Kinematic analysis of bimanual movements during food handling by head-fixed rats.

Bimanual coordination, in which both hands work together to achieve a goal, is crucial for the basic needs of life, such as gathering and feeding. Such coordinated motor skill is highly developed in primates, where it has been most extensively studied. Rodents also exhibit remarkable dexterity and coordination of forelimbs during food handling and consumption. However, rodents have been less commonly used in the study of bimanual coordination because of limited quantitative measuring techniques. In this article we describe a high-resolution tracking system that enables kinematic analysis of rat forelimb movement. The system is used to quantify forelimb movements bilaterally in head-fixed rats during food handling and consumption. Forelimb movements occurring naturally during feeding were encoded as continuous three-dimensional trajectories. The trajectories were then automatically segmented and analyzed, using a novel algorithm, according to the laterality of movement speed or the asymmetry of movement direction across the forelimbs. Bilateral forelimb movements were frequently observed during spontaneous food handling. Both symmetry and asymmetry in movement direction were frequently observed, with symmetric bilateral movements quantitatively more common. The proposed method overcomes a limitation in the precise quantification of bimanual coordination in rodents. This enables the use of powerful rodent-based research tools such as optogenetics and chemogenetics in the further investigation of neural mechanisms of bimanual coordination. NEW & NOTEWORTHY We describe a new method for quantifying and classifying three-dimensional, bilateral forelimb trajectories in head-fixed rats. The method overcomes limits on quantifying bimanual coordination in rats. When applied to kinematic analysis of food handling behavior, continuous forelimb trajectories were automatically segmented and classified. Bilateral forelimb movements were observed more frequently than unilateral movements during spontaneous food handling. Both symmetry and asymmetry in movement direction were frequently observed. However, symmetric bilateral forelimb movements were more common.

Using rodent data to elucidate dopaminergic mechanisms of ADHD: Implications for human personality.

An altered behavioral response to positive reinforcement has been proposed to be a core deficit in attention deficit hyperactivity disorder (ADHD). The spontaneously hypertensive rat (SHR), a congenic animal strain, displays a similarly altered response to reinforcement. The presence of this genetically determined phenotype in a rodent model allows experimental investigation of underlying neural mechanisms. Behaviorally, the SHR displays increased preference for immediate reinforcement, increased sensitivity to individual instances of reinforcement relative to integrated reinforcement history, and a steeper delay of reinforcement gradient compared to other rat strains. The SHR also shows less development of incentive to approach sensory stimuli, or cues, that predict reward after repeated cue-reward pairing. We consider the underlying neural mechanisms for these characteristics. It is well known that midbrain dopamine neurons are initially activated by unexpected reward and gradually transfer their responses to reward-predicting cues. This finding has inspired the dopamine transfer deficit (DTD) hypothesis, which predicts certain behavioral effects that would arise from a deficient transfer of dopamine responses from actual rewards to reward-predicting cues. We argue that the DTD predicts the altered responses to reinforcement seen in the SHR and individuals with ADHD. These altered responses to reinforcement in turn predict core symptoms of ADHD. We also suggest that variations in the degree of dopamine transfer may underlie variations in personality dimensions related to altered reinforcement sensitivity. In doing so, we highlight the value of rodent models to the study of human personality.

Ramping activity in the striatum.

Control of the timing of behavior is thought to require the basal ganglia (BG) and BG pathologies impair performance in timing tasks. Temporal interval discrimination depends on the ramping activity of medium spiny neurons (MSN) in the main BG input structure, the striatum, but the underlying mechanisms driving this activity are unclear. Here, we combine an MSN dynamical network model with an action selection system applied to an interval discrimination task. We find that when network parameters are appropriate for the striatum so that slowly fluctuating marginally stable dynamics are intrinsically generated, up and down ramping populations naturally emerge which enable significantly above chance task performance. We show that emergent population activity is in very good agreement with empirical studies and discuss how MSN network dysfunction in disease may alter temporal perception.

Designing AAV Vectors for Monitoring the Subtle Calcium Fluctuations of Inferior Olive Network in vivo.

Adeno-associated viral (AAV) vectors, used as vehicles for gene transfer into the brain, are a versatile and powerful tool of modern neuroscience that allow identifying specific neuronal populations, monitoring and modulating their activity. For consistent and reproducible results, the AAV vectors must be engineered so that they reliably and accurately target cell populations. Furthermore, transgene expression must be adjusted to sufficient and safe levels compatible with the physiology of studied cells. We undertook the effort to identify and validate an AAV vector that could be utilized for researching the inferior olivary (IO) nucleus, a structure gating critical timing-related signals to the cerebellum. By means of systematic construct generation and quantitative expression profiling, we succeeded in creating a viral tool for specific and strong transfection of the IO neurons without adverse effects on their physiology. The potential of these tools is demonstrated by expressing the calcium sensor GCaMP6s in adult mouse IO neurons. We could monitor subtle calcium fluctuations underlying two signatures of intrinsic IO activity: the subthreshold oscillations (STOs) and the variable-duration action potential waveforms both in-vitro and in-vivo. Further, we show that the expression levels of GCaMP6s allowing such recordings are compatible with the delicate calcium-based dynamics of IO neurons, inviting future work into the network dynamics of the olivo-cerebellar system in behaving animals.

Reward modality modulates striatal responses to reward anticipation in ADHD: Effects of affiliative and food stimuli.

Altered reward sensitivity has been proposed to underlie symptoms of attention deficit hyperactivity disorder (ADHD). Functional magnetic resonance imaging (fMRI) studies have reported hypoactivation to reward-predicting cues in the ventral striatum among individuals with ADHD, using experimental designs with and without behavioral response requirements. These studies have typically used monetary incentives as rewards; however, it is unclear if these findings extend to other reward types. The current study examined striatal responses to anticipation and delivery of both affiliative and food reward images using a classical conditioning paradigm. Data from 20 typically developing young adults, and 20 individuals diagnosed with ADHD were included in a region-of-interest analysis for a priori striatal regions. Consistent with findings from studies using monetary rewards, individuals with ADHD showed decreased activation to cues predicting affiliative rewards in the bilateral ventral and dorsal striatum and increased activation to the delivery of affiliative rewards in the ventral striatum. No group differences were found in striatal responses to food reward cues or images. These results suggest hyposensitivity to reward-predicting cues in ADHD extends to affiliative rewards, with important implications for understanding and managing the learning and social functioning of those with ADHD.

Sequentially switching cell assemblies in random inhibitory networks of spiking neurons in the striatum.

The striatum is composed of GABAergic medium spiny neurons with inhibitory collaterals forming a sparse random asymmetric network and receiving an excitatory glutamatergic cortical projection. Because the inhibitory collaterals are sparse and weak, their role in striatal network dynamics is puzzling. However, here we show by simulation of a striatal inhibitory network model composed of spiking neurons that cells form assemblies that fire in sequential coherent episodes and display complex identity-temporal spiking patterns even when cortical excitation is simply constant or fluctuating noisily. Strongly correlated large-scale firing rate fluctuations on slow behaviorally relevant timescales of hundreds of milliseconds are shown by members of the same assembly whereas members of different assemblies show strong negative correlation, and we show how randomly connected spiking networks can generate this activity. Cells display highly irregular spiking with high coefficients of variation, broadly distributed low firing rates, and interspike interval distributions that are consistent with exponentially tailed power laws. Although firing rates vary coherently on slow timescales, precise spiking synchronization is absent in general. Our model only requires the minimal but striatally realistic assumptions of sparse to intermediate random connectivity, weak inhibitory synapses, and sufficient cortical excitation so that some cells are depolarized above the firing threshold during up states. Our results are in good qualitative agreement with experimental studies, consistent with recently determined striatal anatomy and physiology, and support a new view of endogenously generated metastable state switching dynamics of the striatal network underlying its information processing operations.

Short-latency activation of striatal spiny neurons via subcortical visual pathways.

The striatum is a site of integration of neural pathways involved in reinforcement learning. Traditionally, inputs from cerebral cortex are thought to be reinforced by dopaminergic afferents signaling the occurrence of biologically salient sensory events. Here, we detail an alternative route for short-latency sensory-evoked input to the striatum requiring neither dopamine nor the cortex. Using intracellular recording techniques, we measured subthreshold inputs to spiny projection neurons (SPNs) in urethane-anesthetized rats. Contralateral whole-field light flashes evoked weak membrane potential responses in approximately two-thirds of neurons. However, after local disinhibitory injections of the GABA(A) antagonist bicuculline into the deep layers of the superior colliculus (SC), but not the overlying visual cortex, strong, light-evoked, depolarizations to the up state emerged at short latency (115 +/- 14 ms) in all neurons tested. Dopamine depletion using alpha-methyl-para-tyrosine had no detectable effect on striatal visual responses during SC disinhibition. In contrast, local inhibitory injections of GABA agonists, muscimol and baclofen, into the parafascicular nucleus of the thalamus blocked the early, visual-evoked up-state transitions in SPNs. Comparable muscimol-induced inhibition of the visual cortex failed to suppress the visual responsiveness of SPNs induced by SC disinhibition. Together, these results suggest that short-latency, preattentive visual input can reach the striatum not only via the tecto-nigro-striatal route but also through tecto-thalamo-striatal projections. Thus, after the onset of a biologically significant visual event, closely timed short-latency thalamostriatal (glutamate) and nigrostriatal (dopamine) inputs are likely to converge on striatal SPNs, providing depolarizing and neuromodulator signals necessary for synaptic plasticity mechanisms.

Methylphenidate modifies reward cue responses in adults with ADHD: An fMRI study.

Attention deficit hyperactivity disorder (ADHD) has been associated with neural hyposensitivity to reward-predicting cues. Methylphenidate is widely used in the management of the disorder's symptoms, but its effects on reward sensitivity in ADHD are unknown. The current study used fMRI to measure striatal responses to reward-predicting cues in adults with ADHD on and off methylphenidate and a control group, during a classical conditioning task. Responses to cued reward were also explored. Larger differences in the ventral striatum activation to reward cues versus non-reward cues were observed when the ADHD participants were on methylphenidate compared to placebo. In response to cued-reward outcome, an exploratory analysis showed methylphenidate reduced the BOLD time-series correlation between the dorsal striatum and dorsal medial prefrontal cortex. Methylphenidate's therapeutic effects may be mediated by altering reward processing in individuals with ADHD.

Space, time and dopamine.

In recent years, dopamine has emerged as a key neurotransmitter that is crucially involved in incentive motivation and reinforcement learning. Dopamine release is evoked by rewards. The extensive divergence of outputs from a small number of dopaminergic neurons suggests a spatially nonselective action of dopamine, but it reinforces the specific actions that led to reward. How is this achieved? We propose that the selectivity of dopamine effects is achieved by the timing of dopamine release in relation to the activity of glutamatergic synapses, rather than by spatial localization of the dopamine signal to specific synaptic contacts. The synaptic mechanisms of these actions are unknown but reduced levels of dopamine, for example in Parkinson's disease, leads to a paucity of behavioural output, whereas its excess production has been associated with psychiatric problems. Clearly, there are therapeutic imperatives that require a better understanding of how dopamine functions at a synaptic level.

Origins of altered reinforcement effects in ADHD.

Attention-deficit/hyperactivity disorder (ADHD), characterized by hyperactivity, impulsiveness and deficient sustained attention, is one of the most common and persistent behavioral disorders of childhood. ADHD is associated with catecholamine dysfunction. The catecholamines are important for response selection and memory formation, and dopamine in particular is important for reinforcement of successful behavior. The convergence of dopaminergic mesolimbic and glutamatergic corticostriatal synapses upon individual neostriatal neurons provides a favorable substrate for a three-factor synaptic modification rule underlying acquisition of associations between stimuli in a particular context, responses, and reinforcers. The change in associative strength as a function of delay between key stimuli or responses, and reinforcement, is known as the delay of reinforcement gradient. The gradient is altered by vicissitudes of attention, intrusions of irrelevant events, lapses of memory, and fluctuations in dopamine function. Theoretical and experimental analyses of these moderating factors will help to determine just how reinforcement processes are altered in ADHD. Such analyses can only help to improve treatment strategies for ADHD.

Research review: dopamine transfer deficit: a neurobiological theory of altered reinforcement mechanisms in ADHD.

This review considers the hypothesis that changes in dopamine signalling might account for altered sensitivity to positive reinforcement in children with ADHD. The existing evidence regarding dopamine cell activity in relation to positive reinforcement is reviewed. We focus on the anticipatory firing of dopamine cells brought about by a transfer of dopamine cell responses to cues that precede reinforcers. It is proposed that in children with ADHD there is diminished anticipatory dopamine cell firing, which we call the dopamine transfer deficit (DTD). The DTD theory leads to specific and testable predictions for human and animal research. The extent to which DTD explains symptoms of ADHD and effects of pharmacological interventions is discussed. We conclude by considering the neural changes underlying the etiology of DTD.

Interfacing with Neural Activity via Femtosecond Laser Stimulation of Drug-Encapsulating Liposomal Nanostructures.

External control over rapid and precise release of chemicals in the brain potentially provides a powerful interface with neural activity. Optical manipulation techniques, such as optogenetics and caged compounds, enable remote control of neural activity and behavior with fine spatiotemporal resolution. However, these methods are limited to chemicals that are naturally present in the brain or chemically suitable for caging. Here, we demonstrate the ability to interface with neural functioning via a wide range of neurochemicals released by stimulating loaded liposomal nanostructures with femtosecond lasers. Using a commercial two-photon microscope, we released inhibitory or excitatory neurochemicals to evoke subthreshold and suprathreshold changes in membrane potential in a live mouse brain slice. The responses were repeatable and could be controlled by adjusting laser stimulation characteristics. We also demonstrate the release of a wider range of chemicals-which previously were impossible to release by optogenetics or uncaging-including synthetic analogs of naturally occurring neurochemicals. In particular, we demonstrate the release of a synthetic receptor-specific agonist that exerts physiological effects on long-term synaptic plasticity. Further, we show that the loaded liposomal nanostructures remain functional for weeks in a live mouse. In conclusion, we demonstrate new techniques capable of interfacing with live neurons, and extendable to in vivo applications.

Modulation of an afterhyperpolarization by the substantia nigra induces pauses in the tonic firing of striatal cholinergic interneurons.

Striatal cholinergic interneurons, also known as tonically active neurons (TANs), acquire a pause in firing during learning of stimulus-reward associations. This pause response to a sensory stimulus emerges after repeated pairing with a reward. The conditioned pause is dependent on dopamine from the substantia nigra, but its underlying cellular mechanism is unknown. Using in vivo intracellular recording, we found that both subthreshold and suprathreshold depolarizations in cholinergic interneurons induced a prolonged after-hyperpolarization (AHP) associated with a pause in their tonic firing. The AHP duration was dependent on the level of depolarization, whether elicited by intracellular current injection or by activation of excitatory inputs from the cortex. High-frequency stimulation of the substantia nigra induced potentiation of the cortically evoked excitation and increased the prolonged AHP after the stimulus. These findings from anesthetized animals suggest that a substantia nigra-induced AHP produces stimulus-associated firing pauses in cholinergic interneurons. This mechanism may underlie the acquisition of the pause response in TANs recorded from behaving animals during learning.

Hebb, pandemonium and catastrophic hypermnesia: the hippocampus as a suppressor of inappropriate associations.

The hippocampus has been proposed as a key component of a "behavioural inhibition system". We explore the implications of this idea for the nature of associative memory--i.e. learning that is distinct from the moulding of response sequences by error correction and reinforcement. It leads to the view that all associative memory depends on purely Hebbian mechanisms. Memories involve acquisition of new goals not the strengthening of new stimulus-response links. Critically, memories will consist of affectively positive and affectively negative associations as well "purely cognitive" information. The hippocampus is seen as a supervisor that is normally "just checking" information about current available goals. When one available goal is pre-eminent there is no hippocampal output and the goal controls the response system. When two or more goals are similarly and highly primed there is conflict. This is detected by the hippocampus which sends output that increases the valence of affectively negative perceptions and so resolves the conflict by suppressing more aversive goals. Such conflict resolution occurs with innate as well as acquired goals and is fundamentally non-memorial. But, in memory paradigms, it can often act to suppress interference on the current trial and, through Hebbian association of the increase in negative affect, decrease the probability of interference on later trials and during consolidation. Both memory-driven and innate behaviour is made hippocampal-dependent by innate and acquired conflicting tendencies and not the class of stimulus presented.

Abnormal striatal BOLD responses to reward anticipation and reward delivery in ADHD.

Altered reward processing has been proposed to contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The neurobiological mechanism underlying this alteration remains unclear. We hypothesize that the transfer of dopamine release from reward to reward-predicting cues, as normally observed in animal studies, may be deficient in ADHD. Functional magnetic resonance imaging (fMRI) was used to investigate striatal responses to reward-predicting cues and reward delivery in a classical conditioning paradigm. Data from 14 high-functioning and stimulant-naïve young adults with elevated lifetime symptoms of ADHD (8 males, 6 females) and 15 well-matched controls (8 males, 7 females) were included in the analyses. During reward anticipation, increased blood-oxygen-level-dependent (BOLD) responses in the right ventral and left dorsal striatum were observed in controls, but not in the ADHD group. The opposite pattern was observed in response to reward delivery; the ADHD group demonstrated significantly greater BOLD responses in the ventral striatum bilaterally and the left dorsal striatum relative to controls. In the ADHD group, the number of current hyperactivity/impulsivity symptoms was inversely related to ventral striatal responses during reward anticipation and positively associated with responses to reward. The BOLD response patterns observed in the striatum are consistent with impaired predictive dopamine signaling in ADHD, which may explain altered reward-contingent behaviors and symptoms of ADHD.

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine--a key neurotransmitter of the central nervous system--thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

Input dependent cell assembly dynamics in a model of the striatal medium spiny neuron network.

The striatal medium spiny neuron (MSN) network is sparsely connected with fairly weak GABAergic collaterals receiving an excitatory glutamatergic cortical projection. Peri-stimulus time histograms (PSTH) of MSN population response investigated in various experimental studies display strong firing rate modulations distributed throughout behavioral task epochs. In previous work we have shown by numerical simulation that sparse random networks of inhibitory spiking neurons with characteristics appropriate for UP state MSNs form cell assemblies which fire together coherently in sequences on long behaviorally relevant timescales when the network receives a fixed pattern of constant input excitation. Here we first extend that model to the case where cortical excitation is composed of many independent noisy Poisson processes and demonstrate that cell assembly dynamics is still observed when the input is sufficiently weak. However if cortical excitation strength is increased more regularly firing and completely quiescent cells are found, which depend on the cortical stimulation. Subsequently we further extend previous work to consider what happens when the excitatory input varies as it would when the animal is engaged in behavior. We investigate how sudden switches in excitation interact with network generated patterned activity. We show that sequences of cell assembly activations can be locked to the excitatory input sequence and outline the range of parameters where this behavior is shown. Model cell population PSTH display both stimulus and temporal specificity, with large population firing rate modulations locked to elapsed time from task events. Thus the random network can generate a large diversity of temporally evolving stimulus dependent responses even though the input is fixed between switches. We suggest the MSN network is well suited to the generation of such slow coherent task dependent response which could be utilized by the animal in behavior.

Reinforcement, dopamine and rodent models in drug development for ADHD.

Attention deficit hyperactivity disorder (ADHD) presents special challenges for drug development. Current treatment with psychostimulants and nonstimulants is effective, but their mechanism of action beyond the cellular level is incompletely understood. We review evidence suggesting that altered reinforcement mechanisms are a fundamental characteristic of ADHD. We show that a deficit in the transfer of dopamine signals from established positive reinforcers to cues that predict such reinforcers may underlie these altered reinforcement mechanisms, and in turn explain key symptoms of ADHD. We argue that the neural substrates controlling the excitation and inhibition of dopamine neurons during the transfer process are a promising target for future drug development. There is a need to develop animal models and behavioral paradigms that can be used to experimentally investigate these mechanisms and their effects on sensitivity to reinforcement. More specific and selective targeting of drug development may be possible through this approach.

Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders.

Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both neurological and psychiatric disorders. Parkinson's disease is an archetypal disorder of dopamine dysfunction characterised by motor, cognitive, behavioural, and autonomic symptoms. While effective for motor symptoms, dopamine replacement therapy is associated not only with motor side-effects, such as levodopa-induced dyskinesia, but also behavioural side-effects such as impulse control disorders (eg, pathological gambling and shopping, binge eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive medication use. We review clinical features, overlapping molecular mechanisms, and a specific cognitive mechanism of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.