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The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow (∼1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: (1) BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; and (2) BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested that their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism.SIGNIFICANCE STATEMENTMotor thalamus neurons mediate the influences of basal ganglia and cerebellum on the cerebral cortex to govern movement. Chronic depletion of dopamine from the basal ganglia causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters the ways motor thalamus neurons engage with two distinct oscillations emerging in cortico-basal ganglia circuitsin vivo. We discovered that, after dopamine depletion, neurons in the thalamic zone receiving basal ganglia inputs are particularly prone to becoming dysrhythmic, changing the phases and/or synchronization (but not rate) of their action potential firing. This bolsters cortical dysrhythmia. Our results provide important new insights into how aberrant rhythmicity in select parts of motor thalamus could detrimentally affect neural circuit dynamics and behavior in Parkinsonism.

Closed-loop interaction has the potential to regulate ongoing brain activity by continuously binding an external stimulation to specific dynamics of a neural circuit. Achieving interactive modulation requires a stable brain-machine feedback loop. Here, we demonstrate that it is possible to maintain oscillatory brain activity in a desired state by delivering stimulation accurately aligned with the timing of each cycle. We develop a fast algorithm that responds on a cycle-by-cycle basis to stimulate basal ganglia nuclei at predetermined phases of successive cortical beta cycles in parkinsonian rats. Using this approach, an equilibrium emerges between the modified brain signal and feedback-dependent stimulation pattern, leading to sustained amplification or suppression of the oscillation depending on the phase targeted. Beta amplification slows movement speed by biasing the animal’s mode of locomotion. Together, these findings show that highly responsive, phase-dependent stimulation can achieve a stable brain-machine interaction that leads to robust modulation of ongoing behavior.

Accelerating technological progress in experimental neuroscience is increasing the scale as well as specificity of both observational and perturbational approaches to study circuit physiology. While these techniques have also been used to study disease mechanisms, a wider adoption of these approaches in the field of experimental neurology would greatly facilitate our understanding of neurological dysfunctions and their potential treatments at cellular and circuit level. In this review, we will introduce classic and novel methods ranging from single-cell electrophysiological recordings to state-of-the-art calcium imaging and cell-type specific optogenetic or chemogenetic stimulation. We will focus on their application in rodent models of Parkinson's disease while also presenting their use in the context of motor control and basal ganglia function. By highlighting the scope and limitations of each method, we will discuss how they can be used to study pathophysiological mechanisms at local and global circuit levels and how novel frameworks can help to bridge these scales.

Significance Prevalence and temporal dynamics of transient oscillations in the beta frequency band (15 to 35 Hz), referred to as β bursts, are correlated with motor performance. Disturbance of these activities is a candidate mechanism for motor impairment in Parkinson’s disease (PD), where the excessively long bursts correlate with symptom severity and are reduced by pharmacological and surgical treatments. Here we describe the changes in action potential firing that take place across multiple nodes of the cortical and basal ganglia circuit as these transient oscillations evolve. These analyses provide fresh insights into the network dynamics of β bursts that can guide novel strategies to interfere with their generation and maintenance in PD., Beta frequency oscillations (15 to 35 Hz) in cortical and basal ganglia circuits become abnormally synchronized in Parkinson’s disease (PD). How excessive beta oscillations emerge in these circuits is unclear. We addressed this issue by defining the firing properties of basal ganglia neurons around the emergence of cortical beta bursts (β bursts), transient (50 to 350 ms) increases in the beta amplitude of cortical signals. In PD patients, the phase locking of background spiking activity in the subthalamic nucleus (STN) to frontal electroencephalograms preceded the onset and followed the temporal profile of cortical β bursts, with conditions of synchronization consistent within and across bursts. Neuronal ensemble recordings in multiple basal ganglia structures of parkinsonian rats revealed that these dynamics were recapitulated in STN, but also in external globus pallidus and striatum. The onset of consistent phase-locking conditions was preceded by abrupt phase slips between cortical and basal ganglia ensemble signals. Single-unit recordings demonstrated that ensemble-level properties of synchronization were not underlain by changes in firing rate but, rather, by the timing of action potentials in relation to cortical oscillation phase. Notably, the preferred angle of phase-locked action potential firing in each basal ganglia structure was shifted during burst initiation, then maintained stable phase relations during the burst. Subthalamic, pallidal, and striatal neurons engaged and disengaged with cortical β bursts to different extents and timings. The temporal evolution of cortical and basal ganglia synchronization is cell type-selective, which could be key for the generation/ maintenance of excessive beta oscillations in parkinsonism.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input., Highlights • STN-neurons are selectively entrained to cortical beta oscillations in PD patients. • Phase-locking of STN-neurons is linearly dependent on oscillation magnitude. • Beta bursts in LFP/EEG are accompanied by transient synchronisation of STN spiking. • STN neurons are selectively entrained to cortical beta stimulation in rats. • Beta-selectivity of STN neurons is present in control and dopamine-depleted rats.

Summary Retrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior., Graphical Abstract, Highlights • Neuronal and behavioral reinstatement of a memory trace are dissociable processes • Spatial appetitive memory requires direct dCA1 inputs to two types of NAc neurons • dCA1 exerts feedforward inhibition onto its postsynaptic NAc medium spiny neurons • dCA1 organizes assemblies of co-active medium spiny neurons during memory retrieval, Retrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Trouche et al. show in mice that the behavioral manifestation of spatial appetitive memory requires a direct neural pathway from dorsal hippocampus to nucleus accumbens. This pathway engages dCA1 with a select population of accumbens parvalbumin-expressing fast-spiking interneurons, thereby sculpting the assembly activity of its postsynaptic medium-sized spiny neurons. An indirect pathway through dorsal subiculum is dispensable for appetitive memory but contributes to spatial novelty detection.

Summary Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum., Graphical abstract, Highlights • The Tα1 promoter distinguishes two embryonic progenitor pools in the LGE • Both pools generate intermixed spiny projection neurons in dorsomedial striatum • Excitatory cortical inputs are biased toward SPNs of different embryonic origin • Neurogenic stage rather impacts local inhibitory connections among SPNs, van Heusden et al. demonstrate significant roles for distinct embryonic progenitor pools in the formation of postnatal striatal synaptic circuits. Diverse progenitor pools generate striatal spiny projection neurons with similar intrinsic properties and convey biases in their excitatory cortical synaptic inputs, whereas birthdate affects strength of local inhibitory synaptic inputs.

Parkinson's disease (PD) is a neurodegenerative condition in which aberrant oscillatory synchronization of neuronal activity at beta frequencies (15–35 Hz) across the cortico-basal ganglia-thalamocortical circuit is associated with debilitating motor symptoms, such as bradykinesia and rigidity. Mounting evidence suggests that the magnitude of beta synchrony in the parkinsonian state fluctuates over time, but the mechanisms by which thalamocortical circuitry regulates the dynamic properties of cortical beta in PD are poorly understood. Using the recently developed generic Dynamic Causal Modelling (DCM) framework, we recursively optimized a set of plausible models of the thalamocortical circuit (n = 144) to infer the neural mechanisms that best explain the transitions between low and high beta power states observed in recordings of field potentials made in the motor cortex of anesthetized Parkinsonian rats. Bayesian model comparison suggests that upregulation of cortical rhythmic activity in the beta-frequency band results from changes in the coupling strength both between and within the thalamus and motor cortex. Specifically, our model indicates that high levels of cortical beta synchrony are mainly achieved by a delayed (extrinsic) input from thalamic relay cells to deep pyramidal cells and a fast (intrinsic) input from middle pyramidal cells to superficial pyramidal cells. From a clinical perspective, our study provides insights into potential therapeutic strategies that could be utilized to modulate the network mechanisms responsible for the enhancement of cortical beta in PD. Specifically, we speculate that cortical stimulation aimed to reduce the enhanced excitatory inputs to either the superficial or deep pyramidal cells could be a potential non-invasive therapeutic strategy for PD.

Some motor impairments associated with Parkinson’s disease are thought to arise from pathological activity in the neuronal networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in these networks following dopamine depletion. We recorded local field potentials in the cortex and basal ganglia of anesthetized rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA), with dopamine-intact rats as controls. We performed systematic analyses of the networks using a novel tool for estimation of directed neural interactions, as well as a conditioned variant which permits the analysis of the dependence of a connection upon a third reference signal. We find evidence of the dopamine dependency of both low beta (14-20 Hz) and high beta/low gamma (20-40 Hz) directed interactions within the BG and cortico-BG networks. Notably, 6-OHDA lesions were associated with enhancement of the cortical “hyperdirect” connection to the subthalamic nucleus (STN), as well the STN’s feedback to the cortex and striatum. We find beta synchronization to be robust to conditioning using signals from any one structure. Conversely, we find that high beta/gamma drive from the cortex to subcortical regions is weakened by 6-OHDA lesions and is susceptible to conditioning. Furthermore, we provide evidence that gamma is routed from striatum in a pathway that is independent of STN. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in Parkinsonism.New & NoteworthyWe present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aims of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson’s disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a “short-circuiting” of the network that gives rise to the conditions from which pathological synchronization may arise.

Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits.

The functional organization of the basal ganglia (BG) is often defined according to one of two opposing schemes. The first proposes multiple, essentially independent channels of information processing. The second posits convergence and lateral integration of striatal channels at the level of the globus pallidus (GP). We tested the hypothesis that these proposed aspects of functional connectivity within the striatopallidal axis are dynamic and related to brain state. Local field potentials (LFPs) were simultaneously recorded from multiple sites in striatum and GP in anesthetized rats during slow-wave activity (SWA) and during global activation evoked by sensory stimulation. Functional connectivity was inferred from comparative analyses of the internuclear and intranuclear coherence between bipolar derivations of LFPs. During prominent SWA, as shown in the electrocorticogram and local field potentials in the basal ganglia, intranuclear coherence, and, thus, lateral functional connectivity within striatum or globus pallidus was relatively weak. Furthermore, the temporal coupling of LFPs recorded across these two nuclei involved functional convergence at the level of GP. Global activation, indicated by a loss of SWA, was accompanied by a rapid functional reorganization of the striatopallidal axis. Prominent lateral functional connectivity developed within GP and, to a significantly more constrained spatial extent, striatum. Additionally, functional convergence on GP was no longer apparent, despite increased internuclear coherence. These data demonstrate that functional connectivity within the BG is highly dynamic and suggest that the relative expression of organizational principles, such as parallel, independent processing channels, striatopallidal convergence, and lateral integration within BG nuclei, is dependent on brain state.

The striatum is comprised of medium-sized spiny projection neurons (MSNs) and several types of interneuron, and receives massive glutamatergic input from the cerebral cortex. Understanding of striatal function requires definition of the electrophysiological properties of neurochemically identified interneurons sampled in the same context of ongoing cortical activityin vivo. To address this, we recorded the firing of cholinergic interneurons (expressing choline acetyltransferase; ChAT) and GABAergic interneurons expressing parvalbumin (PV) or nitric oxide synthase (NOS), as well as MSNs, in anesthetized rats during cortically defined brain states. Depending on the cortical state, these interneurons were partly distinguished from each other, and MSNs, on the basis of firing rate and/or pattern. During slow-wave activity (SWA), ChAT+ interneurons, and some PV+ and NOS+ interneurons, were tonically active; NOS+ interneurons fired prominent bursts but, contrary to investigationsin vitro, these were not typical low-threshold spike bursts. Identified MSNs, and other PV+ and NOS+ interneurons, were phasically active. Contrasting with ChAT+ interneurons, whose firing showed poor brain state dependency, PV+ and NOS+ interneurons displayed robust firing increases and decreases, respectively, upon spontaneous or driven transitions from SWA to cortical activation. The firing of most neurons was phase locked to cortical slow oscillations, but only PV+ and ChAT+ interneurons also fired in time with cortical spindle and gamma oscillations. Complementing this diverse temporal coupling, each interneuron type exhibited distinct responses to cortical stimulation. Thus, these striatal interneuron types have distinct temporal signaturesin vivo, including relationships to spontaneous and driven cortical activities, which likely underpin their specialized contributions to striatal microcircuit function.

The basal ganglia play a critical role in controlling seizures in animal models of idiopathic non-convulsive (absence) epilepsy. Inappropriate output from the substantia nigra pars reticulata (SNr) is known to exacerbate seizures, but the precise neuronal mechanisms underlying abnormal activity in SNr remain unclear. To test the hypothesis that cortical spike-wave oscillations, often considered indicative of absence seizures, propagate to the subthalamic nucleus, an important afferent of SNr, we simultaneously recorded local field potentials from the frontal cortex and subthalamic nucleus of freely moving rats. Spontaneous spike-wave oscillations in cortex (mean dominant frequency of 7.4 Hz) were associated with similar oscillations in the subthalamic nucleus (mean of 7.9 Hz). The power of oscillations at 5-9 Hz was significantly higher during spike-wave activity as compared with rest periods without this activity. Importantly, spike-wave oscillations in cortex and subthalamic nucleus were significantly coherent across a range of frequencies (3-40 Hz), and the dominant (7-8 Hz) oscillatory activity in the subthalamic nucleus typically followed that in cortex with a small time lag (mean of 2.7 ms). In conclusion, these data suggest that ensembles of subthalamic nucleus neurons are rapidly recruited into oscillations during cortical spike-wave activity, thus adding further weight to the importance of the subthalamic nucleus in absence epilepsy. An increase in synchronous oscillatory input from the subthalamic nucleus could thus partly underlie the expression of pathological activity in SNr that could, in turn, aggravate seizures. Finally, these findings also reiterate the importance of oscillations in these circuits in normal behaviour.

Corticostriatal afferents can engage parvalbumin-expressing (PV+) interneurons to rapidly curtail the activity of striatal projection neurons (SPNs), thus shaping striatal output. Schemes of basal ganglia circuit dynamics generally consider striatal PV+ interneurons to be homogenous, despite considerable heterogeneity in both form and function. We demonstrate that the selective co-expression of another calcium-binding protein, secretagogin (Scgn), separates PV+ interneurons in rat and primate striatum into two topographically-, physiologically- and structurally-distinct cell populations. In rats, these two interneuron populations differed in their firing rates, patterns and relationships with cortical oscillations in vivo. Moreover, the axons of identified PV+/Scgn+ interneurons preferentially targeted the somata of SPNs of the so-called ‘direct pathway’, whereas PV+/Scgn- interneurons preferentially targeted ‘indirect pathway’ SPNs. These two populations of interneurons could therefore provide a substrate through which either of the striatal output pathways can be rapidly and selectively inhibited to subsequently mediate the expression of behavioral routines. DOI: http://dx.doi.org/10.7554/eLife.16088.001

The striatum is the key site for cortical input to the basal ganglia. Cortical input to striatal microcircuits has been previously studied only in the context of one or two types of neurons. Here, we provide the first description of four putative types of striatal neurons (medium spiny, fast spiking, tonically active, and low-threshold spiking) in a single data set by separating extracellular recordings of sorted single spikes recorded under halothane anesthesia using waveform and burst parameters. Under halothane, the electrocorticograms and striatal local field potential displayed spontaneous oscillations at both low (2–9 Hz) and high (35–80 Hz) frequencies. Putative fast spiking interneurons were significantly more likely to phase lock to high-frequency cortical oscillations and displayed significant cross-correlations in this frequency range. These findings suggest that, as in neocortex and hippocampus, the coordinated activity of fast spiking interneurons may specifically be involved in mediating oscillatory synchronization in the striatum.

The responses of single subthalamic nucleus (STN) neurons to cortical activation are complex and depend on the relative activation of several neuronal circuits, making theoretical extrapolation of single neuron responses to the population level difficult. To understand better the degree of synchrony imposed on STN neurons and associated neuronal networks by cortical activation, we recorded the responses of single units, pairs of neighboring neurons, and local field potentials (LFPs) in STN to discrete electrical stimulation of the cortex in anesthetized rats. Stimulation of ipsilateral frontal cortex, but not temporal cortex, generated synchronized “multiphasic” responses in neighboring units in rostral STN, usually consisting of a brief, short-latency excitation, a brief inhibition, a second excitation, and a long-duration inhibition. Evoked LFPs in STN consistently mirrored unit responses; brief, negative deflections in the LFP coincided with excitations and brief, positive deflections with inhibitions. This characteristic LFP was dissimilar to potentials evoked in cortex and structures surrounding STN and was resistant to fluctuations in forebrain activity. The short-latency excitation and associated LFP deflection exhibited the highest fidelity to low-intensity cortical stimuli. Unit response failures, which mostly occurred in caudal STN, were not associated with LFPs typical of rostral STN. These data suggest that local populations of STN neurons can be synchronized by both direct and indirect cortical inputs. Synchronized ensemble activity is dependent on topography and input intensity. Finally, the stereotypical, multiphasic profile of the evoked LFP indicates that it might be useful for locating the STN in clinical as well as nonclinical settings.

The nucleus accumbens receives limbic inputs from a number of brain regions, including the ventral subiculum. In rats, activation of the ventral subiculum following microinjection of N-methyl-D-aspartate (NMDA) or carbachol increases locomotor activity, whilst ventral subiculum application of NMDA also increases dopamine efflux in the ipsilateral nucleus accumbens. Microdialysis experiments were therefore conducted to ascertain the consequences for dopamine release in the nucleus accumbens following ventral subiculum administration of carbachol, and to explore the acetylcholine receptor subtype(s) that might be involved. We report that, in anaesthetised rats, ventral subiculum administration of carbachol increased dopamine levels in the nucleus accumbens. The response was attenuated by co-administration with atropine, whilst administration of nicotine and the alpha-7 nicotinic acetylcholine receptor agonist AR-R17779 (spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidine]-2'-one monohydrochloride) failed to evoke a response. Oxotremorine-M produced a dose-dependent increase in dopamine efflux confirming sensitivity to muscarinic receptor stimulation. However, the ventral subiculum was insensitive to xanomeline and pilocarpine, muscarinic M(1) receptor-preferring agonists, but sensitive to BuTAC ([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1])octane), a muscarinic M(2)/M(4) receptor agonist. The dopamine response to oxotremorine-M was significantly attenuated, although not abolished by co-administration with the M(2)/M(4) receptor antagonist methoctramine, and studies combining oxotremorine-M with (-)-bicuculline, indicated a dual action in the ventral subiculum that was dependent and independent of reduced GABA neurotransmission. The data presented indicates that activation of the ventral subiculum by carbachol increases dopamine efflux in the nucleus accumbens by stimulation of muscarinic receptors, and that the ventral subiculum-nucleus accumbens projection system is sensitive to muscarinic M(2)/M(4) receptor stimulation.

Hitherto, high-frequency local field potential oscillations in the upper gamma frequency band (40-80 Hz) have been recorded only from the region of subthalamic nucleus (STN) in parkinsonian patients treated with levodopa. Here we show that local field potentials recorded from the STN in the healthy alert rat also have a spectral peak in the upper gamma band (mean 53 Hz, range 46-70 Hz). The power of this high-frequency oscillatory activity was increased by 30 +/- 4% (+/-SEM) during motor activity compared to periods of alert immobility. It was also increased by 86 +/- 36% by systemic injection of the D2 dopamine receptor agonist quinpirole. The similarities between the high-frequency activities in the STN of the healthy rat and in the levodopa-treated parkinsonian human argue that this oscillatory activity may be physiological in nature and not a consequence of the parkinsonian state.

The corticostriatal axis is the main input stage of the basal ganglia and is crucial for their role in motor behavior. Synchronized oscillations might mediate interactions between cortex and striatum during behavior, yet direct evidence remains sparse. Here, we show that, during motor behavior, low- and high-frequency oscillations jointly couple cortex and striatum via cross-frequency interactions. We investigated neuronal oscillations along the corticostriatal axis in rats during rest and treadmill running. We found prominent theta and gamma oscillations in cortex and striatum, the peak frequencies of which scaled with motor demand. Theta and gamma oscillations were functionally coupled through phase-amplitude coupling. Furthermore, theta oscillations were phase coupled between structures. Together, local phase-amplitude coupling and corticostriatal theta phase coupling mediated the temporal correlation of gamma bursts between the cortex and striatum. The coordination of fast oscillations through coherent phase-amplitude coupling may be a general mechanism to regulate neuronal interactions along the corticostriatal axis and beyond.

High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson’s disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.

Cholinergic interneurons are key components of striatal microcircuits. In primates, tonically active neurons (putative cholinergic interneurons) exhibit multiphasic responses to motivationally salient stimuli that mirror those of midbrain dopamine neurons and together these two systems mediate reward-related learning in basal ganglia circuits. Here, we addressed the potential contribution of cortical and thalamic excitatory inputs to the characteristic multiphasic responses of cholinergic interneuronsin vivo. We first recorded and labeled individual cholinergic interneurons in anesthetized rats. Electron microscopic analyses of these labeled neurons demonstrated that an individual interneuron could form synapses with cortical and, more commonly, thalamic afferents. Single-pulse electrical stimulation of ipsilateral frontal cortex led to robust short-latency (

Neurons of the motor thalamus mediate basal ganglia and cerebellar influences on cortical activity. To elucidate the net result of γ-aminobutyric acid-releasing or glutamatergic bombardment of the motor thalamus by basal ganglia or cerebellar afferents, respectively, we recorded the spontaneous activities of thalamocortical neurons in distinct identified “input zones” in anesthetized rats during defined cortical activity states. Unexpectedly, the mean rates and brain state dependencies of the firing of neurons in basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) were matched during slow-wave activity (SWA) and cortical activation. However, neurons were distinguished during SWA by their firing regularities, low-threshold spike bursts and, more strikingly, by the temporal coupling of their activities to ongoing cortical oscillations. The firing of neurons across the BZ was stronger and more precisely phase-locked to cortical slow (∼1 Hz) oscillations, although both neuron groups preferentially fired at the same phase. In contrast, neurons in BZ and CZ fired at different phases of cortical spindles (7–12 Hz), but with similar strengths of coupled firing. Thus, firing rates do not reflect the predicted inhibitory–excitatory imbalance across the motor thalamus, and input zone-specific temporal coding through oscillatory synchronization with the cortex could partly mediate the different roles of basal ganglia and cerebellum in behavior.

The striatum integrates sensory information to enable action selection and behavioural reinforcement. In the rat, a large topographical projection from the rat barrel cortex to widely distributed areas of the striatum is assumed to be an important structural component supporting these processes. The striatal sensory response is, however, not comprehensively understood at a network level. We used a 10-Hz, 100-ms air puff, allowing undamped movement of multiple whiskers, to look at functional connectivity in contralateral cortex and striatum in response to sensory stimulation. Simultaneous recordings of cortical and striatal local field potentials (LFPs) were made under isoflurane anaesthesia in 15 male Brown Norway rats. Four electrodes were placed in the barrel cortex while the dorsolateral striatum was mapped with a 500-μm resolution, resulting in a maximum of 315 recording positions per animal. Significant event-related responses were unevenly distributed throughout the striatum in 34.8% of positions recorded within this area. Only 10.3% of recorded positions displayed significant total power increases in the LFPs during the stimulation period at the stimulus frequency. This suggests that the responses seen in the LFPs are due to phase rearrangement rather than an amplitude increase in the signal. Analysis of corticostriatal imaginary coherence revealed stimulus-induced changes in the functional connectivity of 12% of corticostriatal pairs, the sensory response of sparsely distributed neuronal ensembles within the dorsolateral striatum is reflected in the phase relationship between the cortical and striatal local fields.

In the subthalamic nucleus (STN) of Parkinson's disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15–30 Hz) accompanies movement difficulties. Abnormal beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D1/D2receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise.

Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of untreated patients implanted with stimulation electrodes for the treatment of Parkinson's disease (PD) demonstrate strong coherence with the cortical electroencephalogram over the beta-frequency range (15-30 Hz). However, studies in animal models of PD emphasize increased temporal coupling in cortico-basal ganglia circuits at substantially lower frequencies, undermining the potential usefulness of these models. Here we show that 6-hydroxydopamine (6-OHDA) lesions of midbrain dopamine neurons are associated with significant increases in the power and coherence of beta-frequency oscillatory activity present in LFPs recorded from frontal cortex and STN of awake rats, as compared with the healthy animal. Thus, the pattern of synchronization between population activity in the STN and cortex in the 6-OHDA-lesioned rodent model of PD closely parallels that seen in the parkinsonian human. The peak frequency of coherent activity in the beta-frequency range was increased in lesioned animals during periods of spontaneous and sustained movement. Furthermore, administration of the dopamine receptor agonist apomorphine to lesioned animals suppressed beta-frequency oscillations, and increased coherent activity at higher frequencies in the cortex and STN, before producing the rotational behaviour indicative of successful lesion. Taken together, these results support a crucial role for dopamine in the modulation of population activity in cortico-basal ganglia circuits, whereby dopaminergic mechanisms effectively filter out synchronized, rhythmic activity at beta-frequencies at the systems level, and shift temporal couplings in these circuits to higher frequencies. These changes may be important in regulating movement.

Population activity in cortico-basal ganglia circuits is synchronized at different frequencies according to brain state. However, the structures that are likely to drive the synchronization of activity in these circuits remain unclear. Furthermore, it is not known whether the direction of transmission of activity is fixed or dependent on brain state. We have used the directed transfer function (DTF) to investigate the direction in which coherent activity is effectively driven in cortico-basal ganglia circuits. Local field potentials (LFPs) were simultaneously recorded in the subthalamic nucleus (STN), globus pallidus (GP) and substantia nigra pars reticulata (SNr), together with the ipsilateral frontal electrocorticogram (ECoG) of anaesthetized rats. Directional analysis was performed on recordings made during robust cortical slow-wave activity (SWA) and "global activation". During SWA, there was coherence at approximately 1 Hz between ECoG and basal ganglia LFPs, with much of the coherent activity directed from cortex to basal ganglia. There were similar coherent activities at approximately 1 Hz within the basal ganglia, with more activity directed from SNr to GP and STN, and from STN to GP rather than vice versa. During global activation, peaks in coherent activity were seen at higher frequencies (15-60 Hz), with most coherence also directed from cortex to basal ganglia. Within the basal ganglia, however, coherence was predominantly directed from GP to STN and SNr. Together, these results highlight a lead role for the cortex in activity relationships with the basal ganglia, and further suggest that the effective direction of coupling between basal ganglia nuclei is dynamically organized according to brain state, with activity relationships involving the GP displaying the greatest capacity to change.

The nature of the coupling between neuronal assemblies in the cerebral cortex and basal ganglia (BG) is poorly understood. We tested the hypothesis that coherent population activity is dependent on brain state, frequency range, and/or BG nucleus using data from simultaneous recordings of electrocorticogram (ECoG) and BG local field potentials (LFPs) in anesthetized rats. The coherence between ECoG and LFPs simultaneously recorded from subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNr) was largely confined to slow- (∼1 Hz) and spindle- (7–12 Hz) frequency oscillations during slow-wave activity (SWA). In contrast, during cortical activation, coherence was mostly restricted to high-frequency oscillations (15–60 Hz). The coherence between ECoG and LFPs also depended on BG recording site. Partial coherence analyses showed that, during SWA, STN and SNr shared the same temporal coupling with cortex, thereby forming a single functional axis. Cortex was also tightly, but independently, correlated with GP in a separate functional axis. During activation, STN, GP, and, to a lesser extent, SNr shared the same coherence with cortex as part of one functional axis. In addition, GP formed a second, independently coherent loop with cortex. These data suggest that coherent oscillatory activity is present at the level of LFPs recorded in cortico-basal ganglia circuits, and that synchronized population activity is dynamically organized according to brain state, frequency, and nucleus. These attributes further suggest that synchronized activity should be considered as one of a number of candidate mechanisms underlying the functional organization of these brain circuits.