Coherent mapping of position and head direction across auditory and visual cortex.

Neurons in primary visual cortex (V1) may not only signal current visual input but also relevant contextual information such as reward expectancy and the subject's spatial position. Such contextual representations need not be restricted to V1 but could participate in a coherent mapping throughout sensory cortices. Here, we show that spiking activity coherently represents a location-specific mapping across auditory cortex (AC) and lateral, secondary visual cortex (V2L) of freely moving rats engaged in a sensory detection task on a figure-8 maze. Single-unit activity of both areas showed extensive similarities in terms of spatial distribution, reliability, and position coding. Importantly, reconstructions of subject position based on spiking activity displayed decoding errors that were correlated between areas. Additionally, we found that head direction, but not locomotor speed or head angular velocity, was an important determinant of activity in AC and V2L. By contrast, variables related to the sensory task cues or to trial correctness and reward were not markedly encoded in AC and V2L. We conclude that sensory cortices participate in coherent, multimodal representations of the subject's sensory-specific location. These may provide a common reference frame for distributed cortical sensory and motor processes and may support crossmodal predictive processing.

Neural Correlates of Multisensory Detection Behavior: Comparison of Primary and Higher-Order Visual Cortex.

We act upon stimuli in our surrounding environment by gathering the multisensory information they convey and by integrating this information to decide on a behavioral action. We hypothesized that the anterolateral secondary visual cortex (area AL) of the mouse brain may serve as a hub for sensorimotor transformation of audiovisual information. We imaged neuronal activity in primary visual cortex (V1) and AL of the mouse during a detection task using visual, auditory, and audiovisual stimuli. We found that AL neurons were more sensitive to weak uni- and multisensory stimuli compared to V1. Depending on contrast, different subsets of AL and V1 neurons showed cross-modal modulation of visual responses. During audiovisual stimulation, AL neurons showed stronger differentiation of behaviorally reported versus unreported stimuli compared to V1, whereas V1 showed this distinction during unisensory visual stimulation. Thus, neural population activity in area AL correlates more closely with multisensory detection behavior than V1.

The circuit architecture of cortical multisensory processing: Distinct functions jointly operating within a common anatomical network.

Our perceptual systems continuously process sensory inputs from different modalities and organize these streams of information such that our subjective representation of the outside world is a unified experience. By doing so, they also enable further cognitive processing and behavioral action. While cortical multisensory processing has been extensively investigated in terms of psychophysics and mesoscale neural correlates, an in depth understanding of the underlying circuit-level mechanisms is lacking. Previous studies on circuit-level mechanisms of multisensory processing have predominantly focused on cue integration, i.e. the mechanism by which sensory features from different modalities are combined to yield more reliable stimulus estimates than those obtained by using single sensory modalities. In this review, we expand the framework on the circuit-level mechanisms of cortical multisensory processing by highlighting that multisensory processing is a family of functions - rather than a single operation - which involves not only the integration but also the segregation of modalities. In addition, multisensory processing not only depends on stimulus features, but also on cognitive resources, such as attention and memory, as well as behavioral context, to determine the behavioral outcome. We focus on rodent models as a powerful instrument to study the circuit-level bases of multisensory processes, because they enable combining cell-type-specific recording and interventional techniques with complex behavioral paradigms. We conclude that distinct multisensory processes share overlapping anatomical substrates, are implemented by diverse neuronal micro-circuitries that operate in parallel, and are flexibly recruited based on factors such as stimulus features and behavioral constraints.

Audiovisual Integration Enhances Stimulus Detection Performance in Mice.

The detection of objects in the external world improves when humans and animals integrate object features of multiple sensory modalities. Behavioral and neuronal mechanisms underlying multisensory stimulus detection are poorly understood, mainly because they have not been investigated with suitable behavioral paradigms. Such behavioral paradigms should (i) elicit a robust multisensory gain, (ii) incorporate systematic calibration of stimulus amplitude to the sensory capacities of the individual subject, (iii) yield a high trial count, and (iv) be easily compatible with a large variety of neurophysiological recording techniques. We developed an audiovisual stimulus detection task for head-fixed mice which meets all of these critical behavioral constraints. Behavioral data obtained with this task indicated a robust increase in detection performance of multisensory stimuli compared with unisensory cues, which was maximal when both stimulus constituents were presented at threshold intensity. The multisensory behavioral effect was associated with a change in the perceptual performance which consisted of two components. First, the visual and auditory perceptual systems increased their sensitivity meaning that low intensity stimuli were more often detected. Second, enhanced acuity enabled the systems to better classify whether there was a stimulus or not. Fitting our data to signal detection models revealed that the multisensory gain was more likely to be achieved by integration of sensory signals rather than by stimulus redundancy or competition. This validated behavioral paradigm can be exploited to reliably investigate the neuronal correlates of multisensory stimulus detection at the level of single neurons, microcircuits, and larger perceptual systems.

Model-based spatial navigation in the hippocampus-ventral striatum circuit: A computational analysis.

While the neurobiology of simple and habitual choices is relatively well known, our current understanding of goal-directed choices and planning in the brain is still limited. Theoretical work suggests that goal-directed computations can be productively associated to model-based (reinforcement learning) computations, yet a detailed mapping between computational processes and neuronal circuits remains to be fully established. Here we report a computational analysis that aligns Bayesian nonparametrics and model-based reinforcement learning (MB-RL) to the functioning of the hippocampus (HC) and the ventral striatum (vStr)-a neuronal circuit that increasingly recognized to be an appropriate model system to understand goal-directed (spatial) decisions and planning mechanisms in the brain. We test the MB-RL agent in a contextual conditioning task that depends on intact hippocampus and ventral striatal (shell) function and show that it solves the task while showing key behavioral and neuronal signatures of the HC-vStr circuit. Our simulations also explore the benefits of biological forms of look-ahead prediction (forward sweeps) during both learning and control. This article thus contributes to fill the gap between our current understanding of computational algorithms and biological realizations of (model-based) reinforcement learning.

Audiovisual Modulation in Mouse Primary Visual Cortex Depends on Cross-Modal Stimulus Configuration and Congruency.

The sensory neocortex is a highly connected associative network that integrates information from multiple senses, even at the level of the primary sensory areas. Although a growing body of empirical evidence supports this view, the neural mechanisms of cross-modal integration in primary sensory areas, such as the primary visual cortex (V1), are still largely unknown. Using two-photon calcium imaging in awake mice, we show that the encoding of audiovisual stimuli in V1 neuronal populations is highly dependent on the features of the stimulus constituents. When the visual and auditory stimulus features were modulated at the same rate (i.e., temporally congruent), neurons responded with either an enhancement or suppression compared with unisensory visual stimuli, and their prevalence was balanced. Temporally incongruent tones or white-noise bursts included in audiovisual stimulus pairs resulted in predominant response suppression across the neuronal population. Visual contrast did not influence multisensory processing when the audiovisual stimulus pairs were congruent; however, when white-noise bursts were used, neurons generally showed response suppression when the visual stimulus contrast was high whereas this effect was absent when the visual contrast was low. Furthermore, a small fraction of V1 neurons, predominantly those located near the lateral border of V1, responded to sound alone. These results show that V1 is involved in the encoding of cross-modal interactions in a more versatile way than previously thought.SIGNIFICANCE STATEMENT The neural substrate of cross-modal integration is not limited to specialized cortical association areas but extends to primary sensory areas. Using two-photon imaging of large groups of neurons, we show that multisensory modulation of V1 populations is strongly determined by the individual and shared features of cross-modal stimulus constituents, such as contrast, frequency, congruency, and temporal structure. Congruent audiovisual stimulation resulted in a balanced pattern of response enhancement and suppression compared with unisensory visual stimuli, whereas incongruent or dissimilar stimuli at full contrast gave rise to a population dominated by response-suppressing neurons. Our results indicate that V1 dynamically integrates nonvisual sources of information while still attributing most of its resources to coding visual information.

Reward Expectancy Strengthens CA1 Theta and Beta Band Synchronization and Hippocampal-Ventral Striatal Coupling.

The use of information from the hippocampal memory system in motivated behavior depends on its communication with the ventral striatum. When an animal encounters cues that signal subsequent reward, its reward expectancy is raised. It is unknown, however, how this process affects hippocampal dynamics and their influence on target structures, such as ventral striatum. We show that, in rats, reward-predictive cues result in enhanced hippocampal theta and beta band rhythmic activity during subsequent action, compared with uncued goal-directed navigation. The beta band component, also labeled theta's harmonic, involves selective hippocampal CA1 cell groups showing frequency doubling of firing periodicity relative to theta rhythmicity and it partitions the theta cycle into segments showing clear versus poor spike timing organization. We found that theta phase precession occurred over a wider range than previously reported. This was apparent from spikes emitted near the peak of the theta cycle exhibiting large "phase precessing jumps" relative to spikes in foregoing cycles. Neither this phenomenon nor the regular manifestation of theta phase precession was affected by reward expectancy. Ventral striatal neuronal firing phase-locked not only to hippocampal theta, but also to beta band activity. Both hippocampus and ventral striatum showed increased synchronization between neuronal firing and local field potential activity during cued compared with uncued goal approaches. These results suggest that cue-triggered reward expectancy intensifies hippocampal output to target structures, such as the ventral striatum, by which the hippocampus may gain prioritized access to systems modulating motivated behaviors. SIGNIFICANCE STATEMENT: Here we show that temporally discrete cues raising reward expectancy enhance both theta and beta band activity in the hippocampus once goal-directed navigation has been initiated. These rhythmic activities are associated with increased synchronization of neuronal firing patterns in the hippocampus and the connected ventral striatum. When transmitted to downstream target structures, this expectancy-related state of intensified processing in the hippocampus may modulate goal-directed action.

Population-Level Neural Codes Are Robust to Single-Neuron Variability from a Multidimensional Coding Perspective.

Sensory neurons are often tuned to particular stimulus features, but their responses to repeated presentation of the same stimulus can vary over subsequent trials. This presents a problem for understanding the functioning of the brain, because downstream neuronal populations ought to construct accurate stimulus representations, even upon singular exposure. To study how trial-by-trial fluctuations (i.e., noise) in activity influence cortical representations of sensory input, we performed chronic calcium imaging of GCaMP6-expressing populations in mouse V1. We observed that high-dimensional response correlations, i.e., dependencies in activation strength among multiple neurons, can be used to predict single-trial, single-neuron noise. These multidimensional correlations are structured such that variability in the response of single neurons is relatively harmless to population representations of visual stimuli. We propose that multidimensional coding may represent a canonical principle of cortical circuits, explaining why the apparent noisiness of neuronal responses is compatible with accurate neural representations of stimulus features.

Internally generated sequences in learning and executing goal-directed behavior.

A network of brain structures including hippocampus (HC), prefrontal cortex, and striatum controls goal-directed behavior and decision making. However, the neural mechanisms underlying these functions are unknown. Here, we review the role of 'internally generated sequences': structured, multi-neuron firing patterns in the network that are not confined to signaling the current state or location of an agent, but are generated on the basis of internal brain dynamics. Neurophysiological studies suggest that such sequences fulfill functions in memory consolidation, augmentation of representations, internal simulation, and recombination of acquired information. Using computational modeling, we propose that internally generated sequences may be productively considered a component of goal-directed decision systems, implementing a sampling-based inference engine that optimizes goal acquisition at multiple timescales of on-line choice, action control, and learning.

Functions of gamma-band synchronization in cognition: from single circuits to functional diversity across cortical and subcortical systems.

Gamma-band activity (30-90 Hz) and the synchronization of neural activity in the gamma-frequency range have been observed in different cortical and subcortical structures and have been associated with different cognitive functions. However, it is still unknown whether gamma-band synchronization subserves a single universal function or a diversity of functions across the full spectrum of cognitive processes. Here, we address this question reviewing the mechanisms of gamma-band oscillation generation and the functions associated with gamma-band activity across several cortical and subcortical structures. Additionally, we raise a plausible explanation of why gamma rhythms are found so ubiquitously across brain structures. Gamma band activity originates from the interplay between inhibition and excitation. We stress that gamma oscillations, associated with this interplay, originate from basic functional motifs that conferred advantages for low-level system processing and multiple cognitive functions throughout evolution. We illustrate the multifunctionality of gamma-band activity by considering its role in neural systems for perception, selective attention, memory, motivation and behavioral control. We conclude that gamma-band oscillations support multiple cognitive processes, rather than a single one, which, however, can be traced back to a limited set of circuit motifs which are found universally across species and brain structures.

Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function.

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.

Reward cues in space: commonalities and differences in neural coding by hippocampal and ventral striatal ensembles.

Forming place-reward associations critically depends on the integrity of the hippocampal-ventral striatal system. The ventral striatum (VS) receives a strong hippocampal input conveying spatial-contextual information, but it is unclear how this structure integrates this information to invigorate reward-directed behavior. Neuronal ensembles in rat hippocampus (HC) and VS were simultaneously recorded during a conditioning task in which navigation depended on path integration. In contrast to HC, ventral striatal neurons showed low spatial selectivity, but rather coded behavioral task phases toward reaching goal sites. Outcome-predicting cues induced a remapping of firing patterns in the HC, consistent with its role in episodic memory. VS remapped in conjunction with the HC, indicating that remapping can take place in multiple brain regions engaged in the same task. Subsets of ventral striatal neurons showed a "flip" from high activity when cue lights were illuminated to low activity in intertrial intervals, or vice versa. The cues induced an increase in spatial information transmission and sparsity in both structures. These effects were paralleled by an enhanced temporal specificity of ensemble coding and a more accurate reconstruction of the animal's position from population firing patterns. Altogether, the results reveal strong differences in spatial processing between hippocampal area CA1 and VS, but indicate similarities in how discrete cues impact on this processing.

Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum.

Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high-frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior.

Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons.

While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.

Fast-spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward.

Although previous in vitro studies revealed inhibitory synaptic connections of fast-spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast-spiking neurons were distinguished from putative medium-sized spiny neurons on the basis of their spike waveforms and rates. Cross-correlograms of fast-spiking and putative medium-sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium-sized spiny neuron spiking around fast-spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast-spiking unit firing. Many of these temporal relationships were dependent on the sleep-wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast-spiking units and putative medium-sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast-spiking neurons in a reward-searching task, they generally showed a pre-reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed-forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast-spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward-related changes in firing rate.

Reward-associated gamma oscillations in ventral striatum are regionally differentiated and modulate local firing activity.

Oscillations of local field potentials (LFPs) in the gamma range are found in many brain regions and are supposed to support the temporal organization of cognitive, perceptual, and motor functions. Even though gamma oscillations have also been observed in ventral striatum, one of the brain's most important structures for motivated behavior and reward processing, their specific function during ongoing behavior is unknown. Using a movable tetrode array, we recorded LFPs and activity of neural ensembles in the ventral striatum of rats performing a reward-collection task. Rats were running along a triangle track and in each round collected one of three different types of rewards. The gamma power of LFPs on subsets of tetrodes was modulated by reward-site visits, discriminated between reward types, between baitedness of reward locations and was different before versus after arrival at a reward site. Many single units in ventral striatum phase-locked their discharge pattern to the gamma oscillations of the LFPs. Phase-locking occurred more often in reward-related than in reward-unrelated neurons and LFPs. A substantial number of simultaneously recorded LFPs correlated poorly with each other in terms of gamma rhythmicity, indicating that the expression of gamma activity was heterogeneous and regionally differentiated. The orchestration of LFPs and single-unit activity by way of gamma rhythmicity sheds light on the functional architecture of the ventral striatum and the temporal coordination of ventral striatal activity for modulating downstream areas and regulating synaptic plasticity.

Integrating early results on ventral striatal gamma oscillations in the rat.

A vast literature implicates the ventral striatum in the processing of reward-related information and in mediating the impact of such information on behavior. It is characterized by heterogeneity at the local circuit, connectivity, and functional levels. A tool for dissecting this complex structure that has received relatively little attention until recently is the analysis of ventral striatal local field potential oscillations, which are more prominent in the gamma band compared to the dorsal striatum. Here we review recent results on gamma oscillations recorded from freely moving rats. Ventral striatal gamma separates into distinct frequency bands (gamma-50 and gamma-80) with distinct behavioral correlates, relationships to different inputs, and separate populations of phase-locked putative fast-spiking interneurons. Fast switching between gamma-50 and gamma-80 occurs spontaneously but is influenced by reward delivery as well as the application of dopaminergic drugs. These results provide novel insights into ventral striatal processing and highlight the importance of considering fast-timescale dynamics of ventral striatal activity.

Corticostriatal Interactions during Learning, Memory Processing, and Decision Making.

This mini-symposium aims to integrate recent insights from anatomy, behavior, and neurophysiology, highlighting the anatomical organization, behavioral significance, and information-processing mechanisms of corticostriatal interactions. In this summary of topics, which is not meant to provide a comprehensive survey, we will first review the anatomy of corticostriatal circuits, comparing different ways by which "loops" of cortical-basal ganglia circuits communicate. Next, we will address the causal importance and systems-neurophysiological mechanisms of corticostriatal interactions for memory, emphasizing the communication between hippocampus and ventral striatum during contextual conditioning. Furthermore, ensemble recording techniques have been applied to compare information processing in the dorsal and ventral striatum to predictions from reinforcement learning theory. We will next discuss how neural activity develops in corticostriatal areas when habits are learned. Finally, we will evaluate the role of GABAergic interneurons in dynamically transforming cortical inputs into striatal output during learning and decision making.

Hippocampus leads ventral striatum in replay of place-reward information.

Associating spatial locations with rewards is fundamental to survival in natural environments and requires the integrity of the hippocampus and ventral striatum. In joint multineuron recordings from these areas, hippocampal-striatal ensembles reactivated together during sleep. This process was especially strong in pairs in which the hippocampal cell processed spatial information and ventral striatal firing correlated to reward. Replay was dominated by cell pairs in which the hippocampal "place" cell fired preferentially before the striatal reward-related neuron. Our results suggest a plausible mechanism for consolidating place-reward associations and are consistent with a central tenet of consolidation theory, showing that the hippocampus leads reactivation in a projection area.

Preferential reactivation of motivationally relevant information in the ventral striatum.

Spontaneous "off-line" reactivation of neuronal activity patterns may contribute to the consolidation of memory traces. The ventral striatum exhibits reactivation and has been implicated in the processing of motivational information. It is unknown, however, whether reactivating neuronal ensembles specifically recapitulate information relating to rewards that were encountered during wakefulness. We demonstrate a prolonged reactivation in rat ventral striatum during quiet wakefulness and slow-wave but not rapid eye movement sleep. Reactivation of reward-related information processed in this structure was particularly prominent, and this was primarily attributable to spike trains temporally linked to reward sites. It was accounted for by small, strongly correlated subgroups in recorded cell assemblies and can thus be characterized as a sparse phenomenon. Our results indicate that reactivated memory traces may not only comprise feature- and context-specific information but also contain a value component.