal cortex; nucleus accumbens
20.  Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington’s disease: interactions between neurons and astrocytes 
Basal ganglia  2012;2(2):57-66.
Huntington’s Disease (HD) is a fatally inherited neurodegenerative disorder caused by an expanded glutamine repeat in the N-terminal region of the huntingtin (HTT) protein. The result is a progressively worsening triad of cognitive, emotional, and motor alterations that typically begin in adulthood and end in death 10-20 years later. Autopsy of HD patients indicates massive cell loss in the striatum and its main source of input, the cerebral cortex. Further studies of HD patients and transgenic animal models of HD indicate that corticostriatal neuronal processing is altered long before neuronal death takes place. In fact, altered neuronal function appears to be the primary driver of the HD behavioral phenotype, and dysregulation of glutamate, the excitatory amino acid released by corticostriatal afferents, is believed to play a critical role. Although mutant HTT interferes with the operation of multiple proteins related to glutamate transmission, consistent evidence links the expression of mutant HTT with reduced activity of glutamate transporter 1 (rodent GLT1 or human EAAT2), the astrocytic protein responsible for the bulk of glutamate uptake. Here, we review corticostriatal dysfunction in HD and focus on GLT1 and its expression in astrocytes as a possible therapeutic target.
doi:10.1016/j.baga.2012.04.029
PMCID: PMC3418680  PMID: 22905336
ascorbate; astrocytes; electrophysiology; glutamate transport; huntingtin; oxidative stress; transgenic models
21.  Altered information processing in the prefrontal cortex of Huntington’s disease mouse models 
Understanding cortical information processing in Huntington’s disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBAxC57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (>85%) that was significantly attenuated in both corresponding HD models (decreases of ~20% and ~30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.
doi:10.1523/JNEUROSCI.2804-08.2008
PMCID: PMC2597399  PMID: 18768691
bursting; spike synchrony; electrophysiology; transgenic; knock-in; corticostriatal pathway
22.  Real-Time Dopamine Efflux in the Nucleus Accumbens Core During Pavlovian Conditioning 
Behavioral neuroscience  2008;122(2):358-367.
To assess the role of dopamine input to the nucleus accumbens core in anticipatory learning, fast-scan cyclic voltammetry was combined with appetitive Pavlovian conditioning. One group of rats (Paired) received 16 tone-food pairings for at least four daily sessions while the control group (Unpaired) received the same number of unpaired tone and food presentations. Both groups showed transient dopamine responses during food presentation throughout training, confirming dopamine involvement in reward processing. Only the Paired Group, however, showed consistently timed dopamine transients during the 10-s tone presentation. Transients first appeared near the end of the tone period as each animal acquired the tone-food association and then occurred progressively sooner on subsequent sessions. Later sessions also revealed a consistently timed dopamine response soon after food delivery in Paired animals. Collectively, these results implicate phasic dopamine release in the acquisition of Pavlovian learning and also suggest an early dopamine response to the unconditioned stimulus as training continues.
doi:10.1037/0735-7044.122.2.358
PMCID: PMC2664557  PMID: 18410174
dopamine transients; nucleus accumbens core; Pavlovian conditioning; voltammetry
23.  Up-regulation of GLT1 Expression Increases Glutamate Uptake and Attenuates the Huntington's Disease Phenotype in the R6/2 Mouse 
Neuroscience  2008;153(1):329-337.
The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a β-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, ip, for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype.
doi:10.1016/j.neuroscience.2008.02.004
PMCID: PMC2424273  PMID: 18353560
Huntington's disease; ceftriaxone; R6/2; striatum; microdialysis; glutamate
24.  Reinstatement of MDMA (ecstasy) seeking by exposure to discrete drug-conditioned cues 
The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-naïve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 hr sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding.
doi:10.1016/j.pbb.2007.05.018
PMCID: PMC2067991  PMID: 17602729
ADDICTION; CUE; MDMA; REINSTATEMENT; RELAPSE; SELF-ADMINISTRATION
25.  Sex differences in behavior and striatal ascorbate release in the 140 CAG knock-in mouse model of Huntington’s disease 
Behavioural brain research  2007;178(1):90-97.
Ethological assessment of murine models of Huntington’s disease (HD), an inherited neurodegenerative disorder, enables correlation between phenotype and pathophysiology. Currently, the most characterized model is the R6/2 line that develops a progressive behavioral and neurological phenotype by six weeks of age. A recently developed knock-in model with 140 CAG repeats (KI) exhibits a subtle phenotype with a longer progressive course, more typical of adult-onset HD in humans. We evaluated rotarod performance, open-field behavior, and motor activity across the diurnal cycle in KI mice during early to mid-adulthood. Although we did not observe any effects of age, relative to wild-type (WT) mice, KI mice showed significant deficits in both open-field climbing behavior and home-cage running wheel activity during the light phase of the diurnal cycle. An interesting sex difference also emerged. KI females spent more time in the open-field grooming and more time running during the diurnal dark phase than KI males and WT mice of both sexes. In striatum, the primary site of HD pathology, we measured behavior-related changes in extracellular ascorbate (AA), which is abnormally low in the R6/2 line, consistent with a loss of antioxidant protection in HD. KI males exhibited a 20–40% decrease in striatal AA from anesthesia baseline to behavioral activation that was not observed in other groups. Collectively, our results indicate behavioral deficits in KI mice that may be specific to the diurnal cycle. Furthermore, sex differences observed in behavior and striatal AA release suggest sex-dependent variation in the phenotype and neuropathology of HD.
doi:10.1016/j.bbr.2006.12.004
PMCID: PMC1868463  PMID: 17239451
Huntington’s disease; sex; rotarod; open-field; diurnal cycle; ascorbate; voltammetry; oxidative stress

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