Striatal Cholinergic Interneurons Are Required for Contending Strategy Selection While Solving Spatial Navigation Problems.

How do animals adopt a given behavioral strategy to solve a recurrent problem when several effective strategies are available to reach the goal? Here we provide evidence that striatal cholinergic interneurons (SCINs) modulate their activity when mice must select between different strategies with similar goal-reaching effectiveness. Using a cell type-specific transgenic murine system, we show that adult SCIN ablation impairs strategy selection in navigational tasks where a goal can be independently achieved by adopting an allocentric or egocentric strategy. SCIN-depleted mice learn to achieve the goal in these tasks, regardless of their appetitive or aversive nature, in a similar way as controls. However, they cannot shift away from their initially adopted strategies, as control mice do, as training progresses. Our results indicate that SCINs are required for shaping the probability function used for strategy selection as experience accumulates throughout training. Thus, SCINs may be critical for the resolution of cognitive conflicts emerging when several strategies compete for behavioral control while adapting to environmental demands. Our findings may increase our understanding about the emergence of perseverative/compulsive traits in neuropsychiatric disorders with a reported SCIN reduction, such as Tourette and Williams syndromes.SIGNIFICANCE STATEMENT Selecting the best suited strategy to solve a problem is vital. Accordingly, available strategies must be compared across multiple dimensions, such as goal attainment effectiveness, cost-benefit trade-off, and cognitive load. The striatum is involved in strategy selection when strategies clearly diverge in their goal attainment capacity; however, its role whenever several strategies can be used for goal reaching-therefore making selection dependent on additional strategy dimensions-remains poorly understood. Here, we show that striatal cholinergic interneurons can signal strategy competition. Furthermore, they are required to adopt a given strategy whenever strategies with similar goal attainment capacity compete for behavioral control. Our study suggests that striatal cholinergic dysfunction may result in anomalous resolution of problems whenever complex cognitive valuations are required.

Behavioral sensitization and cellular responses to psychostimulants are reduced in D2R knockout mice.

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2-/- ) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine- and amphetamine-induced behavioral sensitization is deficient in D2-/- mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve- and in cocaine- or amphetamine-treated D2-/- mice. Moreover, c-Fos expression observed in D2-/- mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation.

Compulsive Social Behavior Emerges after Selective Ablation of Striatal Cholinergic Interneurons.

The mechanisms underlying social dysfunction in neuropsychiatric conditions such as obsessive-compulsive disorder and Tourette syndrome remain uncertain. However, it is known that dysfunctions in basal ganglia, including a reduced number of striatal cholinergic interneurons (SCIN), are involved in their pathophysiology. To explore the role of SCIN in relation to perseverative behaviors, we characterized a new transgenic mouse model in which inducible ablation of SCIN is achieved with high efficiency in a cell-type- and region-specific manner. Mice were subjected to extensive behavioral testing, including assessment of social behaviors, and corticostriatal functional connectivity was evaluated in vivo Selective SCIN ablation leads to altered social interactions together with exacerbated spontaneously emitted repetitive behaviors. Lesioned mice showed normal motor coordination, balance, and general locomotion. Interestingly, only environmentally driven, but not self-directed, repetitive behaviors were exacerbated in lesioned mice. Remarkably, in mice with SCIN ablation, the normal pattern of social exploration was replayed continuously. The emerging pattern of social interactions is highly predictable and invariant across time. In vivo electrophysiological recordings indicate that SCIN ablation results in an increase of the functional connectivity between different cortical areas and the motor, but not associative, region of the striatum. Our results identify a role of SCIN in suppressing perseverative behaviors, including socially related ones. In sum, SCIN ablation in mice leads to exacerbated ritualistic-like behaviors that affect social performance, providing a link between SCIN dysfunction and the social impairments present in psychiatric disorders.SIGNIFICANCE STATEMENT We sought to uncover the impact of striatal cholinergic interneuron (SCIN) degeneration on perseverative behaviors related to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We found that extensive SCIN ablation results in exacerbated social interactions, in which normal social contacts were replayed continuously in a highly stereotyped, ritualistic pattern. SCIN ablation also leads to an increase in other spontaneously emitted repetitive behaviors without alteration of motor coordination, balance, or locomotion. Moreover, we identify an increase of functional connectivity between frontal cortical areas and the motor region of the striatum as a putative substrate for the observed behavioral alterations. Therefore, perseveration induced by SCIN ablation extends to social performance as occurs in neuropsychiatric conditions such as OCD and TS.

Loss of Homeostasis in the Direct Pathway in a Mouse Model of Asymptomatic Parkinson's Disease.

UNLABELLED: The characteristic slowness of movement in Parkinson's disease relates to an imbalance in the activity of striatal medium spiny neurons (MSNs) of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear whether this imbalance emerges during the asymptomatic phase of the disease or if it correlates with symptom severity. Here, we have used in vivo juxtacellular recordings and transgenic mice showing MSN-type-specific expression of fluorescent proteins to examine striatal imbalance after lesioning dopaminergic neurons of the substantia nigra. Multivariate clustering analysis of behavioral data discriminated 2 groups of dopamine-lesioned mice: asymptomatic (42 ± 7% dopaminergic neuron loss) and symptomatic (85 ± 5% cell loss). Contrary to the view that both pathways have similar gain in control conditions, dMSNs respond more intensely than iMSNs to cortical inputs in control animals. Importantly, asymptomatic mice show significant functional disconnection of dMSNs from motor cortex without changes in iMSN connectivity. Moreover, not only the gain but also the timing of the pathways is altered in symptomatic parkinsonism, where iMSNs fire significantly more and earlier than dMSNs. Therefore, cortical drive to dMSNs decreases after partial nigrostriatal lesions producing no behavioral impairment, but additional alterations in the gain and timing of iMSNs characterize symptomatic rodent parkinsonism. SIGNIFICANCE STATEMENT: Prevailing models of Parkinson's disease state that motor symptoms arise from an imbalance in the activity of medium spiny neurons (MSNs) from the direct (dMSNs) and indirect (iMSNs) pathways. Therefore, it is hypothesized that symptom severity and the magnitude of this imbalanced activity are correlated. Using a mouse model of Parkinson's disease, we found that behaviorally undetectable nigrostriatal lesions induced a significant disconnection of dMSNs from the motor cortex. In contrast, iMSNs show an increased connectivity with the motor cortex, but only after a severe dopaminergic lesion associated with an evident parkinsonian syndrome. Overall, our data suggest that the lack of symptoms after a partial dopaminergic lesion is not due to compensatory mechanisms maintaining the activity of both striatal pathways balanced.

Striatal NMDA receptors gate cortico-pallidal synchronization in a rat model of Parkinson's disease.

Anomalous patterns of synchronization between basal ganglia and cortex underlie the symptoms of Parkinson's disease. Computational modeling studies suggest that changes in cortical feedback loops involving trans-striatal and trans-subthalamic circuits bring up this anomalous synchronization. We asked whether striatal outflow synchronizes globus pallidus neurons with cortical activity in a rat model of Parkinson's disease. We found that striatal firing is highly increased in rats with chronic nigrostriatal lesion and that this hyperactivity can be reduced by locally infusing a competitive NMDA receptor antagonist. Moreover, NMDA receptor-dependent striatal output had frequency dependent effects on distinct pathological patterns of cortico-pallidal coupling. Blockade of striatal NMDA receptors almost completely abolished an anomalous ~1Hz cortico-pallidal anti-phase synchronization induced by nigrostriatal degeneration. Moreover, under striatal NMDA receptor blockade, synchronization with 2.5-5Hz cortical oscillations falls to negligible levels and oscillations at 10-20Hz are markedly attenuated, whereas beta synchronization (with a peak at ~26Hz) is marginally reduced. Thus, tonic activation of striatal NMDA receptors allows different forms of anomalous oscillations along the cortico-striato-pallidal axis. Moreover, the frequency dependent effects of NMDA receptors suggest that low and high frequency parkinsonian oscillations stem from partially different mechanisms. Finally, our results may help to reconcile views about the contributions of changes in firing rate and oscillatory synchronization to Parkinson's disease symptoms by showing that they are related to each other.

Functional integration across a gradient of corticostriatal channels controls UP state transitions in the dorsal striatum.

Coordinated near-threshold depolarized states in cortical and striatal neurons may contribute to form functionally segregated channels of information processing. Recent anatomical studies have identified pathways that could support spiraling interactions across corticostriatal channels, but a functional outcome of such spiraling remains to be identified. Here, we examined whether plateau depolarizations (UP states) in striatal neurons relate better to active epochs in local field potentials recorded from closely related cortical areas than to those recorded in less-related cortical areas. Our results show that, in anesthetized rats, the coordination between cortical areas and striatal regions obeys a mediolateral gradient and keeps track of slow wave trajectory across the neocortex. Moreover, activity in one cortical area induced phase advances in UP state onset and phase delays in UP state termination in nonmatching striatal regions, reflecting the existence of functional connections that could encode large-scale interactions between corticostriatal channels as subthreshold influences on striatal projection neurons.

Dopamine-dependent periadolescent maturation of corticostriatal functional connectivity in mouse.

Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined preadolescent and postadolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation, and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals regardless of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional capacities of the corticostriatal system.

NMDA receptor gating of information flow through the striatum in vivo.

A role of NMDA receptors in corticostriatal synaptic plasticity is widely acknowledged. However, the conditions that allow NMDA receptor activation in the striatum in vivo remain obscure. Here we show that NMDA receptors contribute to sustain the membrane potential of striatal medium spiny projection neurons close to threshold during spontaneous UP states in vivo. Moreover, we found that the blockade of striatal NMDA receptors reduces markedly the spontaneous firing of ensembles of medium spiny neurons during slow waves in urethane-anesthetized rats. We speculate that recurrent activation of NMDA receptors during UP states allows off-line information flow through the striatum and system level consolidation during habit formation.

D2 receptor stimulation, but not D1, restores striatal equilibrium in a rat model of Parkinsonism.

In Parkinson's disease dopamine depletion imbalances the two major output pathways of the striatum. L-DOPA replacement therapy is believed to correct this imbalance by providing effective D1 and D2 receptor stimulation to striatonigral and striatopallidal neurons, respectively. Here we tested this assumption in the rat model of Parkinsonism by monitoring the spike response of identified striatal neurons to cortical stimulation. As predicted, in 6-hydroxydopamine lesioned rats we observed that L-DOPA (6 mg/kg+benserazide), apomorphine and the D2 agonist quinpirole (0.5 mg/kg i.p.) counteract the enhanced responsiveness of striatopallidal neurons. Unexpectedly, the depressed responsiveness of striatonigral neurons was corrected by quinpirole whereas D1 stimulation exerted no (apomorphine, cPB) or worsening effects (L-DOPA, SKF38393 10 mg/kg). Therefore, quinpirole, but not D1 stimulation, restores functional equilibrium between the two striatal output pathways. Our results might explain the therapeutic effect of D2-based medications in Parkinson's disease.

Properties of the corticostriatal long term depression induced by medial prefrontal cortex high frequency stimulation in vivo.

Repetitive stimulation of cognitive forebrain circuits at frequencies capable of inducing corticostriatal long term plasticity is increasingly being used with therapeutic purposes in patients with neuropsychiatric disorders. However, corticostriatal plasticity is rarely studied in the intact brain. Our aim was to study the mechanisms of corticostriatal long term depression (LTD) induced by high frequency stimulation (HFS) of the medial prefrontal cortex in vivo. Our main finding is that the LTD induced in the dorsomedial striatum by medial prefrontal cortex HFS in vivo (prefrontostriatal LTD) is not affected by manipulations that block or reduce the LTD induced in the dorsolateral striatum by motor cortex HFS in brain slices, including pharmacological dopamine receptor and CB1 receptor blockade, chronic nigrostriatal dopamine depletion, CB1 receptor genetic deletion and selective striatal cholinergic interneuron (SCIN) ablation. Conversely, like in the hippocampus and other brain areas, prefrontostriatal LTD is NMDA receptor dependent. Thus, we describe a novel form of corticostriatal LTD that operates in brain circuits involved in reward and cognition and could be relevant for understanding the therapeutic effects of deep brain stimulation.

The phenylephrine blood pressure clamp in pharmacologic magnetic resonance imaging: reduction of systemic confounds and improved detectability of drug-induced BOLD signal changes.

RATIONALE: Peripheral physiologic changes accompany many central pharmacologic manipulations and can interact with brain activity and cerebral perfusion in complex ways. This considerably complicates the interpretation of drug-induced brain activity changes. OBJECTIVES: To evaluate a method whereby drug-induced blood pressure (BP) changes are prevented. METHODS: A continuously adjusted infusion of the peripheral vasoconstrictor phenylephrine (PEP) was used to counter-regulate BP changes elicited by application of the dopamine receptor agonist apomorphine (APO) in the rat. Central effects of APO were measured using pharmacologic magnetic resonance imaging (phMRI) with blood oxygenation level dependent (BOLD) contrast at a field strength of 7 T. RESULTS: Compared to a NOPEP control group, the PEP blood pressure clamp successfully prevented BP changes and improved the detectability of central APO effects. Moreover, APO-induced central changes no longer correlated with BP time courses. CONCLUSIONS: The method is suitable for isolating central drug effects from peripherally originating (BP) confounds in high-field functional magnetic resonance imaging (fMRI) studies. It may also be useful in fMRI studies of autonomic regulation, cognition, and emotion if the experimental manipulation entails BP changes.

Immunodetection of heparin-binding growth associated molecule (pleiotrophin) in striatal interneurons.

Pleiotrophin (PTN), a developmentally-regulated trophic factor, is over-expressed in the striatum of parkinsonian rats. Because striatal PTN can provide trophic support to dopamine neurons, we identified the cellular types containing PTN in the striatum of adult rats. By means of fluorescent double-immunolabeling, we found PTN to co-localize with a neuronal nuclei marker but not with glial fibrillary acidic protein. The number, distribution, and morphology of the PTN-immunolabeled cells suggested that they were interneurons. Further double-immunolabeling studies ruled out PTN localization to calretinin- and parvalbumin-containing interneurons. Instead, approximately 40% of the PTN-immunolabeled neurons contained nitric oxide synthase or somatostatin and approximately 60% expressed the vesicular acetylcholine transporter, supporting that they were GABAergic nitric oxide synthase/somatostatin-containing and cholinergic interneurons. Further work is necessary to determine if PTN from striatal interneurons can provide trophic support to dopamine neurons.

Altered Corticostriatal Connectivity and Exploration/Exploitation Imbalance Emerge as Intermediate Phenotypes for a Neonatal Dopamine Dysfunction.

Findings showing that neonatal lesions of the forebrain dopaminergic system in rodents lead to juvenile locomotor hyperactivity and learning deficits have been taken as evidence of face validity for the attention deficit hyperactivity disorder. However, the core cognitive and physiological intermediate phenotypes underlying this rodent syndrome remain unknown. Here we show that early postnatal dopaminergic lesions cause long-lasting deficits in exploitation of shelter, social and nutritional resources, and an imbalanced exploratory behavior, where nondirected local exploration is exacerbated, whereas sophisticated search behaviors involving sequences of goal directed actions are degraded. Importantly, some behavioral deficits do not diminish after adolescence but instead worsen or mutate, particularly those related to the exploration of wide and spatially complex environments. The in vivo electrophysiological recordings and morphological reconstructions of striatal medium spiny neurons reveal corticostriatal alterations associated to the behavioral phenotype. More specifically, an attenuation of corticostriatal functional connectivity, affecting medial prefrontal inputs more markedly than cingulate and motor inputs, is accompanied by a contraction of the dendritic arbor of striatal projection neurons in this animal model. Thus, dopaminergic neurons are essential during postnatal development for the functional and structural maturation of corticostriatal connections. From a bottom-up viewpoint, our findings suggest that neuropsychiatric conditions presumably linked to developmental alterations of the dopaminergic system should be evaluated for deficits in foraging decision making, alterations in the recruitment of corticostriatal circuits during foraging tasks, and structural disorganization of the frontostriatal connections.

Effects of orally administered levodopa on mesencephalic dopaminergic neurons undergoing a degenerative process.

Although the issue of in vivo levodopa toxicity appears to be settled by now in the light of recent findings, a crucial aspect was not accounted for the experiments designed to tackle that question. Levodopa could in fact be non-toxic on surviving dopamine neurons, but that could not be the case when the drug is administered at the same time those neurons are undergoing degeneration, which is what happens in the clinical setting. Dopaminergic neurons could in that situation be more vulnerable to levodopa's potential toxic action. Our aim was to determine if oral administration of levodopa is toxic for mesencephalic dopaminergic neurons that are actively involved in a degenerative process. We induced delayed retrograde degeneration of the nigrostriatal system in rats by injecting 6-hydroxydopamine (6-OHDA) intrastriatally. Treatment was started the day after the injection. Dopaminergic markers were histologically studied at the striatal and nigral levels, to determine degree of damage of the nigrostriatal dopaminergic system in levodopa- and vehicle-treated rats. No significant differences between levodopa or vehicle-treated rats were found in: (i) striatal immunoautoradiographic labeling for tyrosine hydroxylase (TH) and the membrane dopamine transporter (DAT); (ii) cell counts of TH-immunoreactive (TH-ir) neurons remaining in the substantia nigra and ventral tegmental area (VTA); (iii) surface area of remaining TH-immunoreactive neurons in the substantia nigra. The present experiments demonstrate that levodopa does not enhance delayed retrograde degeneration of dopaminergic neurons induced by intrastriatal administration of 6-OHDA.

Striatal dysfunction increases basal ganglia output during motor cortex activation in parkinsonian rats.

During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.

Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of rats.

There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.

Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson's disease experimental models.

The main clinical manifestations of Parkinson's disease are caused by alterations of basal ganglia activity that are tied in with the progressive loss of mesencephalic dopaminergic neurons. Recent theoretical and modeling studies have suggested that changes in resting neuronal activity occurred later in the course of the disease than those evoked by phasic cortical input. However, there is no empirical support for this proposal. Here we report a marked increase in the responsiveness of globus pallidus neurons to electrical motor cortex stimulation, in the absence of noticeable changes in resting activity, in anesthetized rats that had consistently shown a deficit in forelimb use during behavioral testing before the experiments, and had approximately 45% dopamine neurons spared in the substantia nigra. Pallidal neurons were also over-responsive to motor cortex stimulation and lost spatial selectivity for cortical inputs in rats with extensive nigrostriatal damage. After partial lesions, over-responsiveness was mainly due to an increased proportion of neurons showing excitatory responses, while extensive lesions led to an increased likelihood of inhibitory responding neurons. Changes in resting neuronal activity, comprising pauses disrupting tonic discharge, occurred across different global brain states, including an activated condition which shares similarities with natural patterns of cortical activity seen in awake states and rapid eye-movement sleep, but only after massive nigrostriatal degeneration. These results suggest that a loss of functional segregation and an abnormal temporal encoding of phasic cortical inputs by globus pallidus neurons may contribute to inducing early motor impairment in Parkinson's disease.

Turning off cortical ensembles stops striatal Up states and elicits phase perturbations in cortical and striatal slow oscillations in rat in vivo.

In vivo, cortical neurons and striatal medium spiny neurons (MSN) display robust subthreshold depolarizations (Up states) during which they are enabled to fire action potentials. In the cortex, Up states are believed to occur simultaneously in a neuronal ensemble and to be sustained by local network interactions. It is known that MSN are impelled into the Up state by extra-striatal (primarily cortical) inputs, but the mechanisms that sustain and determine the end of striatal Up states are still debated. Furthermore, it has not been established if brisk perturbations of ongoing cortical oscillations alter rhythmic transitions between Up and Down states in striatal neurons. Here we report that MSN Up states terminate abruptly when persistent activity in cortical ensembles providing afferents to a given striatal region is turned off by local electrical stimulation or ends spontaneously. In addition, we found that phase perturbations in MSN membrane potential slow oscillations induced by cortical stimulation replicate the stimulus-induced dynamics of spiking activity in cortical ensembles. Overall, these results suggest that striatal Up states are single-cell subthreshold representations of episodes of persistent spiking in cortical ensembles. A precise spatial and temporal alignment between episodes of cortical persistent activity and striatal Up states would allow MSN to detect specific cortical inputs embedded within a more general cortical signal.

Consequences of partial and severe dopaminergic lesion on basal ganglia oscillatory activity and akinesia.

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.

Disruption of the two-state membrane potential of striatal neurones during cortical desynchronisation in anaesthetised rats.

In anaesthetised animals, the very negative resting membrane potential of striatal spiny neurones (down state) is interrupted periodically by depolarising plateaux (up states) which are probably driven by excitatory input. In the absence of active synaptic input, as occurs in vitro, potassium currents hold the membrane potential of striatal spiny neurones in the down state. Because striatal spiny neurones fire action potentials only during the up state, these plateau depolarisations have been perceived as enabling events that allow information processing through cerebral cortex-basal ganglia circuits. Recent studies have demonstrated that the robust membrane potential fluctuation of spiny neurones is strongly correlated to the slow electroencephalographic rhythms that are typical of slow wave sleep and anaesthesia. To further understand the impact of cortical activity states on striatal function, we studied the membrane potential of striatal neurones during cortical desynchronised states. Simultaneous in vivo recordings of striatal neurones and the electrocorticogram in urethane-anaesthetised rats revealed that rhythmic alternation between up and down states was disrupted during episodes of spontaneous or induced cortical desynchronisation. Instead of showing robust two-state fluctuations, the membrane potential of striatal neurones displayed a persisting depolarised state with fast, low-amplitude modulations. Spiny neurones remained in this persistent up state until the cortex resumed ~1 Hz synchronous activity. Most of the recorded neurones exhibited a low firing probability, irrespective of the cortical activity state. Time series analysis failed to reveal significant correlations between the membrane potential of striatal neurones and the desynchronised electrocorticogram. Our results suggest that during cortical desynchronisation continuous uncorrelated excitatory input sustains the membrane potential of striatal neurones in a persisting depolarised state, but that substantial additional input is necessary to impel the neurones to threshold. Our data support that the prevailing cortical activity state determines the duration of the enabling depolarising events that take place in striatal spiny neurones.