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  • The basal ganglia (BG) are a group of interconnected nuclei which play a pivotal part in limbic, associative, and motor functions. This role is mirrored by the wide range of motor and behavioral abnormalities directly resulting from dysfunction of the BG. Studies of normal behavior have found that BG neurons tend to phasically modulate their activity in relation to different behavioral events. In the normal BG, this modulation is highly specific, with each neuron related only to a small subset of behavioral events depending on specific combinations of movement parameters and context. In many pathological conditions involving BG dysfunction and motor abnormalities, this neuronal specificity is lost. Loss of specificity (LOS) manifests in neuronal activity related to a larger spectrum of events and consequently a large overlap of movement-related activation patterns between different neurons. We review the existing evidence for LOS in BG-related movement disorders, the possible neural mechanisms underlying LOS, its effects on frequently used measures of neuronal activity and its relation to theoretical models of the BG. The prevalence of LOS in a many BG-related disorders suggests that neuronal specificity may represent a key feature of normal information processing in the BG system. Thus, the concept of neuronal specificity may underlie a unifying conceptual framework for the BG role in normal and abnormal motor control.
    Basal gangliaLoss of specificityRelativesNormalityNeuronal specificityEventsNeuronAbnormalitiesModulationMovement disorder...
  • Once the flavor of the ingested food (conditioned stimulus, CS) is associated with a preferable (e.g., good taste or nutritive satisfaction) or aversive (e.g., malaise with displeasure) signal (unconditioned stimulus, US), animals react to its subsequent exposure by increasing or decreasing ingestion to the food. These two types of association learning (preference learning vs. aversion learning) are known as classical conditioned reactions which are basic learning and memory phenomena, leading selection of food and proper food intake. Since the perception of flavor is generated by interaction of taste and odor during food intake, taste and/or odor are mainly associated with bodily signals in the flavor learning. After briefly reviewing flavor learning in general, brain mechanisms of conditioned taste aversion is described in more detail. The CS–US association leading to long-term potentiation in the amygdala, especially in its basolateral nucleus, is the basis of establishment of conditioned taste aversion. The novelty of the CS detected by the cortical gustatory area may be supportive in CS–US association. After the association, CS input is conveyed through the amygdala to different brain regions including the hippocampus for contextual fear formation, to the supramammillary and thalamic paraventricular nuclei for stressful anxiety or memory dependent fearful or stressful emotion, to the reward system to induce aversive expression to the CS, or hedonic shift from positive to negative, and to the CS-responsive neurons in the gustatory system to enhance the responsiveness to facilitate to detect the harmful stimulus.
    Conditional stimulusAssociatorFlavor learningU.SFoodTasteBrain mechanismsIngestionAversivenessFlavor...
  • Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABA A receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons.
    Subthalamic nucleusExcitatory postsynaptic currentDopamine depletionBurstPallidal neuronsBasal ganglia sliceGeneratorBasal gangliaHigh-frequencyPolysynaptic...
  • Electrophysiological studies in patients and animal models of Parkinson's disease (PD) often reported increased burst activity of neurons in the basal ganglia. Neurons in the globus pallidus external (GPe) segment in 6-hydroxydopamine (6-OHDA)-treated hemi-parkinsonian rats fire with strong bursts interrupted by pauses. The goal of this study was to evaluate the hypothesis that dopamine (DA)-depletion increases burst firings of striatal (Str) neurons projecting to the GPe and that the increased Str–GPe burst inputs play a significant role in the generation of pauses and bursts in GPe and its projection sites. To evaluate this hypothesis, the unitary activity of Str and GPe was recorded from control and 6-OHDA-treated rats anesthetized with 0.5–1% isoflurane. The occurrence of pauses and bursts in the firings of GPe neurons was significantly higher in 6-OHDA than in normal rats. Muscimol injection into the Str of 6-OHDA rats increased average firing rate and greatly reduced the pauses and bursts in GPe. Recordings from Str revealed that most of the presumed projection neurons in control rats have very low spontaneous activity, and even the occasional neurons that did exhibit spontaneous burst firings did so with an average rate of less than 2 Hz. In DA-depleted Str, neurons having stronger bursts and a higher average firing rate were encountered more frequently. Juxtacellular labeling revealed that most of these neurons were medium spiny neurons projecting only to GPe. Injection of a behaviorally effective dose of methyl-l-DOPA into the Str of 6-OHDA rats significantly increased the average firing rate and decreased the number of pauses of GPe neurons. These data validate the hypothesis that DA-depletion increases burst firings of Str neurons projecting to the GPe and that the increased Str–GPe burst inputs play a significant role in the generation of pauses and bursts in GPe. These results suggest that treatment to reduce burst Str–GPe inhibitory inputs may help to restore some PD disabilities.
    Globus pallidus externusNeuronBurstRatFiringInjectionSpikeL DOPAFiring rateProjection neuron...
  • We have recently shown in vitro that striatal tyrosine hydroxylase-expressing interneurons identified in transgenic mice by expression of enhanced green fluorescent protein (TH-eGFP) display electrophysiological profiles that are distinct from those of other striatal interneurons. Furthermore, striatal TH-eGFP interneurons show marked diversity in their electrophysiological properties and have been divided into four distinct subtypes. One question that arises from these observations is whether striatal TH-eGFP interneurons are distributed randomly, or obey some sort of organizational plan as has been shown to be the case with other striatal interneurons. An understanding of the striatal TH-eGFP interneuronal patterning is a vital step in understanding the role of these neurons in striatal functioning. Therefore, in the present set of studies the location of electrophysiologically identified striatal TH-eGFP interneurons was mapped. In addition, the distribution of TH-eGFP interneurons with respect to the striatal striosome–matrix compartmental organization was determined using μ-opioid receptor (MOR) immunofluorescence or intrinsic TH-eGFP fluorescence to delineate striosome and matrix compartments. Overall, the distribution of the different TH-eGFP interneuronal subtypes did not differ in dorsal versus ventral striatum. However, striatal TH-eGFP interneurons were found to be mostly in the matrix in the dorsal striatum whereas a significantly higher proportion of these neurons was located in MOR-enriched domains of the ventral striatum. Further, the majority of striatal TH-eGFP interneurons was found to be located within 100 μm of a striosome–matrix boundary. Taken together, the current results suggest that TH-eGFP interneurons obey different organizational principles in dorsal versus ventral striatum, and may play a role in communication between striatal striosome and matrix compartments.
    NeuronStriatalInterneuronVentral striatumStriosomeStriatumMatrixTyrosine HydroxylaseDorsal StriatumOrganism...
  • Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4-dihidroxifenilalanine ( l -DOPA)-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of l -DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-l -Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated AIMs induced by chronic and acute l -DOPA. In contrast, rotational behavior was attenuated only after chronic l -DOPA. The 6-OHDA lesion and the l -DOPA treatment induced a bilateral increase (1.5 times) in the neuronal nitric oxide synthase (nNOS) protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/ΔFosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic l -DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under l -DOPA acute and chronic treatment. The l -DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that l -DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the l -DOPA structural modifications in the Parkinsonian brain. Taken together, these data provided a rationale for further evaluation of NOS inhibitors in the treatment of l -DOPA-induced dyskinesia.
    L DOPATreatmentRatStriatumNitric oxide synthaseProteinLesionAnimalInhibitorDyskinesia...
  • Robust self-sustained oscillations are a ubiquitous characteristic of circadian rhythms. These include Drosophila locomotor activity rhythms, which persist for weeks in constant darkness (DD). Yet the molecular oscillations that underlie circadian rhythms damp rapidly in many Drosophila tissues. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms that underlie the differences between damped and self-sustaining oscillations remain largely unknown. A small cluster of neurons in adult Drosophila brain, the ventral lateral neurons (LN v s), is essential for self-sustained behavioral rhythms and has been proposed to be the primary pacemaker for locomotor activity rhythms. With an LN v -specific driver, we restricted functional clocks to these neurons and showed that they are not sufficient to drive circadian locomotor activity rhythms. Also contrary to expectation, we found that all brain clock neurons manifest robust circadian oscillations of timeless and cryptochrome RNA for many days in DD. This persistent molecular rhythm requires pigment-dispersing factor (PDF), an LN v -specific neuropeptide, because the molecular oscillations are gradually lost when Pdf 01 mutant flies are exposed to free-running conditions. This observation precisely parallels the previously reported effect on behavioral rhythms of the Pdf 01 mutant. PDF is likely to affect some clock neurons directly, since the peptide appears to bind to the surface of many clock neurons, including the LN v s themselves. We showed that the brain circadian clock in Drosophila is clearly distinguishable from the eyes and other rapidly damping peripheral tissues, as it sustains robust molecular oscillations in DD. At the same time, different clock neurons are likely to work cooperatively within the brain, because the LN v s alone are insufficient to support the circadian program. Based on the damping results with Pdf 01 mutant flies, we propose that LN v s, and specifically the PDF neuropeptide that it synthesizes, are important in coordinating a circadian cellular network within the brain. The cooperative function of this network appears to be necessary for maintaining robust molecular oscillations in DD and is the basis of sustained circadian locomotor activity rhythms.
    OscillationClock neuronBrainBehaviorNeuronDrosophilaPeptideConditioningLocomotor activityMutant...
  • Dystonia is a neurological disorder characterized by sustained or repetitive involuntary muscle contractions and abnormal postures. In the present article, we will introduce our recent electrophysiological studies in hyperkinetic transgenic mice generated as a model of DYT1 dystonia and in a human cervical dystonia patient, and discuss the pathophysiology of dystonia on the basis of these electrophysiological findings. Recording of neuronal activity in the awake state of DYT1 dystonia model mice revealed reduced spontaneous activity with bursts and pauses in both internal (GPi) and external (GPe) segments of the globus pallidus. Electrical stimulation of the primary motor cortex evoked responses composed of excitation and subsequent long-lasting inhibition, the latter of which was never observed in normal mice. In addition, somatotopic arrangements were disorganized in the GPi and GPe of dystonia model mice. In a human cervical dystonia patient, electrical stimulation of the primary motor cortex evoked similar long-lasting inhibition in the GPi and GPe. Thus, reduced GPi output may cause increased thalamic and cortical activity, resulting in the involuntary movements observed in dystonia.
    Globus pallidus internusDystoniaGlobus pallidus externusPatientNeuronGPe neuronHumanPathwayBurstNeuronal activity...
  • Taste is the final arbiter of which chemicals from the environment will be admitted to the body. The action of swallowing a substance leads to a physiological consequence of which the taste system should be informed. Accordingly, taste neurons in the central nervous system are closely allied with those that receive input from the viscera so as to monitor the impact of a recently ingested substance. There is behavioral, anatomical, electrophysiological, gene expression, and neurochemical evidence that the consequences of ingestion influence subsequent food selection through development of either a conditioned taste aversion (CTA) (if illness ensues) or a conditioned taste preference (CTP) (if nutrition). This ongoing communication between taste and the viscera permits the animal to tailor its taste system to its individual needs over a lifetime.
    TasteConditioningLearningRatLesionBehaviorAmygdalaAnimalNeuronChemical...
  • Movement disorders in Parkinson’s disease (PD) are commonly associated with slow oscillations and increased synchrony of neuronal activity in the basal ganglia. The neural mechanisms underlying this dynamic network dysfunction, however, are only poorly understood. Here, we show that the strength of inhibitory inputs from striatum to globus pallidus external (GPe) is a key parameter controlling oscillations in the basal ganglia. Specifically, the increase in striatal activity observed in PD is sufficient to unleash the oscillations in the basal ganglia. This finding allows us to propose a unified explanation for different phenomena: absence of oscillation in the healthy state of the basal ganglia, oscillations in dopamine-depleted state and quenching of oscillations under deep-brain-stimulation (DBS). These novel insights help us to better understand and optimize the function of DBS protocols. Furthermore, studying the model behavior under transient increase of activity of the striatal neurons projecting to the indirect pathway, we are able to account for both motor impairment in PD patients and for reduced response inhibition in DBS implanted patients.
    OscillationNeuronSTN neuronFiring rateBasal gangliaPopulationStriatumStriatalA/JProtocol...
  • The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABA A and glycine receptors in regulating synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc). Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 μM), inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 μM) and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate) only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate) decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially subregion-specific manner.
    BaselineGlycineDopamineReceptorStriatumConcentrationEnhancerGABA A receptorDrugSlice...
  • The organization of representations in the brain has been observed to locally reflect subspaces of inputs that are relevant to behavioral or perceptual feature combinations, such as in areas receptive to lower and higher-order features in the visual system. The early olfactory system developed highly plastic mechanisms and convergent evidence indicates that projections from primary neurons converge onto the glomerular level of the olfactory bulb (OB) to form a code composed of continuous spatial zones that are differentially active for particular physico-chemical feature combinations, some of which are known to trigger behavioral responses. In a model study of the early human olfactory system, we derive a glomerular organization based on a set of real-world, biologically relevant stimuli, a distribution of receptors that respond each to a set of odorants of similar ranges of molecular properties, and a mechanism of axon guidance based on activity. Apart from demonstrating activity-dependent glomeruli formation and reproducing the relationship of glomerular recruitment with concentration, it is shown that glomerular responses reflect similarities of human odor category perceptions and that further, a spatial code provides a better correlation than a distributed population code. These results are consistent with evidence of functional compartmentalization in the OB and could suggest a function for the bulb in encoding of perceptual dimensions.
    OdorPopulationAxonConcentrationBehaviorOrganismHumanReceptorPerceptionLigand...
  • The subthalamic nucleus (STN) has been considered a motor structure for a long time. Over the last 20 years, anatomical and behavioral data have highlighted the position of the STN within a prefrontal-associative and a limbic loops, suggesting that the STN should play a critical role in frontal functions such as attention, inhibitory control (including impulsive action, compulsivity, impulsive choice), and motivation. Here we will review the work highlighting these functions of the STN.
    STN HFSLesionRewardFoodRatAttentionAnimalConditioningCortexBehavior...
  • In sensory processing of odors, the olfactory bulb is an important relay station, where odor representations are noise-filtered, sharpened, and possibly re-organized. An organization by perceptual qualities has been found previously in the piriform cortex, however several recent studies indicate that the olfactory bulb code reflects behaviorally relevant dimensions spatially as well as at the population level. We apply a statistical analysis on 2-deoxyglucose images, taken over the entire bulb of glomerular layer of the rat, in order to see how the recognition of odors in the nose is translated into a map of odor quality in the brain. We first confirm previous studies that the first principal component could be related to pleasantness, however the next higher principal components are not directly clear. We then find mostly continuous spatial representations for perceptual categories. We compare the space spanned by spatial and population codes to human reports of perceptual similarity between odors and our results suggest that perceptual categories could be already embedded in glomerular activations and that spatial representations give a better match than population codes. This suggests that human and rat perceptual dimensions of odorant coding are related and indicates that perceptual qualities could be represented as continuous spatial codes of the olfactory bulb glomerulus population.
    OdorPopulationRatImagingOrganismAlcoholGlomerular layerBehaviorFitnessGlomerulus...
  • Controversy remains about how orientation selectivity emerges in simple cells of the mammalian primary visual cortex. In this paper, we present a computational model of how the orientation-biased responses of cells in lateral geniculate nucleus (LGN) can contribute to the orientation selectivity in simple cells in cats. We propose that simple cells are excited by lateral geniculate fields with an orientation-bias and disynaptically inhibited by unoriented lateral geniculate fields (or biased fields pooled across orientations), both at approximately the same retinotopic co-ordinates. This interaction, combined with recurrent cortical excitation and inhibition, helps to create the sharp orientation tuning seen in simple cell responses. Along with describing orientation selectivity, the model also accounts for the spatial frequency and length–response functions in simple cells, in normal conditions as well as under the influence of the GABA A antagonist, bicuculline. In addition, the model captures the response properties of LGN and simple cells to simultaneous visual stimulation and electrical stimulation of the LGN. We show that the sharp selectivity for stimulus orientation seen in primary visual cortical cells can be achieved without the excitatory convergence of the LGN input cells with receptive fields along a line in visual space, which has been a core assumption in classical models of visual cortex. We have also simulated how the full range of orientations seen in the cortex can emerge from the activity among broadly tuned channels tuned to a limited number of optimum orientations, just as in the classical case of coding for color in trichromatic primates.
    OrientationElectrical stimulationCortexOrientation selectivityGabor patchCortical cellSpatial frequencyVisual stimulationCell typeComputational model...
  • In this paper, we pursue recent observations that, through selective dendritic filtering, single neurons respond to specific sequences of presynaptic inputs. We try to provide a principled and mechanistic account of this selectivity by applying a recent free-energy principle to a dendrite that is immersed in its neuropil or environment. We assume that neurons self-organize to minimize a variational free-energy bound on the self-information or surprise of presynaptic inputs that are sampled. We model this as a selective pruning of dendritic spines that are expressed on a dendritic branch. This pruning occurs when postsynaptic gain falls below a threshold. Crucially, postsynaptic gain is itself optimized with respect to free energy. Pruning suppresses free energy as the dendrite selects presynaptic signals that conform to its expectations, specified by a generative model implicit in its intracellular kinetics. Not only does this provide a principled account of how neurons organize and selectively sample the myriad of potential presynaptic inputs they are exposed to, but it also connects the optimization of elemental neuronal (dendritic) processing to generic (surprise or evidence-based) schemes in statistics and machine learning, such as Bayesian model selection and automatic relevance determination.
    DendriteSequencingNeuronSegmentationSynapseSynaptic inputSynaptic connectionSingle neuronConditioningAxon...
  • It is considered that memory consolidation is a progressive process that requires post-trial stabilization of the information. In this regard, it has been speculated that waves of receptors activation, expression of immediate early genes, and replenishment of receptor subunit pools occur to induce functional or morphological changes to maintain the information for longer periods. In this paper, we will review data related to neuronal changes in the post-acquisition stage of taste aversion learning that could be involved in further stabilization of the memory trace. In order to achieve such stabilization, evidence suggests that the functional integrity of the insular cortex (IC) and the amygdala (AMY) is required. Particularly the increase of extracellular levels of glutamate and activation of N -methyl-d -aspartate (NMDA) receptors within the IC shows a main role in the consolidation process. Additionally the modulatory actions of the dopaminergic system in the IC appear to be involved in the mechanisms that lead to taste aversion memory consolidation through the activation of pathways related to enhancement of protein synthesis such as the Protein Kinase A pathway. In summary, we suggest that post-acquisition molecular and neuronal changes underlying memory consolidation are dependent on the interactions between the AMY and the IC.
    TasteTrainingAmygdalaConditioningDopamineNeuronLearningGlutamateInjectionEnhancer...
  • Taste is a primary reinforcer. Olfactory–taste and visual–taste association learning takes place in the primate including human orbitofrontal cortex to build representations of flavor. Rapid reversal of this learning can occur using a rule-based learning system that can be reset when an expected taste or flavor reward is not obtained, that is by negative reward prediction error, to which a population of neurons in the orbitofrontal cortex responds. The representation in the orbitofrontal cortex but not the primary taste or olfactory cortex is of the reward value of the visual/olfactory/taste input as shown by devaluation experiments in which food is fed to satiety, and by correlations of the activations with subjective pleasantness ratings in humans. Sensory-specific satiety for taste, olfactory, visual, and oral somatosensory inputs produced by feeding a particular food to satiety is implemented it is proposed by medium-term synaptic adaptation in the orbitofrontal cortex. Cognitive factors, including word-level descriptions, modulate the representation of the reward value of food in the orbitofrontal cortex, and this effect is learned it is proposed by associative modification of top-down synapses onto neurons activated by bottom-up taste and olfactory inputs when both are active in the orbitofrontal cortex. A similar associative synaptic learning process is proposed to be part of the mechanism for the top-down attentional control to the reward value vs. the sensory properties such as intensity of taste and olfactory inputs in the orbitofrontal cortex, as part of a biased activation theory of selective attention.
    TasteNeuronRewardOrbitofrontal cortexFoodOdorLearningCortexHumanAssociative learning...
  • Local field potentials (LFPs) capture the electrical activity produced by principal cells during integration of converging synaptic inputs from multiple neuronal populations. However, since synaptic currents mix in the extracellular volume, LFPs have complex spatiotemporal structure, making them hard to exploit. Here we propose a biophysical framework to identify and separate LFP-generators. First we use a computational multineuronal model that scales up single cell electrogenesis driven by several synaptic inputs to realistic aggregate LFPs. This approach relies on the fixed but distinct locations of synaptic inputs from different presynaptic populations targeting a laminated brain structure. Thus the LFPs are contributed by several pathway-specific LFP-generators, whose electrical activity is defined by the spatial distribution of synaptic terminals and the time course of synaptic currents initiated in target cells by the corresponding presynaptic population. Then we explore the efficacy of independent component analysis to blindly separate converging sources and reconstruct pathway-specific LFP-generators. This approach can optimally locate synaptic inputs with subcellular accuracy while the reconstructed time course of pathway-specific LFP-generators is reliable in the millisecond scale. We also describe few cases where the non-linear intracellular interaction of strongly overlapping LFP-generators may lead to a significant cross-contamination and the appearance of derivative generators. We show that the approach reliably disentangle ongoing LFPs in the hippocampus into contribution of several LFP-generators. We were able to readout in parallel the pathway-specific presynaptic activity of projection cells in the entorhinal cortex and pyramidal cells in the ipsilateral and contralateral CA3. Thus we provide formal mathematical and experimental support for parallel readout of the activity of converging presynaptic populations in working neuronal circuits from common LFPs.
    NeuronSpatial distributionTime courseSynaptic inputPopulationSynaptic currentDendritePathwayScaleAxon...
  • Although metaphorical and conceptual connections between the human brain and the financial markets have often been drawn, rigorous physical or mathematical underpinnings of this analogy remain largely unexplored. Here, we apply a statistical and graph theoretic approach to the study of two datasets – the time series of 90 stocks from the New York stock exchange over a 3-year period, and the fMRI-derived time series acquired from 90 brain regions over the course of a 10-min-long functional MRI scan of resting brain function in healthy volunteers. Despite the many obvious substantive differences between these two datasets, graphical analysis demonstrated striking commonalities in terms of global network topological properties. Both the human brain and the market networks were non-random, small-world, modular, hierarchical systems with fat-tailed degree distributions indicating the presence of highly connected hubs. These properties could not be trivially explained by the univariate time series statistics of stock price returns. This degree of topological isomorphism suggests that brains and markets can be regarded broadly as members of the same family of networks. The two systems, however, were not topologically identical. The financial market was more efficient and more modular – more highly optimized for information processing – than the brain networks; but also less robust to systemic disintegration as a result of hub deletion. We conclude that the conceptual connections between brains and markets are not merely metaphorical; rather these two information processing systems can be rigorously compared in the same mathematical language and turn out often to share important topological properties in common to some degree. There will be interesting scientific arbitrage opportunities in further work at the graph-theoretically mediated interface between systems neuroscience and the statistical physics of financial markets.
    A/JGraphTime seriesBrain functional networkBrain networkBrainHuman brainDegree distributionMatrixImaging...
  • We present a behavioral paradigm for the study of duration perception in the rat, and report the result of neurotoxic lesions that have the goal of identifying sites that mediate duration perception. Using a two-alternative forced-choice paradigm, rats were either trained to discriminate durations of pure tones (range = [200,500] ms; boundary = 316 ms; Weber fraction after training = 0.24 ± 0.04), or were trained to discriminate frequencies of pure tones (range = [8,16] kHz; boundary = 11.3 kHz; Weber = 0.16 ± 0.11); the latter task is a control for non-timing-specific aspects of the former. Both groups discriminate the same class of sensory stimuli, use the same motions to indicate decisions, have identical trial structures, and are trained to psychophysical threshold; the tasks are thus matched in a number of sensorimotor and cognitive demands. We made neurotoxic lesions of candidate timing-perception areas in the cerebral cortex of both groups. Following extensive bilateral lesions of the auditory cortex, the performance of the frequency discrimination group was significantly more impaired than that of the duration discrimination group. We also found that extensive bilateral lesions of the medial prefrontal cortex resulted in little to no impairment of both groups. The behavioral framework presented here provides an audition-based approach to study the neural mechanisms of time estimation and memory for durations.
    AnimalLesionDurationRatTrainingBehaviorInjectionFitnessCortexAcid...
  • Brain activity differs in the various sleep stages and in conscious wakefulness. Awakening from sleep requires restoration of the complex nerve impulse patterns in neuronal network assemblies necessary to re-create and sustain conscious wakefulness. Herein I propose that the brain uses rapid eye movement (REM) to help wake itself up after it has had a sufficient amount of sleep. Evidence suggesting this hypothesis includes the facts that, (1) when first going to sleep, the brain plunges into Stage N3 (formerly called Stage IV), a deep abyss of sleep, and, as the night progresses, the sleep is punctuated by episodes of REM that become longer and more frequent toward morning, (2) conscious-like dreams are a reliable component of the REM state in which the dreamer is an active mental observer or agent in the dream, (3) the last awakening during a night's sleep usually occurs in a REM episode during or at the end of a dream, (4) both REM and awake consciousness seem to arise out of a similar brainstem ascending arousal system (5) N3 is a functionally perturbed state that eventually must be corrected so that embodied brain can direct adaptive behavior, and (6) cortico-fugal projections to brainstem arousal areas provide a way to trigger increased cortical activity in REM to progressively raise the sleeping brain to the threshold required for wakefulness. This paper shows how the hypothesis conforms to common experience and has substantial predictive and explanatory power regarding the phenomenology of sleep in terms of ontogeny, aging, phylogeny, abnormal/disease states, cognition, and behavioral physiology. That broad range of consistency is not matched by competing theories, which are summarized herein. Specific ways to test this wake-up hypothesis are suggested. Such research could lead to a better understanding of awake consciousness.
    RemSleepBrainNeuronNeocortexBrainstemArousalREM sleepAnimalEye movement...
  • In this study we report that larval zebrafish display adaptive locomotor output that can be driven by unexpected visual feedback. We develop a new assay that addresses visuomotor integration in restrained larval zebrafish. The assay involves a closed-loop environment in which the visual feedback a larva receives depends on its own motor output in a way that resembles freely swimming conditions. The experimenter can control the gain of this closed feedback loop, so that following a given motor output the larva experiences more or less visual feedback depending on whether the gain is high or low. We show that increases and decreases in this gain setting result in adaptive changes in behavior that lead to a generalized decrease or increase of motor output, respectively. Our behavioral analysis shows that both the duration and tail beat frequency of individual swim bouts can be modified, as well as the frequency with which bouts are elicited. These changes can be implemented rapidly, following an exposure to a new gain of just 175 ms. In addition, modifications in some behavioral parameters accumulate over tens of seconds and effects last for at least 30 s from trial to trial. These results suggest that larvae establish an internal representation of the visual feedback expected from a given motor output and that the behavioral modifications are driven by an error signal that arises from the discrepancy between this expectation and the actual visual feedback. The assay we develop presents a unique possibility for studying visuomotor integration using imaging techniques available in the larval zebrafish.
    DurationLarvaBehaviorVisual feedbackConditioningLarval zebrafishT -testMotor learningArousalA/J...
  • Functional brain imaging and neurosurgery in subcortical areas often requires visualization of brain nuclei beyond the resolution of current magnetic resonance imaging (MRI) methods. We present techniques used to create: (1) a lower resolution 3D atlas, based on the Schaltenbrand and Wahren print atlas, which was integrated into a stereotactic neurosurgery planning and visualization platform (VIPER); and (2) a higher resolution 3D atlas derived from a single set of manually segmented histological slices containing nuclei of the basal ganglia, thalamus, basal forebrain, and medial temporal lobe. Both atlases were integrated to a canonical MRI (Colin27) from a young male participant by manually identifying homologous landmarks. The lower resolution atlas was then warped to fit the MRI based on the identified landmarks. A pseudo-MRI representation of the high-resolution atlas was created, and a non-linear transformation was calculated in order to match the atlas to the template MRI. The atlas can then be warped to match the anatomy of Parkinson's disease surgical candidates by using 3D automated non-linear deformation methods. By way of functional validation of the atlas, the location of the sensory thalamus was correlated with stereotactic intraoperative physiological data. The position of subthalamic electrode positions in patients with Parkinson's disease was also evaluated in the atlas-integrated MRI space. Finally, probabilistic maps of subthalamic stimulation electrodes were developed, in order to allow group analysis of the location of contacts associated with the best motor outcomes. We have therefore developed, and are continuing to validate, a high-resolution computerized MRI-integrated 3D histological atlas, which is useful in functional neurosurgery, and for functional and anatomical studies of the human basal ganglia, thalamus, and basal forebrain.
    Magnetic resonance imagingThalamusPatientElectrodeImagingBasal gangliaSliceVisualBasal forebrainBrain...
  • In the present study we characterized the strength and time course of category-selective responses in prefrontal cortex and area 7a of the posterior parietal cortex during a match-to-sample spatial categorization task. A monkey was trained to categorize whether the height of a horizontal sample bar, presented in rectangular frame at one of three vertical locations, was “high” or “low,” depending on whether its position was above or below the frame's midline. After the display of this sample bar, and after a delay, choice bars were sequentially flashed in two locations: at the top and at the bottom of the frame (“choice” epoch). If the monkey timed its response to the display of the choice bar that matched the sample bar, he was rewarded. We found that cells in prefrontal cortex discriminated category early after the initial sample bar was shown, and continued to differentiate “up” from “down” trials throughout the delay and choice periods. In contrast, parietal cells did not differentiate category until the choice period. Therefore, our results support the notion of a top-down categorical signal that originates in prefrontal cortex and that is only represented in parietal cortex when it is necessary to express the categorical decision through a movement.
    MonkeyPrefrontal cortexChoiceTime courseNeuronVisualBrain areaFiring rateFixativePopulation...
  • Striatal dopamine denervation is the pathological hallmark of Parkinson's disease (PD). Another major pathological change described in animal models and PD patients is a significant reduction in the density of dendritic spines on medium spiny striatal projection neurons. Simultaneously, the ultrastructural features of the neuronal synaptic elements at the remaining corticostriatal and thalamostriatal glutamatergic axo-spinous synapses undergo complex ultrastructural remodeling consistent with increased synaptic activity (Villalba and Smith, 2011 ). The concept of tripartite synapses (TS) was introduced a decade ago, according to which astrocytes process and exchange information with neuronal synaptic elements at glutamatergic synapses (Araque et al., 1999a ). Although there has been compelling evidence that astrocytes are integral functional elements of tripartite glutamatergic synaptic complexes in the cerebral cortex and hippocampus, their exact functional role, degree of plasticity and preponderance in other CNS regions remain poorly understood. In this review, we discuss our recent findings showing that neuronal elements at cortical and thalamic glutamatergic synapses undergo significant plastic changes in the striatum of MPTP-treated parkinsonian monkeys. We also present new ultrastructural data that demonstrate a significant expansion of the astrocytic coverage of striatal TS synapses in the parkinsonian state, providing further evidence for ultrastructural compensatory changes that affect both neuronal and glial elements at TS. Together with our limited understanding of the mechanisms by which astrocytes respond to changes in neuronal activity and extracellular transmitter homeostasis, the role of both neuronal and glial components of excitatory synapses must be considered, if one hopes to take advantage of glia–neuronal communication knowledge to better understand the pathophysiology of striatal processing in parkinsonism, and develop new PD therapeutics.
    AstrocyteSynapseMonkeyStriatalSpineGlutamatergic synapseStriatumNeuronDendritic spineAnimal...
  • Classical rate-based pathway models are invaluable for conceptualizing direct/indirect basal ganglia pathways, but cannot account for many aspects of normal and abnormal motor control. To better understand the contribution of patterned basal ganglia signaling to normal and pathological motor control, we simultaneously recorded multi-neuronal and EMG activity in normal and dystonic rats. We used the jaundiced Gunn rat model of kernicterus as our experimental model of dystonia. Stainless steel head fixtures were implanted on the skulls and EMG wires were inserted into antagonistic hip muscles in nine dystonic and nine control rats. Under awake, head-restrained conditions, neuronal activity was collected from up to three microelectrodes inserted in the principal motor regions of the globus pallidus (GP), subthalamic nucleus, and entopeduncular nucleus (EP). In normal animals, most neurons discharged in regular or irregular patterns, without appreciable bursting. In contrast, in dystonic animals, neurons discharged in slow bursty or irregular, less bursty patterns. In normal rats, a subset of neurons showed brief discharge bursts coinciding with individual agonist or antagonist EMG bursts. In contrast, in dystonics, movement related discharges were characterized by more prolonged bursts which persist over multiple dystonic co-contraction epics. The pattern of movement related decreases in discharge activity however did not differ in dystonics compared to controls. In severely dystonic rats, exclusively, simultaneously recorded units often showed abnormally synchronized movement related pauses in GP and bursts in EP. In conclusion, our findings support that slow, abnormally patterned neuronal signaling is a fundamental pathophysiological feature of intrinsic basal ganglia nuclei in dystonia. Moreover, from our findings, we suggest that excessive movement related silencing of neuronal signaling in GP profoundly disinhibits EP and in turn contributes to sustained, unfocused dystonic muscle contractions.
    NeuronBurstDystoniaRatAnimalBasal gangliaMethodGlobus pallidus internusHumanGlobus pallidus externus...
  • The current paper briefly outlines the historical development of the concept of habit learning and discusses its relationship to the basal ganglia. Habit learning has been studied in many different fields of neuroscience using different species, tasks, and methodologies, and as a result it has taken on a wide range of definitions from these various perspectives. We identify five common but not universal, definitional features of habit learning: that it is inflexible, slow or incremental, unconscious, automatic, and insensitive to reinforcer devaluation. We critically evaluate for each of these how it has been defined, its utility for research in both humans and non-human animals, and the evidence that it serves as an accurate description of basal ganglia function. In conclusion, we propose a multi-faceted approach to habit learning and its relationship to the basal ganglia, emphasizing the need for formal definitions that will provide directions for future research.
    LearningHabit learningBasal gangliaHabitAnimalDual taskRewardStriatumCognitive psychologyReinforcement learning...
  • GABA transporter type 1 and 3 (GAT-1 and GAT-3, respectively) are the two main subtypes of GATs responsible for the regulation of extracellular GABA levels in the central nervous system. These transporters are widely expressed in neuronal (mainly GAT-1) and glial (mainly GAT-3) elements throughout the brain, but most data obtained so far relate to their role in the regulation of GABA A receptor-mediated postsynaptic tonic and phasic inhibition in the hippocampus, cerebral cortex and cerebellum. Taking into consideration the key role of GABAergic transmission within basal ganglia networks, and the importance for these systems to be properly balanced to mediate normal basal ganglia function, we analyzed in detail the localization and function of GAT-1 and GAT-3 in the globus pallidus of normal and Parkinsonian animals, in order to further understand the substrate and possible mechanisms by which GABA transporters may regulate basal ganglia outflow, and may become relevant targets for new therapeutic approaches for the treatment of basal ganglia-related disorders. In this review, we describe the general features of GATs in the basal ganglia, and give a detailed account of recent evidence that GAT-1 and GAT-3 regulation can have a major impact on the firing rate and pattern of basal ganglia neurons through pre- and post-synaptic GABAA - and GABAB -receptor-mediated effects.
    GABARatBasal gangliaNeuronMonkeyStriatalStriatumBrain areaGABA levelGlobus pallidus...
  • The relationship between molecular properties of odorants and neural activities is arguably one of the most important issues in olfaction and the rules governing this relationship are still not clear. In the olfactory bulb (OB), glomeruli relay olfactory information to second-order neurons which in turn project to cortical areas. We investigate relevance of odorant properties, spatial localization of glomerular coding sites, and size of coding zones in a dataset of [ 14 C] 2-deoxyglucose images of glomeruli over the entire OB of the rat. We relate molecular properties to activation of glomeruli in the OB using a non-parametric statistical test and a support-vector machine classification study. Our method permits to systematically map the topographic representation of various classes of odorants in the OB. Our results suggest many localized coding sites for particular molecular properties and some molecular properties that could form the basis for a spatial map of olfactory information. We found that alkynes, alkanes, alkenes, and amines affect activation maps very strongly as compared to other properties and that amines, sulfur-containing compounds, and alkynes have small zones and high relevance to activation changes, while aromatics, alkanes, and carboxylics acid recruit very big zones in the dataset. Results suggest a local spatial encoding for molecular properties.
    OdorCompoundCarboxylic acidAlcoholImagingFunctional groupConcentrationPixelClassification performanceRat...
  • Huntington's disease (HD) is characterized by numerous alterations within the corticostriatal circuitry. The striatum is innervated by a dense array of dopaminergic (DA) terminals and these DA synapses are critical to the proper execution of motor functions. As motor disturbances are prevalent in HD we examined DA neurotransmission in the striatum in transgenic (tg) murine models of HD. We used in vivo microdialysis to compare extracellular concentrations of striatal DA in both a fragment (R6/2) model, which displays a rapid and severe phenotype, and a full-length (YAC128) model that expresses a more progressive phenotype. Extracellular striatal DA concentrations were significantly reduced in R6/2 mice and decreased concomitantly with age-dependent increasing motor impairments on the rotarod task (7, 9, and 11 weeks). In a sample of 11-week-old R6/2 mice, we also measured tissue concentrations of striatal DA and found that total levels of DA were significantly depleted. However, the loss of total DA content (<50%) was insufficient to account for the full extent of DA depletion in the extracellular fluid (ECF; ∼75%). We also observed a significant reduction in extracellular DA concentrations in the striatum of 7-month-old YAC128 mice. In a separate set of experiments, we applied d -amphetamine (AMPH; 10 μm) locally into the striatum to stimulate the release of intracellular DA into the ECF. The AMPH-induced increase in extracellular DA levels was significantly blunted in 9-week-old R6/2 mice. There also was a decrease in AMPH-stimulated DA efflux in 7-month-old YAC128 mice in comparison to WT controls, although the effect was milder. In the same cohort of 7-month-old YAC128 mice we observed a significant reduction in the total locomotor activity in response to systemic AMPH (2 mg/kg). Our data demonstrate that extracellular DA release is attenuated in both a fragment and full-length tg mouse model of HD and support the concept of DA involvement in aspects of the syndrome.
    DopamineWild typeStriatalConcentrationProbeTissueStriatal dopamineDopamine releaseStriatumTransgenic mouse...
  • Exposure to psychostimulants increases brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the cerebral cortex and subcortical structures. Because BDNF is co-localized with dopamine and glutamate in afferents to the striatum of rats, it may be co-released with those neurotransmitters upon stimulation. Further, there may be an interaction between the intracellular signaling cascades activated by dopamine, glutamate, and TrkB receptors in medium spiny striatal neurons. In the present study, the effect of acute amphetamine administration on TrkB phosphorylation, as an indirect indicator of activation, and striatal gene expression, was evaluated. In Experiment 1, 15 min or 2 h after a single saline or amphetamine (2.5 mg/kg, i.p.) injection, the caudate–putamen (CPu), nucleus accumbens (NAc), and dorsomedial prefrontal cortex (dmPFC) were extracted and processed for phospho (p)-TrkB immunoreactivity. Immunoprecipitation analyses indicated that neither the tyrosine phosphorylation (p-Tyr) or autophosphorylation sites of TrkB (706) were changed in NAc, CPu, or dmPFC 15 min after amphetamine administration. In contrast, p-Tyr and the PLCγ phosphorylation site of TrkB (816) were increased in the NAc and CPu 2 h after amphetamine. In Experiment 2, intra-striatal infusion of the tyrosine kinase inhibitor, K252a, increased amphetamine-induced vertical activity but not total distance traveled. In addition, K252a inhibited amphetamine-induced preprodynorphin, but not preproenkephalin, mRNA expression in the striatum. These data indicate that acute amphetamine administration induces p-TrkB activation and signaling in a time- and brain region-dependent manner and that TrkB/BDNF signaling plays an important role in amphetamine-induced behavior and striatal gene expression.
    BDNFReceptorStriatumInjectionRatDopamineKinaseStriatalGlutamateBehavior...
  • The cognitive deficits associated with schizophrenia are commonly believed to arise from the abnormal temporal integration of information, however a quantitative approach to assess network coordination is lacking. Here, we propose to use cross-frequency modulation (cfM), the dependence of local high-frequency activity on the phase of widespread low-frequency oscillations, as an indicator of network coordination and functional integration. In an exploratory analysis based on pre-existing data, we measured cfM from multi-channel EEG recordings acquired while schizophrenia patients ( n = 47) and healthy controls (n = 130) performed an auditory oddball task. Novel application of independent component analysis (ICA) to modulation data delineated components with specific spatial and spectral profiles, the weights of which showed covariation with diagnosis. Global cfM was significantly greater in healthy controls (F 1,175 = 9.25, P < 0.005), while modulation at fronto-temporal electrodes was greater in patients (F 1,175 = 17.5, P < 0.0001). We further found that the weights of schizophrenia-relevant components were associated with genetic polymorphisms at previously identified risk loci. Global cfM decreased with copies of 957C allele in the gene for the dopamine D2 receptor (r = −0.20, P < 0.01) across all subjects. Additionally, greater “aberrant” fronto-temporal modulation in schizophrenia patients was correlated with several polymorphisms in the gene for the α2-subunit of the GABAA receptor (GABRA2 ) as well as the total number of risk alleles in GABRA2 (r = 0.45, P < 0.01). Overall, our results indicate great promise for this approach in establishing patterns of cfM in health and disease and elucidating the roles of oscillatory interactions in functional connectivity.
    GenotypeGeneticsConditioningPatientPolymorphismSchizophreniaOscillationSchizophrenia patientElectrodeMethod...
  • This review focuses on the role of long-range connectivity as one element of brain structure that is of key importance for the functional–anatomical organization of the cortex. In this context, we discuss the putative guiding principles for mapping brain function and structure onto the cortical surface. Such mappings reveal a high degree of functional–anatomical segregation. Given that brain regions frequently maintain characteristic connectivity profiles and the functional repertoire of a cortical area is closely related to its anatomical connections, long-range connectivity may be used to define segregated cortical areas. This methodology is called connectivity-based parcellation. Within this framework, we investigate different techniques to estimate connectivity profiles with emphasis given to non-invasive methods based on diffusion magnetic resonance imaging (dMRI) and diffusion tractography. Cortical parcellation is then defined based on similarity between diffusion tractograms, and different clustering approaches are discussed. We conclude that the use of non-invasively acquired connectivity estimates to characterize the functional–anatomical organization of the brain is a valid, relevant, and necessary endeavor. Current and future developments in dMRI technology, tractography algorithms, and models of the similarity structure hold great potential for a substantial improvement and enrichment of the results of the technique.
    BrainCortexVoxelAxonFiberCortical areaSeedOrganismNeuronImaging...
  • In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo , these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.
    NeuronSpikeSynapseStriatalFiringInterneuronElectrical couplingSpike synchronizationSpike trainDendrite...
  • Trace amines (TAs) are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism, and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as “false” neurotransmitters. The discovery in 2001 of a new family of G-protein-coupled receptors (GPCRs), namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA 1 ) and trace amine receptor 2 (TA2 ), were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson's disease, all of which are characterized by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA1 receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA1 receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004 ). Further research is needed to address this point, and to further characterize the mechanism of action of TAs on dopaminergic neurons.
    Trace aminesReceptorNeuronGABAD2 receptorDopamineFiringDopaminergic neuronDepressionBrain...
  • Striatal nitric oxide (NO)-producing interneurons play an important role in the regulation of corticostriatal synaptic transmission and motor behavior. Striatal NO synthesis is driven by concurrent activation of NMDA and dopamine (DA) D1 receptors. NO diffuses into the dendrites of medium-sized spiny neurons which contain high levels of NO receptors called soluble guanylyl cyclases (sGC). NO-mediated activation of sGC leads to the synthesis of the second messenger cGMP. In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic corticostriatal transmission. NO–cGMP signaling also functionally opposes the inhibitory effects of DA D2 receptor activation on corticostriatal transmission. Not surprisingly, abnormal striatal NO–sGC–cGMP signaling becomes apparent following striatal DA depletion, an alteration thought to contribute to pathophysiological changes observed in basal ganglia circuits in Parkinson's disease (PD). Here, we discuss recent developments in the field which have shed light on the role of NO–sGC–cGMP signaling pathways in basal ganglia dysfunction and motor symptoms associated with PD and l -DOPA-induced dyskinesias.
    StriatalNMDA receptorStriatumInterneuronNeuronD1 receptorD2 receptorRatInhibitorCyclic nucleotide...
  • In the healthy primate, neurons of the external and internal segments of the globus pallidus (GP) present a primarily irregular firing pattern, and a negligible level of synchrony is observed between pairs of neurons. This holds even for neighboring cells, despite their higher probability to receive common inputs and to innervate each other via lateral connectivity. In the Parkinsonian primate, this changes drastically, and many pairs of GP cells show synchronous oscillations. To address the relation between distance and synchrony in the Parkinsonian state, we compared the synchrony of discharge of close pairs of neurons, recorded by the same electrode, with remote pairs, recorded by different ones. However, spike trains of neighboring cells recorded by the same extracellular electrode exhibit the shadowing effect; i.e., lack of detection of spikes that occur within a few milliseconds of each other. Here, we demonstrate that the shadowing artifact can both induce apparent correlations between non-correlated neurons, as well as conceal existing correlations between neighboring ones. We therefore introduced artificial shadowing in the remote pairs, similar to the effect we observed in the close ones. After the artificial shadowing, neighboring cells did not show a higher tendency to oscillate synchronously than remote ones. On the contrary, the average percentage (over all sessions) of artificially shadowed remote pairs exhibiting synchronous oscillations was 35.4% compared to 17.2% in the close ones. Similar trend was found when the unshadowed remote pairs were separated according to the estimated distance between electrode tips: 29.9% of pairs at approximate distance of less than 750 μm were significantly synchronized, in comparison with 28.5% of the pairs whose distance was more than 750 μm. We conclude that the synchronous oscillations in the GP of MPTP treated primates are homogenously distributed.
    OscillationMonkeyNeuronElectrodePopulationPrimateMPTPSpikeBasal gangliaSegmentation...
  • The sparse connectivity within the striatum in vivo makes the investigation of individual corticostriatal synapses very difficult. Most studies of the corticostriatal input have been done using electrical stimulation under conditions where it is hard to identify the precise origin of the cortical input. We have employed an in vitro dissociated cell culture system that allows the identification of individual corticostriatal pairs and have been developing methods to study individual neuron inputs to striatal neurons. In mixed corticostriatal cultures, neurons had resting activity similar to the system in vivo . Up/down states were obvious and seemed to encompass the entire culture. Mixed cultures of cortical neurons from transgenic mice expressing green fluorescent protein with striatal neurons from wild-type mice of the same developmental stage allowed visual identification of individual candidate corticostriatal pairs. Recordings were performed between 12 and 37 days in vitro (DIV). To investigate synaptic connections we recorded from 69 corticostriatal pairs of which 44 were connected in one direction and 25 reciprocally. Of these connections 41 were corticostriatal (nine inhibitory) and 53 striatocortical (all inhibitory). The observed excitatory responses were of variable amplitude (−10 to −370 pA, n = 32). We found the connections very secure – with negligible failures on repeated stimulation (approximately 1 Hz) of the cortical neuron. Inhibitory corticostriatal responses were also observed (−13 to −314 pA, n = 9). Possibly due to the mixed type of culture we found an inhibitory striatocortical response (−14 to −598 pA, n = 53). We are now recording from neurons in separate compartments to more closely emulate neuroanatomical conditions but still with the possibility of the easier identification of the connectivity.
    NeuronStriatal neuronCortical neuronBurstFiringStriatalCortexSynapseSliceRest...
  • High frequency deep-brain stimulation of the subthalamic nucleus (deep brain stimulation, DBS) relieves many of the symptoms of Parkinson's disease in humans and animal models. Although the treatment has seen widespread use, its therapeutic mechanism remains paradoxical. The subthalamic nucleus is excitatory, so its stimulation at rates higher than its normal firing rate should worsen the disease by increasing subthalamic excitation of the globus pallidus. The therapeutic effectiveness of DBS is also frequency and intensity sensitive, and the stimulation must be periodic; aperiodic stimulation at the same mean rate is ineffective. These requirements are not adequately explained by existing models, whether based on firing rate changes or on reduced bursting. Here we report modeling studies suggesting that high frequency periodic excitation of the subthalamic nucleus may act by desynchronizing the firing of neurons in the globus pallidus, rather than by changing the firing rate or pattern of individual cells. Globus pallidus neurons are normally desynchronized, but their activity becomes correlated in Parkinson's disease. Periodic stimulation may induce chaotic desynchronization by interacting with the intrinsic oscillatory mechanism of globus pallidus neurons. Our modeling results suggest a mechanism of action of DBS and a pathophysiology of Parkinsonism in which synchrony, rather than firing rate, is the critical pathological feature.
    NeuronFiringFiring rateGlobus pallidusStimulus intensityOscillationAction potentialCompoundBurstPulse...
  • Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3–7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A 2A antagonists). TJMs occur in the same 3–7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1–2 Hz), and postural tremor (8–14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor.
    TremorRatHumanAdenosineInjectionRestDrugTreatmentPatientConditioning...
  • 5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD). Clinical studies have suggested that 5-HT 2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of PD.
    5-HT2A receptorGlutamateMPTPStriatumParkinson's diseaseAnimalStriatalTreatmentBasal gangliaDose...
  • Studies of animal models of Huntington's disease (HD) have revealed that neocortical and neostriatal neurons of these animals in vitro exhibit a number of morphological and physiological changes, including increased input resistance and changes in neocortical synaptic inputs. We measured the functional effects of polyglutamate accumulation in neocortical neurons in R6/2 mice (8–14 weeks of age) and their age-matched non-transgenic littermates using in vivo intracellular recordings. All neurons showed spontaneous membrane potential fluctuations. The current/voltage and the firing properties of the HD neocortical neurons were significantly altered, especially in the physiologically relevant current range around and below threshold. As a result, membrane potential transitions from the Down state to Up state were evoked with smaller currents in HD neocortical neurons than in controls. The excitation-to-frequency curves of the HD mice were significantly steeper than those of controls, indicating a smaller input–output dynamic range for these neurons. Increased likelihood of Down to Up state transitions could cause pathological recruitment of corticostriatal assemblies by increasing correlated neuronal activity. We measured coherence of the in vivo intracellular recordings with simultaneously recorded electrocorticograms. We found that the peak of the coherence at <5 Hz was significantly smaller in the HD animals, indicating that the amount of coherence in the state transitions of single neurons is less correlated with global activity than non-transgenic controls. We propose that decreased correlation of neocortical inputs may be a major physiological cause underlying the errors in sensorimotor pattern generation in HD.
    NeuronNeocortical neuronMembrane potentialDurationAnimalInput resistanceElectrodeIntracellular recordingPulseSpike...
  • Imbalance in the activity of striatal direct and indirect pathway neurons contributes to motor disturbances in several neurodegenerative diseases. In Huntington's disease (HD), indirect pathway [dopamine (DA) D2 receptor-expressing] medium-sized spiny neurons (MSNs) are believed to show earlier vulnerability than direct pathway MSNs. We examined synaptic activity and DA modulation in MSNs forming the direct and indirect pathways in YAC128 and BACHD mouse models of HD. To visualize the two types of MSNs, we used mice expressing enhanced green fluorescent protein under the control of the promoter for the DA D1 or D2 receptor. Experiments were performed in early symptomatic (1.5 months) and symptomatic (12 months) mice. Behaviorally, early symptomatic mice showed increased stereotypies while symptomatic mice showed decreased motor activity. Electrophysiologically, at the early stage, excitatory and inhibitory transmission onto D1-YAC128 and D1-BACHD MSNs were increased, while there was no change in D2 MSNs. DA modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in slices was absent in YAC128 cells at the early stage, but was restored by treating the slices with the DA depleter tetrabenazine (TBZ). In BACHD mice TBZ restored paired-pulse ratios and a D1 receptor antagonist induced a larger decrease of sEPSCs than in D1-WT cells, suggesting increased DA tone. Finally, TBZ decreased stereotypies in BACHD mice. These results indicate that by reducing DA or antagonizing D1 receptors, increases in inhibitory and excitatory transmission in early phenotypic direct pathway neurons can be normalized. In symptomatic YAC128 mice, excitatory synaptic transmission onto D1 MSNs was decreased, while inhibitory transmission was increased in D2 MSNs. These studies provide evidence for differential and complex imbalances in glutamate and GABA transmission, as well as in DA modulation, in direct and indirect pathway MSNs during HD progression.
    DBA/2JIndirect pathwayGlutamateD2 receptorGABANeuronSlicePathwayGABA releaseStriatal...
  • Striatal fast-spiking interneurons (FSIs) have a major influence over behavioral output, and a deficit in these cells has been observed in dystonia and Tourette syndrome. FSIs receive cortical input, are coupled together by gap junctions, and make perisomatic GABAergic synapses onto many nearby projection neurons. Despite being critical components of striatal microcircuits, until recently little was known about FSI activity in behaving animals. Striatal FSIs are near-continuously active in awake rodents, but even neighboring FSIs show uncorrelated activity most of the time. A coordinated “pulse” of increased FSI firing occurs throughout striatum when rats initiate one chosen action while suppressing a highly trained alternative. This pulse coincides with a drop in globus pallidus population activity, suggesting that pallidostriatal disinhibition may have a important role in timing or coordinating action execution. In addition to changes in firing rate, FSIs show behavior-linked modulation of spike timing. The variability of inter-spike intervals decreases markedly following instruction cues, and FSIs also participate in fast striatal oscillations that are linked to rewarding events and dopaminergic drugs. These studies have revealed novel and unexpected properties of FSIs, that should help inform new models of striatal information processing in both normal and aberrant conditions.
    StriatalStriatumFiring rateSpikeBehaviorAnimalFiringRatDrugInterneuron...
  • Animal model studies of amblyopia have generally concluded that enduring effects of monocular deprivation (MD) on visual behavior (i.e., loss of visual acuity) are limited to the deprived eye, and are restricted to juvenile life. We have previously reported, however, that lasting effects of MD on visual function can be elicited in adulthood by stimulating visuomotor experience through the non-deprived eye. To test whether stimulating experience would also induce interocular plasticity of vision in infancy, we assessed in rats from eye-opening on postnatal day (P) 15, the effect of pairing MD with the daily experience of measuring thresholds for optokinetic tracking (OKT). MD with visuomotor experience from P15 to P25 led to a ~60% enhancement of the spatial frequency threshold for OKT through the non-deprived eye during the deprivation, which was followed by loss-of-function (~60% below normal) through both eyes when the deprived eye was opened. Reduced thresholds were maintained into adulthood with binocular OKT experience from P25 to P30. The ability to generate the plasticity and maintain lost function was dependent on visual cortex. Strictly limiting the period of deprivation to infancy by opening the deprived eye at P19 resulted in a comparable loss-of-function. Animals with reduced OKT responses also had significantly reduced visual acuity, measured independently in a discrimination task. Thus, experience-dependent cortical plasticity that can lead to amblyopia is present earlier in life than previously recognized.
    EyeVisualAnimalEnhancerVisual cortexLoss of functionRatCortexAdultInfant...
  • The rapid increase in published genomic sequences for bacteria presents the first opportunity to reconstruct evolutionary events on the scale of entire genomes. However, extensive lateral gene transfer (LGT) may thwart this goal by preventing the establishment of organismal relationships based on individual gene phylogenies. The group for which cases of LGT are most frequently documented and for which the greatest density of complete genome sequences is available is the γ-Proteobacteria, an ecologically diverse and ancient group including free-living species as well as pathogens and intracellular symbionts of plants and animals. We propose an approach to multigene phylogeny using complete genomes and apply it to the case of the γ-Proteobacteria. We first applied stringent criteria to identify a set of likely gene orthologs and then tested the compatibilities of the resulting protein alignments with several phylogenetic hypotheses. Our results demonstrate phylogenetic concordance among virtually all (203 of 205) of the selected gene families, with each of the exceptions consistent with a single LGT event. The concatenated sequences of the concordant families yield a fully resolved phylogeny. This topology also received strong support in analyses aimed at excluding effects of heterogeneity in nucleotide base composition across lineages. Our analysis indicates that single-copy orthologous genes are resistant to horizontal transfer, even in ancient bacterial groups subject to high rates of LGT. This gene set can be identified and used to yield robust hypotheses for organismal phylogenies, thus establishing a foundation for reconstructing the evolutionary transitions, such as gene transfer, that underlie diversity in genome content and organization.
    GeneGenomeOrthologous geneProteinSequencingMethodHomologyGenome sequenceEvolutionSalmonella...
  • Dendrodendritic electrical signaling via gap junctions is now an accepted feature of neuronal communication in mammalian brain, whereas axodendritic and axosomatic gap junctions have rarely been described. We present ultrastructural, immunocytochemical, and dye-coupling evidence for “mixed” (electrical/chemical) synapses on both principal cells and interneurons in adult rat hippocampus. Thin-section electron microscopic images of small gap junction-like appositions were found at mossy fiber (MF) terminals on thorny excrescences of CA3 pyramidal neurons (CA3pyr), apparently forming glutamatergic mixed synapses. Lucifer Yellow injected into weakly fixed CA3pyr was detected in MF axons that contacted four injected CA3pyr, supporting gap junction-mediated coupling between those two types of principal cells. Freeze-fracture replica immunogold labeling revealed diverse sizes and morphologies of connexin-36-containing gap junctions throughout hippocampus. Of 20 immunogold-labeled gap junctions, seven were large (328–1140 connexons), three of which were consistent with electrical synapses between interneurons; but nine were at axon terminal synapses, three of which were immediately adjacent to distinctive glutamate receptor-containing postsynaptic densities, forming mixed glutamatergic synapses. Four others were adjacent to small clusters of immunogold-labeled 10-nm E-face intramembrane particles, apparently representing extrasynaptic glutamate receptor particles. Gap junctions also were on spines in stratum lucidum , stratum oriens , dentate gyrus, and hilus, on both interneurons and unidentified neurons. In addition, one putative GABAergic mixed synapse was found in thin-section images of a CA3pyr, but none were found by immunogold labeling, suggesting the rarity of GABAergic mixed synapses. Cx36-containing gap junctions throughout hippocampus suggest the possibility of reciprocal modulation of electrical and chemical signals in diverse hippocampal neurons.
    Gap junctionSynapseDendriteMossy fibersNeuronSpineGlutamate receptorInterneuronAxon terminalImaging...
  • We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging ( 1 H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ’s and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.
    PatientWhite matterDisorderHumanVoxelMetaboliteConcentrationMetabolite concentrationImagingCompound...
  • How can flexible phasing be generated by a central pattern generator (CPG)? To address this question, we have extended an existing model of the leech heartbeat CPG's timing network to construct a model of the CPG core and explore how appropriate phasing is set up by parameter variation. Within the CPG, the phasing among premotor interneurons switches regularly between two well defined states – synchronous and peristaltic. To reproduce experimentally observed phasing, we varied the strength of inhibitory synaptic and excitatory electrical input from the timing network to follower premotor interneurons. Neither inhibitory nor electrical input alone was sufficient to produce proper phasing on both sides, but instead a balance was required. Our model suggests that the different phasing of the two sides arises because the inhibitory synapses and electrical coupling oppose one another on one side (peristaltic) and reinforce one another on the other (synchronous). Our search of parameter space defined by the strength of inhibitory synaptic and excitatory electrical input strength led to a CPG model that well approximates the experimentally observed phase relations. The strength values derived from this analysis constitute model predictions that we tested by measurements made in the living system. Further, variation of the intrinsic properties of follower interneurons showed that they too systematically influence phasing. We conclude that a combination of inhibitory synaptic and excitatory electrical input interacting with neuronal intrinsic properties can flexibly generate a variety of phase relations so that almost any phasing is possible.
    InterneuronBurstNeuronHeartElectrical couplingSpikeFiringOscillationSynaptic inputSynaptic current...