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Evaluating and quantifying the many aspects of movement - from open-field locomotion and stepping patterns in rodent models to stride trajectory and postural sway in human patients - are key to understanding brain function. Various experimental approaches have been used in applying these lines of research to investigate the brain mechanisms underlying neurodegenerative disease. Although valuable, data on movement are often limited by the shortcomings inherent in the data collection process itself. Steve Fowler and his research group have been instrumental in pioneering a technology that both minimizes these pitfalls in studies of rodent behavior and has applications to research on human patients. At the center of this technology is the force-plate actometer, developed by the Fowler group to assess multiple aspects of movement in rodent models. Our review highlights how use of the actometer and related behavioral measurements provides valuable insight into Huntington's disease (HD), an autosomal dominant condition of progressively deteriorating behavioral control. HD typically emerges in mid-life and has been replicated in multiple genetically engineered mouse models. The actometer also can be a valuable addition to cutting-edge neuronal and synaptic technologies that are now increasingly applied to studies of behaving animals. In short, the impact of the Fowler contribution to the neuroscience of movement is both meaningful and ongoing.

Abnormal communication between cerebral cortex and striatum plays a major role in the motor symptoms of Huntington’s disease (HD), a neurodegenerative disorder caused by a mutation of the huntingtin gene ( mHTT). Because cortex is the main driver of striatal processing, we recorded local field potential (LFP) activity simultaneously in primary motor cortex (M1) and dorsal striatum (DS) in BACHD mice, a full-length HD gene model, and in a conditional BACHD/Emx-1 Cre (BE) model in which mHTT is suppressed in cortical efferents, while mice freely explored a plus-shaped maze beginning at 20 wk of age. Relative to wild-type (WT) controls, BACHD mice were just as active across >40 wk of testing but became progressively less likely to turn into a perpendicular arm as they approached the choice point of the maze, a sign of HD motor inflexibility. BE mice, in contrast, turned as freely as WT throughout testing. Although BE mice did not exactly match WT in LFP activity, the reduction in alpha (8–13 Hz), beta (13–30 Hz), and low-gamma (30–50 Hz) power that occurred in M1 of turning-impaired BACHD mice was reversed. No reversal occurred in DS. In fact, BE mice showed further reductions in DS theta (4–8 Hz), beta, and low-gamma power relative to the BACHD model. Coherence analysis indicated a dysregulation of corticostriatal information flow in both BACHD and BE mice. Collectively, our results suggest that mHTT in cortical outputs drives the dysregulation of select cortical frequencies that accompany the loss of behavioral flexibility in HD. NEW & NOTEWORTHY BACHD mice, a full-length genetic model of Huntington’s disease (HD), express aberrant local field potential (LFP) activity in primary motor cortex (M1) along with decreased probability of turning into a perpendicular arm of a plus-shaped maze, a motor inflexibility phenotype. Suppression of the mutant huntingtin gene in cortical output neurons prevents decline in turning and improves alpha, beta, and low-gamma activity in M1. Our results implicate cortical networks in the search for therapeutic strategies to alleviate HD motor signs.

Abnormal gamma band power across cortex and striatum is an important phenotype of Huntington’s disease (HD) in both patients and animal models, but neither the origin nor the functional relevance of this phenotype is well understood. Here, we analyzed local field potential (LFP) activity in freely behaving, symptomatic R6/2 and Q175 mouse models and corresponding wild-type (WT) controls. We focused on periods of quiet rest, which show strong γ activity in HD mice. Simultaneous recording from motor cortex and its target area in dorsal striatum in the R6/2 model revealed exaggerated functional coupling over that observed in WT between the phase of delta frequencies (1–4 Hz) in cortex and striatum and striatal amplitude modulation of low γ frequencies (25–55 Hz; i.e., phase-amplitude coupling, PAC), but no evidence that abnormal cortical activity alone can account for the increase in striatal γ power. Both HD mouse models had stronger coupling of γ amplitude to δ phase and more unimodal phase distributions than their WT counterparts. To assess the possible role of striatal fast-spiking interneurons (FSIs) in these phenomena, we developed a computational model based on additional striatal recordings from Q175 mice. Changes in peak γ frequency and power ratio were readily reproduced by our computational model, accounting for several experimental findings reported in the literature. Our results suggest that HD is characterized by both a reorganization of cortico-striatal drive and specific population changes related to intrastriatal synaptic coupling.

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.

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 β-lactam antibiotic previously shown to increase GLT1 expression and function in rodents, upregulates 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, i.p.) upregulated 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 upregulation 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 intracore or intrashell infusions of one of two GLT1 blockers, dihydrokainic acid (500 μm) ordl-threo-β-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.

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, glutamate type 1 transporter (GLT1), the transporter responsible for >90% of glutamate uptake, is downregulated in NAc after several days of withdrawal in rats previously trained to self-administer cocaine under limited access conditions (1–2 h/d). Human addiction, however, appears to be better modeled by extending daily drug access (6–8 h/d) 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 downregulation sensitive to both access and withdrawal. In fact, after long withdrawal, GLT1 in core is downregulated 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.

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.

Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Preclinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because activity of dopamine neurons are regulated by D2-like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D2-like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self-administer intravenous cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. Then the effect of quinpirole, a selective D2-like receptor agonist microinjected into the ventral tegmental area on cocaine-induced reinstatement was assessed. Quinpirole (0 – 3.2 μg/side) dose-dependently decreased cocaine-induced reinstatement and such effects were reversed by the selective D2-like receptor antagonist eticlopride when co-microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D2-like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the prefrontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D2-like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.

We examined whether repeated exposure to the increasingly abused amphetamine (AMPH) 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 (s.c.) 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 hours 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.

Transgenic mouse models of Huntington's disease (HD), a neurodegenerative condition caused by a single gene mutation, have been transformative in their ability to reveal the molecular processes and pathophysiological mechanisms underlying the HD behavioral phenotype. Three model categories have been generated depending on the genetic context in which the mutation is expressed: truncated, full-length, and knock-in. No single model, however, broadly replicates the behavioral symptoms and massive neuronal loss that occur in human patients. The disparity between model and patient requires careful consideration of what each model has to offer when testing potential treatments. Although the translation of animal data to the clinic has been limited, each model can make unique contributions toward an improved understanding of the neurobehavioral underpinnings of HD. Thus, conclusions based on data obtained from more than one model are likely to have the most success in the search for new treatment targets. © 2018 by John Wiley & Sons, Inc.

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 two daily injections of either 5.0 mg/kg (+/-)-MDMA or saline vehicle, approximately 6 h 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.

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 CBA x C57BL/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 approximately 20% and approximately 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.

Although the subthalamic nucleus (STN) is commonly assumed to be a relay for striatal (STR) output, anatomical evidence suggests the two structures are connected in parallel, raising the possibility that parallel STN and STR firing patterns mediate behavioral processes. The STR is known to play a role in associative and limbic processes, and although behavioral studies suggest that the STN may do so as well, evaluation of this hypothesis is complicated by a lack of pertinent STN physiological data. We recorded concurrent STN and STR firing patterns in rats learning an operant nose-poke task. Both structures responded in similar proportions to task events including instructive cues, discriminative nose-pokes, and sucrose reinforcement. Neuronal responses to reinforcement comprised phasic excitations preceding reinforcement and inhibitions afterward; the inhibition was attenuated when reinforcement was absent. Reinforcement responses occurred more frequently during later training sessions in which discriminative action was required, suggesting that responses were context-dependent. Nose-pokes were typically preceded by excitations; there also was a nonsignificant trend toward inhibition encoding correct nose-pokes. Sustained changes in firing rate coinciding with specific task events suggested that both nuclei were encoding behavioral sequences; this is the first report of such behavior in the STN. Our findings also reveal complex STN responses to reinforcement. Thus both STN and STR neurons show concurrent involvement in motor, limbic, and associative processes.

Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell–cell interaction model, we used BACHD/Emx1–Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction.

One of the core symptoms of cocaine addiction is compulsive drug-seeking behavior. Although the precise neural substrates are unknown, it has been hypothesized that this behavior involves cocaine-induced hypofunction of the prefrontal cortex (PFC) or "hypofrontality." To test this hypothesis, PFC neuronal activity was monitored in rats during approximately 3 weeks of cocaine self-administration (SA). Rats were trained to press a lever to self-administer cocaine in daily 2 h sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. In the first SA session, the overall firing rate and burst rate were significantly decreased after cocaine infusions relative to the period immediately before the session. These effects disappeared after > or = 10 d of drug SA and were replaced by a significant increase in burst duration and firing rate within a burst. Notably, however, the level of basal activity before the first drug infusion of each SA session decreased significantly after multiple weeks of cocaine exposure. Collectively, these data support the view that although repeated sessions of cocaine SA decrease basal PFC activity, increased burst-related firing in response to cocaine infusions suggests that processing of cocaine-related information is enhanced and may contribute to increased control by cocaine over cocaine-seeking behavior.

The striatum, which receives projections from the entire cortical mantle, is highly responsive to sensorimotor activity. Because either systemic or intra-striatal injections of ascorbate (AA) influence behavior known to involve striatal circuits, it is possible that the level of striatal AA, which is known to fluctuate with behavioral activation, directly alters striatal neuronal processing. To test this hypothesis, we recorded the activity of 94 presumed medium spiny striatal neurons in behaving rats treated with AA or vehicle and examined firing rate during periods of quiescence and sensorimotor stimulation (e.g., stroking of the whiskers, mid-back, and rump). Slow-scan voltammetry was used in separate rats to determine the extent to which AA treatment elevated striatal AA. Vehicle-treated rats had relatively slow basal firing rates at rest that routinely increased during sensorimotor stimulation. Comparable results were obtained in rats treated with 100 mg/kg AA, which failed to alter AA levels in striatum. Dose-dependent increases in striatal AA, however, occurred after injection of 500 and 1000 mg/kg AA, and at these doses, there was a significant decrease in the number of sensorimotor-related excitations. In fact, treatment with 1000 mg/kg AA reversed a significant proportion of excitations to inhibitions. Our results substantiate the role of the striatum in sensorimotor processing and emphasize extracellular AA as a modulator of striatal neuronal function.

Membrane and morphological abnormalities occur in the striatum of R6/2 transgenics, a widely used mouse model of Huntington's disease. To assess changes in behavior-related neuronal activity, we implanted micro-wire bundles in the striatum of symptomatic R6/2 mice and wild-type controls. Unit activity was recorded in an open-field arena once weekly for the next several weeks. For each recording session, firing rate was monitored before, during, and after a period of light anesthesia to assess the influence of behavioral arousal. Because low ascorbate in striatal extracellular fluid may contribute to Huntington's disease symptoms, all animals received an injection of either 300 mg/kg sodium ascorbate or vehicle for three consecutive days prior to each recording session. In R6/2 mice, regardless of treatment, striatal unit activity was significantly faster than in wild-type controls. The difference in mean (+/-S.E.M.) firing was most apparent during wakefulness (6.4+/-0.8 vs. 3.5+/-0.3 spikes/s) but also persisted during anesthesia (2.0+/-0.3 vs. 0.7+/-0.1 spikes/s). Assessment of treatment duration indicated that R6/2 mean waking discharge rate was significantly slower after three weeks than after one week of ascorbate treatment (3.1+/-0.6 vs. 10.2+/-2.7 spikes/s). Vehicle-treated R6/2s showed no such decline in striatal activity ruling out an age- or injection-related effect. Slow-scan voltammetry in separate animals confirmed that ascorbate-injections returned the level of striatal extracellular ascorbate in R6/2 mice to that of wild-type controls. Our results indicate that although striatal neurons modulate firing in relation to behavioral state, impulse activity is consistently elevated in transgenic relative to wild-type mice. Restoring extracellular ascorbate to the wild-type level reverses this effect suggesting a role for ascorbate in normalizing neuronal function in Huntington's disease striatum.

To assess the role of nucleus accumbens (NAcc) during approach to novel sexually arousing stimuli, we evaluated NAcc single-unit activity in male rats during the presentation of vaginal estrus extracted from novel and familiar female rats. After control stimulus presentations, animals were exposed to two estrous presentations from a female in the same or separate colony. A significantly larger proportion of units increased firing rate in the novel (11/32; 34%) than the familiar condition (2/28; 7%) during approach to the first but not the second presentation. Response magnitudes to novel but not familiar estrus were also greater than those during control trials. Collectively, these results provide further evidence of a role for the NAcc in the processing of novel sexually arousing information.

Systemic or intra-striatal administration of d-amphetamine (AMPH) elicits a dose-dependent pattern of behavioral activation and neuronal firing in the striatum. To determine if the AMPH-induced striatal firing pattern is expressed in the substantia nigra pars reticulata (SNr), a main target of striatal efferents and the primary output nucleus of the basal ganglia, we recorded the activity of 214 SNr units in alert, behaving rats responding to either systemic (1.0 or 5.0 mg/kg, sc) or intra-striatal (20 microg/microl/min) AMPH. Both routes of administration increased behavior but the strongest effects occurred after systemic injection. A dose of 1.0 mg/kg progressively increased locomotion, head movements, and sniffing, whereas after 5.0 mg/kg behavioral responding became progressively more focused and stereotyped. The collective response of SNr neurons was a net increase in firing rate that was most apparent after the low systemic dose and intra-striatal infusion. Further analysis revealed significant unit populations that were either excited, inhibited or showed no change. Although excitations predominated over inhibitions in all cases, a sizable population of units was unresponsive: approximately 25% to systemic AMPH and almost half to intra-striatal infusion. Subsequent injection of haloperidol (0.5 or 1.0 mg/kg, sc), a dopamine receptor antagonist, reversed both the behavioral and electrophysiological effects of AMPH. Thus, as in striatum, dopamine appears to play a critical role in AMPH-induced changes in SNr activity. Interestingly, however, SNr activity did not closely parallel the striatal response, suggesting that patterns of neuronal responding to AMPH in striatum are not reliably relayed to SNr.

3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused amphetamine derivative that increases dopamine (DA) and serotonin release via a reverse transport mechanism. Changes in the activity of striatal neurons in response to increased DA transmission may shape the behavioral patterns associated with amphetamine-like stimulants. To determine how the striatum participates in MDMA-induced locomotor activation, we recorded the activity of >100 single units in the striatum of freely moving rats in response to a dose that increased motor activation (5.0 mg/kg). MDMA had a predominantly excitatory effect on neuronal activity that was positively correlated with the magnitude of locomotor activation. Categorizing neurons according to baseline locomotor responsiveness revealed that MDMA excited significantly more neurons showing movement-related increases in activity compared to units that were non-movement-related or associated with movement-related decreases in activity. Further analysis revealed that the drug-induced striatal activation was not simply secondary to the behavioral change, indicating a primary action of MDMA on striatal motor circuits. Prior administration of SCH-23390 (0.2 mg/kg), a D(1) antagonist, resulted in a late onset of MDMA-induced locomotion, which correlated positively with delayed neuronal excitations. Conversely, prior administration of eticlopride (0.2 mg/kg), a D(2) antagonist, completely abolished MDMA-induced locomotion, which paralleled its blockade of MDMA-induced excitatory neuronal responses. Our results highlight the importance of striatal neuronal activity in shaping the behavioral response to MDMA, and suggest that DA D(1) and D(2) receptors have distinct functional roles in the expression of MDMA-induced striatal and locomotor activation.

The role of the ventral subiculum in cocaine- or cue-induced cocaine-seeking behavior was investigated in rats tested on a between-session reinstatement model. Rats were trained to self-administer cocaine (0.25 mg/infusion, i.v.) in a lever-pressing operant task in a daily 2 hr session. Responding was reinforced contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after the lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Bilateral microinjections of lidocaine (100 μg) into the ventral subiculum decreased cocaine- or cue-induced reinstatement of cocaine-seeking behavior compared with saline microinjections into the same area in another group of rats. Lidocaine microinjections, however, had no effect on cocaine self-administration behavior or food-maintained or food-reinstated responding. Collectively, these results suggest that the ventral subiculum plays an important role in cocaine-seeking behavior. Considering the role of this structure in context learning, our data suggest that the full expression of cocaine- or cue-induced reinstatement may depend on the context in which the cocaine experience occurred.

Motor-control models of basal ganglia function have emphasized disinhibition through reduction of tonic, inhibitory output. Although these models have shed important light on basal ganglia operations, evidence emerging from electrophysiological studies of behaving primates suggests that disinhibition alone may not adequately explain the role of the basal ganglia in movement. To assess this role in the rat, the most frequently used subject in studies of basal ganglia function, we recorded neuronal activity in the primary output nucleus, the substantia nigra pars reticulata, during an operant task. After rats were trained to nosepoke into an illuminated hole for access to a 10% sucrose solution delivered through a spout, single- and multiple-unit activity was recorded during 60–120 nosepoke trials. Compared to the period 60 s before the start of the first trial in the task, 110 of 225 reticulata units increased firing >200% while 17 of 225 decreased to 40% of baseline. Of these 225 units, >60% responded coincident with specific task events such as nosepokes and spout licking. Most nosepoke-responsive units showed either excitation (>50%) or a combination of excitation and inhibition (>25%) rather than inhibition alone (>20%). Increases in firing were also common during approach and licking at the spout, with inhibitions alone comprising 30% of responses. In some units, there was evidence of reward-related responding, with changes occurring in anticipation of reward delivery or during the delivery of sucrose, but not the persistent licking that continued for several seconds after its offset. While 70% of units responded during both nosepokes and spout licking, changes in firing were typically unique depending on the motor behavior required (i.e. nosepoking vs. licking). Our results, which indicate a prominent role for increases in nigra reticulata activity during movement, add to growing evidence that although inhibitions may allow desired motor responses to emerge, excitations may help shape behavioral output by suppressing competing motor programs.

Background Cross-frequency coupling (CFC) occurs when non-identical frequency components entrain one another. A ubiquitous example from neuroscience is low frequency phase to high frequency amplitude coupling in electrophysiological signals. Seminal work by Canolty revealed CFC in human ECoG data. Established methods band-pass the data into component frequencies then convert the band-passed signals into the analytic representation, from which we infer the instantaneous amplitude and phase of each component. Though powerful, such methods resolve signals with respect to time and frequency without addressing the multiresolution problem. New method We build upon the ground-breaking work of Canolty and others and derive a wavelet-based CFC detection algorithm that efficiently searches a range of frequencies using a sequence of filters with optimal trade-off between time and frequency resolution. We validate our method using simulated data and analyze CFC within and between the primary motor cortex and dorsal striatum of rats under ketamine-xylazine anesthesia. Results Our method detects the correct CFC in simulated data and reveals CFC between frequency bands that were previously shown to participate in corticostriatal effective connectivity. Comparison with existing methods Other CFC detection methods address the need to increase bandwidth when analyzing high frequency components but none to date permit rigorous bandwidth selection with no a priori knowledge of underlying CFC. Our method is thus particularly useful for exploratory studies. Conclusions The method developed here permits rigorous and efficient exploration of a hypothesis space and is particularly useful when the frequencies participating in CFC are unknown.

Increasing evidence suggests that dopamine (DA) mechanisms alone cannot fully explain the psychoemotional and behavioural effects of cocaine, including its ability to induce drug-taking behaviour. Although it is known that cocaine, after intravenous administration or smoking, may reach brain levels high enough to inhibit Na+ transport, the role of this action remains unclear. To examine the contribution of local anaesthetic and DA mechanisms to changes in striatal and accumbal neuronal activity induced by cocaine, single-unit recording was combined with iontophoresis in awake, unrestrained rats. Most spontaneously active and glutamate-stimulated neurons were highly sensitive to brief cocaine applications (0-40 nA); cocaine-induced inhibitions occurred at small ejection currents (0-5 nA), were dose-dependent, highly stable during repeated applications and strongly dependent on basal activity rates. These neuronal responses remained almost unchanged after systemic administration of either a selective D1 antagonist (SCH-23390, 0.2 mg/kg) or a combination of SCH-23390 (1 mg/kg) and eticlopride (1 mg/kg), a D2 antagonist. Whereas SCH-23390 alone had a weak attenuating effect, no effect and even a slight enhancement of responses to cocaine occurred in fast-firing glutamate (GLU)-stimulated units after the combined blockade of D1 and D2 receptors. Responses to cocaine were mimicked by iontophoretic procaine (0-40 nA), a short-acting local anaesthetic with minimal effect on DA uptake. Procaine-induced inhibitions occurred at the same low currents, had a similar time-course, and were also strongly dependent on basal discharge rate. Our data support the existence of a DA-independent mechanism for the action of cocaine involving a direct interaction with Na+ channels. Although further studies are required to clarify this mechanism and its interaction with other pharmacological and behavioural variables, a direct interaction with Na+ channels may contribute to changes in neuronal activity induced by self-injected cocaine, thereby playing a role in mediating the psychoemotional and behavioural effects of this drug.

A relatively high level of extracellular ascorbate in the striatum, which is known to modulate impulse flow in striatal neurons, originates primarily from glutamate-containing corticostriatal afferents. Increasing evidence suggests that ascorbate release from these fibers is regulated by a multisynaptic loop that includes gamma-aminobutyric acid (GABA) mechanisms in the substantia nigra. To assess the role that nigral GABA plays in striatal ascorbate release, extracellular ascorbate was monitored voltammetrically in the striatum during infusions of GABA into the substantia nigra pars reticulata (SNr) of awake, unrestrained rats. Compared to vehicle infusions, intranigral GABA lowered striatal ascorbate by50%. In contrast, intranigral application of picrotoxin, a GABA antagonist, had the opposite effect. Neither GABA nor picrotoxin altered striatal 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite. Collectively, these results indicate that intranigral GABA exerts a tonic inhibitory influence on ascorbate release in the striatum.

As psychomotor stimulants, both amphetamine and cocaine elicit episodes of repetitive motor activation (focused stereotypy) known to involve the mesostriatal dopamine system. During amphetamine-induced focused stereotypy, motor-related neurons in the striatum respond with either an excitation or inhibition, depending on dose and behavioral pattern, whereas nonmotor-related units are inhibited. To assess striatal activity during the focused stereotypy induced by cocaine, both types of striatal units were recorded in ambulant rats. Either 20 or 40 mg/kg cocaine caused highly focused sniffing and head bobbing, which occurred in conjunction with activation of both motor- and nonmotor-related neurons. The activation of motor-related units was evident even when firing rate was compared during periods of matched pre- and post-drug behavior, arguing against movement as the sole basis for the drug-induced neuronal excitation. Subsequent administration of haloperidol (1.0 mg/kg) reversed but did not completely block the neuronal activation, while the behavioral response shifted away from focused stereotypy toward an increase in ambulation. Thus, the level of activation of both motor- and nonmotor-related striatal neurons may play a critical role in the behavioral response pattern induced by cocaine.

To assess the role of ascorbate (AA), an antioxidant vitamin, in modulating striatal activity, single-unit recording was combined with iontophoresis in awake, unrestrained rats. Brief applications of AA (20 s, 5-80 nA) elicited few changes in either basal activity or activity evoked by continuous application of glutamate (GLU), but relatively high AA ejection currents (>40 nA) often inhibited fast-firing units. Comparable results were obtained with the antioxidant isomer, iso-AA, suggesting the AA-induced inhibition represents a high-dose, antioxidant effect. When applied for prolonged periods (2-4 min) at doses that failed to alter basal activity, AA either enhanced or attenuated the excitatory response to test pulses of GLU. The AA-induced enhancement occurred more frequently (16 vs. 6 applications) and was characterized by a more rapid (shorter onset and peak latencies) and more pronounced (greater peak magnitude) excitation to GLU without an evident change in offset latency. In most cases, further increases in AA ejection current attenuated the GLU response. Iso-AA, in contrast, had only inhibitory effects, which occurred at moderate- to high-dose applications. Collectively, these results suggest that AA, apart from its antioxidant effects, modulates phasic changes in striatal excitability induced by GLU. Because extracellular levels of striatal AA fluctuate in relation to behavioral activation, this neuromodulatory action of AA may contribute to behaviorally relevant changes in sensorimotor responsivity.

Scheduled daily injections of methamphetamine (MA) produced locomotor activity that preceded and followed the usual time of injection in rats housed under conditions of constant, moderately dim light and temporally distributed feeding. A circadian basis for pre-injection time activity was supported by its anticipatory timing in the apparent absence of reliable preceding external cues and by its persistence on a test day on which the rats remained undisturbed. Post-injection time locomotor activity also persisted on the test day, occurring from 24 to 29 h after the final MA injection. These results indicate that MA injections engage circadian processes underlying locomotor activity, and they raise the possibility that intake of drugs of abuse by humans may facilitate drug taking or relapse at times of day related to previous drug use.

The activity of single neurons in the striatum of freely moving rats was recorded in response to systemic administration of dopamine agonists selective for either the D1 or D2 family of receptors. At a dose that induced behavioral activation, SKF-38393 (5.0 mg/kg s.c.), a D1 agonist, had no consistent effect on striatal activity, whereas quinpirole (1.0-5.0 mg/kg s.c.), a D2 agonist, inhibited the great majority of striatal neurons. In addition, quinpirole (1.0 mg/kg s.c.) excited neurons of the globus pallidus, which receives an inhibitory projection from the striatum. These results are consistent with models of the basal ganglia in which dopamine, via D2 receptors, inhibits striatopallidal activity, resulting in a disinhibition of neurons in globus pallidus.

Voltammetric recordings with electrochemically modified carbon-fiber electrodes were obtained from specific regions of the forebrain in rats given free-choice access to a novel environment. Entry into novelty increased the catechol signal in the medial prefrontal cortex and shell of the nucleus accumbens by more than 100%, but had no consistent effect in either the neostriatum or accumbal core. In both the medial prefrontal cortex and accumbal shell, moreover, the novelty-induced increase in catecholaminergic activity was detectable only during the initial entry into the novel compartment and did not reappear when animals returned to the familiar environment. These results support increasing evidence for a functional distinction between the accumbal core and shell, with the latter having been linked to brain reward mechanisms. The results also indicate that novelty activates, albeit very transiently, some of the same neurochemical systems believed to play a critical role in the reinforcing effects of certain drugs of abuse.

In ambulant rats, iontophoresis of low concentrations of dopamine (DA) enhances the response of neurons in striatum and nucleus accumbens to iontophoretic glutamate. In an extension of this line of investigation, we tested the effects of acetylcholine (ACh), a presumed modulator of neuronal function in these same brain regions, and assessed possible DA-ACh interactions. Data were obtained from spontaneously active neurons known to respond to ACh (5-30 nA) when the animals rested quietly with no overt movement. ACh iontophoresis either excited or inhibited striatal and accumbal activity but excitatory effects predominated in both areas. With multiple applications of ACh, especially at the lowest currents tested, either response often was interspersed with instances of no change in firing rate. Responsiveness to ACh also diminished during periods of spontaneous movement when basal firing showed phasic increases in activity. In fact, neurons with the highest rates of basal activity showed the smallest magnitude response to ACh. Prolonged applications (120-180 s) of DA attenuated basal firing as well as the iontophoretic effects of ACh both during the DA application itself and for up to 1 min after DA ejection offset. The result of these inhibitory effects was no net change in the relative magnitude of the ACh response. Thus, although ACh can modulate striatal and accumbal neuronal activity, DA does not regulate this effect in the same way that it regulates the neuronal responsiveness to glutamate.

The R6/2 mouse line expresses exon I of the human gene for Huntington disease (HD) and shows behavioral symptoms as early as 6 weeks of age. In the striatum, a forebrain target of HD, these animals show a behavior-related deficit in extracellular ascorbate, the deprotonated form of vitamin C. We report here that this deficit may contribute to the HD behavioral phenotype. Regular injections of ascorbate (300 mg/ kg/day, 4 days/week) beginning at symptom onset restored the behavior-related release of ascorbate in striatum and also improved behavioral responding. Compared to vehicle, ascorbate treatment significantly attenuated the neurological motor signs of HD without altering overall motor activity. Ascorbate regulation of striatal function appears key for understanding HD.

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 16–40 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.

Ascorbate is an antioxidant vitamin that the brain accumulates from the blood supply and maintains at a relatively high concentration under widely varying conditions. Although neurons are known to use this vitamin in many different chemical and enzymatic reactions, only recently has sufficient evidence emerged to suggest a role for ascorbate in interneuronal communication. Ascorbate is released from glutamatergic neurons as part of the glutamate reuptake process, in which the high-affinity glutamate transporter exchanges ascorbate for glutamate. This heteroexchange process, which also may occur in glial cells, ensures a relatively high level of extracellular ascorbate in many forebrain regions. Ascorbate release is regulated, at least in part, by dopaminergic mechanisms, which appear to involve both the D1 and D2 family of dopamine receptors. Thus, amphetamine, GBR-12909, apomorphine, and the combined administration of D1 and D2 agonists all facilitate ascorbate release from glutamatergic terminals in the neostriatum, and this effect is blocked by dopamine receptor antagonists. Even though the neostriatum itself contains a high concentration of dopamine receptors, the critical site for dopamine-mediated ascorbate release in the neostriatum is the substantia nigra. Intranigral dopamine regulates the activity of nigrothalamic efferents, which in turn regulate thalamocortical fibers and eventually the glutamatergic corticoneostriatal pathway. In addition, neostriatonigral fibers project to nigrothalamic efferents, completing a complex multisynaptic loop that plays a major role in neostriatal ascorbate release. Although extracellular ascorbate appears to modulate the synaptic action of dopamine, the mechanisms underlying this effect are unclear. Evidence from receptor binding studies suggests that ascorbate alters dopamine receptors either as an allosteric inhibitor or as an inducer of iron-dependent lipid peroxidation. The applicability of these studies to dopamine receptor function, however, remains to be established in view of reports that ascorbate can protect against lipid peroxidation in vivo. Nevertheless, ample behavioral evidence supports an antidopaminergic action of ascorbate. Systemic, intraventricular, or intraneostriatal ascorbate administration, for example, attenuates the behavioral effects of amphetamine and potentiates the behavioral response to haloperidol. Some of these behavioral effects, however, may be dose-dependent in that treatment with relatively low doses of ascorbate has been reported to enhance dopamine-mediated behaviors. Ascorbate also appears to modulate glutamatergic transmission in the neostriatum. In fact, by facilitating glutamate release, ascorbate may indirectly oppose the action of dopamine, though the nature of the neostriatal dopaminergic-glutamatergic interaction is far from settled. Ascorbate also may alter the redox state of the NMDA glutamate receptor thus block NMDA-gated channel function.(ABSTRACT TRUNCATED AT 400 WORDS)

A methodology was developed to combine extracellular electrophysiological recording techniques in awake, behaving rats with immunohistochemical protocols to determine the placement of recording sites in the patch (striosome) or matrix (extrastriosome) regions of the striatum. The recording system includes a 3-barrel glass micropipette, which can be used to deposit Pontamine Sky Blue to mark a small number of neurons at the recording site. Subsequent immunostaining for calbindin allows the site to be localized within the patch-matrix organization. Other dyes or neuroanatomical probes can be ejected from other barrels of the recording pipette to label afferent and efferent structures. The methodology can be applied to many brain regions, providing for integrative studies of behavior and nervous system structure and function.

Neural activity was recorded from 218 sites in the striatum (caudate-putamen and nucleus accumbens) of rats trained on a lever-release version of the conditioned avoidance response (CAR) task, in which an auditory signal elicits a short-latency, forelimb withdrawal. > 80% of these recording sites showed task-related activity, including neurons that responded to the auditory stimulus (signal-related cells), the lever-release (response-related cells), or both of these events (signal/response-related cells). Histological analysis revealed a predominance of signal-related neurons in medial striatum, whereas lateral recording sites mainly showed response-related activity. Haloperidol (0.1 mg/kg s.c.), a widely used neuroleptic that impairs CAR performance, significantly attenuated task-related neural activity without altering the latency of the neural response or spontaneous firing rate. Collectively, these results, which demonstrate the usefulness of the lever-release CAR paradigm for assessing striatal function, suggest that the sensory and motor aspects of the CAR task are processed by different striatal regions. Moreover, haloperidol appears to disrupt the striatal processing of both sensory and motor information.

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 intravenous infusion) in a lever-pressing task in a daily 2 h session for 10–14 d followed by 5 d of extinction training. Immediately after each extinction session, rats received ceftriaxone (intraperitoneally), 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.

Fetal alcohol exposure is known to induce cell death through apoptosis. We found that colivelin (CLN), a novel peptide with the sequence SALLRSIPAPAGASRLLLLTGEIDLP, prevents this apoptosis. Our initial experiment revealed that CLN enhanced the viability of primary cortical neurons exposed to alcohol. We then used a mouse model of fetal alcohol exposure to identify the intracellular mechanisms underlying these neuroprotective effects. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet 25% (4.49% v/v) ethanol derived calories; (2) pair-fed control; (3) normal chow; (4) ethanol liquid diet combined with administration (i.p.) of CLN (20 microg/20 g body weight); and (5) pair-fed combined with administration (i.p.) of CLN (20 microg/20 g body weight). On E13, fetal brains were collected and assayed for TdT-mediated dUTP nick end labeling staining, caspase-3 colorimetric assay, enzyme-linked immunosorbent assay, and Meso scale discovery electrochemiluminescence. CLN blocked the alcohol-induced decline in brain weight and prevented alcohol-induced: apoptosis, activation of caspase-3 and increases of cytosolic cytochrome c, and decreases of mitochondrial cytochrome c Analysis of proteins in the upstream signaling pathway revealed that CLN down-regulated the phosphorylation of the c-Jun N-terminal kinase. Moreover, CLN prevented alcohol-induced reduction in phosphorylation of BAD protein. Thus, CLN appears to act directly on upstream signaling proteins to prevent alcohol-induced apoptosis. Further assessment of these proteins and their signaling mechanisms is likely to enhance development of neuroprotective therapies.

Single-unit recordings from neostriatal neurons showing movement-related excitations were obtained in freely moving, cortically ablated rats and sham-lesioned controls. d -Amphetamine (AMPH, 1.0 mg/kg s.c.) increased neuronal activity relative to resting baseline firing rates in both groups of animals, but cortical ablation significantly attenuated this effect. A behavioral clamping analysis, which compared neuronal activity during identically rated pre- and post-AMPH behaviors, revealed that: (a) AMPH enhanced movement-related neuronal activity in sham-lesioned controls, but not in cortically ablated rats; and (b) the drug-induced neuronal activation in control rats was not simply secondary to the behavioral activation produced by AMPH. In contrast to its neuronal effects, cortical ablation did not affect ratings of AMPH-induced locomotion, rearing, or head movements, though sniffing scores showed a postive correlation with lesion size. Thus, corticostriatal projections are critically involved in AMPH-induced excitations of neostriatal motor-related neurons.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D 2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [ 3 H]spiperone saturation studies showed, as expected, an up-regulation of striatal D 2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density ( B max but not affinity ( K D ). Ascorbate treatment, however, had no effect on D 2 receptor density or the distribution of [ 3 H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D 2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [ 3 H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

In vivo voltammetry was used to study the regional distribution of extracellular ascorbate (AA) and 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, in the striatum of the rat. An electrochemically-modified carbon-fiber electrode, which provides distinct oxidation curves for each of these substances, was lowered in 1-mm increments through one of four striatal regions selected to sample the entire extent of this structure, including the nucleus accumbens. In anteromedial striatum, the level of AA was highest in the most dorsal and ventral aspects and lowest in the middle, whereas DOPAC levels generally showed the opposite pattern. This inverse relationship between AA and DOPAC was not evident in either lateral or posterior areas. To the extent that AA and DOPAC are released from different axon terminals, as mounting evidence suggests, regional differences in the extracellular concentration of these compounds may reflect the different and, in some cases, reciprocal distributions of two neuronal populations.

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.

Huntington's disease (HD) is an autosomal dominant condition that compromises behavioral output. Dysfunction of medium spiny neurons (MSNs), which are the sole output system of the striatum, is thought to underlie HD pathophysiology. What is not known is how HD alters MSN information processing during behavior, which likely drives the HD behavioral phenotype. We recorded from populations of MSNs in two freely behaving and symptomatic HD mouse models: R6/2 transgenics are based on a C57BL/6J*CBA/J background and show robust behavioral symptoms, whereas knock-in (KI) mice have a 129sv background and express relatively mild behavioral signs. At the single-unit level, we found that the MSN firing rate was elevated in R6/2 but not in KI mice compared with their respective wild-type (WT) controls. In contrast, burst activity, which corresponds to periods of high-frequency firing, was altered in both HD models compared with WT. At the population level, we found that correlated firing between pairs of MSNs was a prominent feature in WT that was reduced in both HD models. Similarly, coincident bursts, which are bursts between pairs of neurons that overlap in time and occur more often in pairs of MSNs that exhibit correlated firing, were decreased in HD mice. Our results indicate an important role in both bursting and correlated burst firing for information processing in MSNs. Dysregulation of this processing scheme, moreover, is a key component of HD pathophysiology regardless of the severity of HD symptoms, genetic construct, and background strain of the mouse models.

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 beta-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, i.p., 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.

The selectivity of Nafion-coated, carbon-fiber electrodes was evaluated for the voltammetric detection of dopamine in the presence of 3,4-dihydroxyphenylacetic acid (DOPAC) and ascorbate, which are interferant anions in the brain. Nafion coating was applied to both polished carbon-disk electrodes and electrochemically modified electrodes. During in vitro testing, polished disk electrodes showed the greatest selectivity for dopamine at the fastest scan rate tested (300 V s−1), but the drift in signal made slow changes in dopamine difficult to determine. Electrochemically modified electrodes already provide an ascorbate wave distinct from that for dopamine, but Nafion coating actually decreased dopamine selectivity with respect to DOPAC. In vivo testing was carried out in the neostriatum of urethane-anesthetized rats in response to drug- or stimulation-induced increases in dopamine transmission. Administration of haloperidol (0.5 mg kg−1) followed by GBR 12909 (20 mg kg−1), which is known to cause a 10-fold increase in extracellular dopamine, failed to produce a selective signal for dopamine when measured voltammetrically. Comparable results were obtained following administration of amphetamine (2.5 mg kg−1), which also increases dopamine overflow. Voltammetric detection of dopamine was possible, however, during electrical stimulation of dopaminergic afferents in the medial forebrain bundle. Thus, voltammetry with Nafion-coated electrodes is best suited to the measurement of transient changes in extracellular dopamine rather than the relatively prolonged changes in dopamine overflow produced by various drugs.

Background A physiological increase in extracellular ascorbate (AA), an antioxidant vitamin found throughout the striatum, elevates extracellular glutamate (GLU). To determine the role of behavioral arousal in this interaction, microdialysis was used to measure striatal GLU efflux in rats tested in either a lights-off or lights-on condition while reverse dialysis either maintained the concentration of AA at 250 μM or increased it to 1000 μM to approximate endogenous changes. Results When lights were off, both locomotion and GLU increased regardless of AA dose. In contrast, animals in the lights-on condition were behaviorally inactive, and infusion of 1000, but not 250, μM AA significantly increased extracellular GLU. Interestingly, when ambient light returned to the lights-off group, 1000 μM prolonged the GLU increase relative to the 250 μM group. Conclusion Our results not only support evidence that elevated striatal AA increases extracellular GLU but also indicate that this effect depends on behavioral state and the corresponding level of endogenous GLU release.

To investigate the neuronal mechanisms underlying the behavioural alterations that accompany repeated exposure to MDMA (ecstasy), we recorded the activity of > 200 striatal units in response to multiple, intermittent, locomotor-activating doses (5.0 mg/kg) of MDMA. Rats were treated with once-daily injections of either saline or MDMA for 5 days when housed in their home cage, followed by a challenge injection 3-5 days later when housed in a recording chamber. Because contextual drug associations might be particularly important to the expression of behavioural sensitization to chronic MDMA, a separate group of rats received repeated injections of MDMA alternately in the recording chamber or home cage, according to the above timeline. A sensitized locomotor response was observed only in rats that had previously experienced MDMA in the context of the recording chamber, and only on the challenge day. These sensitized animals also showed a decreased basal firing rate in neurons that were subsequently excited by MDMA when compared with the same category of neurons earlier in the treatment regimen. This resulted in a greater percentage increase from the baseline firing rate on the challenge day compared with the first and fifth days of treatment, even though this trend was not evident with an analysis of absolute firing rate. These results strongly support a role for context in the expression of MDMA-induced locomotor sensitization, and implicate striatal involvement in the neurobehavioural changes associated with the repeated use of MDMA.

Nitrous oxide (N2O) has been reported to reduce post-withdrawal craving in alcoholic humans, aiding in their continued abstinence. This article assessed the ability of N2O to suppress alcohol drinking in genetically selected high alcohol-drinking (HAD) and alcohol-preferring (P) rats. Although water was available ad libitum, they were accustomed to a limited access (1 h/day) choice between 10% ethanol (EtOH) and water. When drinking stabilized, the rats were exposed for 30, 60, or 120 min to a mixture of N2O and pure oxygen, timed to end 1 h before the limited access. N2O suppressed EtOH consumption at 1, but not 25 h after exposure in both HAD and P rats. This result is consistent with the efficacy of N2O for acute reduction of EtOH drinking, and supports further research into the use of N2O as an adjunct to treatment.

Environmentally enriched (EE) rats show neurobehavioral differences relative to less stimulated, socially isolated (SI) littermates. Although experience-dependent cortical changes are presumed to underlie learning differences in these differentially housed animals, EE rats show reduced reward-seeking behavior and altered cytoarchitecture and dopaminergic function in the nucleus accumbens (NAcc), a brain area involved in adaptive, goal-directed activity. Given that glutamate and its interaction with dopamine regulate motivational and associative processing in this brain region, we assessed expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor and the GluR1 subunit of the a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in the NAcc core and shell of EE and SI rats. Our results indicate fewer intensely stained NR1 immunopositive neurons in both core and shell of EE relative to SI rats. No such differences were observed in GluR1 staining. These results suggest that environmental experience alters NMDA but not AMPA receptor expression in NAcc. Increased expression of the NR1 subunit in the NAcc of SI rats may augment impulsivity and reward-seeking behavior relative to EE rats. D 2005 Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Neural plasticity

To determine if extracellular ascorbate, which may increase by several hundred micromolar in striatum during behavioral activation, directly alters glutamate transmission, we monitored striatal glutamate transients evoked by electrical stimulation of cerebral cortex in anesthetized rats tested with varying concentrations of ascorbate (0, 50, 200, and 500 μM) by reverse dialysis. Capillary electrophoresis coupled with laser-induced fluorescence detection was used to analyze dialysates collected at 3-s intervals. Ascorbate elevated striatal glutamate in a concentration-dependent fashion. Addition of 500 μM ascorbate not only more than doubled basal glutamate levels relative to the ascorbate-free condition, but significantly increased both the magnitude of the electrically evoked glutamate response as well as its subsequent return to baseline. In fact, the time required to return to within 10% of the pre-stimulation baseline increased by >100 s. Reverse dialysis of iso-ascorbate, in contrast, had no effect on stimulation-evoked glutamate release arguing against an antioxidant effect. It appears, therefore, that the level of extracellular ascorbate plays a critical role in regulating corticostriatal glutamate transmission.