Rhythmic oscillations in the midbrain dopaminergic nuclei in mice.

Introduction: Dopamine release in the forebrain by midbrain ventral tegmental nucleus (VTA) and substantia nigra pars compacta (SNc) neurons is implicated in reward processing, goal-directed learning, and decision-making. Rhythmic oscillations of neural excitability underlie coordination of network processing, and have been reported in these dopaminergic nuclei at several frequency bands. This paper provides a comparative characterization of several frequencies of oscillations of local field potential and single unit activity, highlighting some behavioral correlates. Methods: We recorded from optogenetically identified dopaminergic sites in four mice training in operant olfactory and visual discrimination tasks. Results: Rayleigh and Pairwise Phase Consistency (PPC) analyses revealed some VTA/SNc neurons phase-locked to each frequency range, with fast spiking interneurons (FSIs) prevalent at 1-2.5 Hz (slow) and 4 Hz bands, and dopaminergic neurons predominant in the theta band. More FSIs than dopaminergic neurons were phase-locked in the slow and 4 Hz bands during many task events. The highest incidence of phase-locking in neurons was in the slow and 4 Hz bands, and occurred during the delay between the operant choice and trial outcome (reward or punishment) signals. Discussion: These data provide a basis for further examination of rhythmic coordination of activity of dopaminergic nuclei with other brain structures, and its impact for adaptive behavior.

Activation of prefrontal cortex and striatal regions in rats after shifting between rules in a T-maze.

Prefrontal cortical and striatal areas have been identified by inactivation or lesion studies to be required for behavioral flexibility, including selecting and processing of different types of information. In order to identify these networks activated selectively during the acquisition of new reward contingency rules, rats were trained to discriminate orientations of bars presented in pseudorandom sequence on two video monitors positioned behind the goal sites on a T-maze with return arms. A second group already trained in the visual discrimination task learned to alternate left and right goal arm visits in the same maze while ignoring the visual cues still being presented. In each experimental group, once the rats reached criterion performance, the brains were prepared after a 90-min delay for later processing for c-fos immunohistochemistry. While both groups extinguished a prior strategy and acquired a new rule, they differed by the identity of the strategies and previous learning experience. Among the 28 forebrain areas examined, there were significant increases in the relative density of c-fos immunoreactive cell bodies after learning the second rule in the prefrontal cortex cingulate, the prelimbic and infralimbic areas, the dorsomedial striatum and the core of the nucleus accumbens, the ventral subiculum, and the central nucleus of the amygdala. These largely correspond to structures previously identified in inactivation studies, and their neurons fire synchronously during learning and strategy shifts. The data suggest that this dynamic network may underlie reward-based selection for action-a type of cognitive flexibility.

Locus coeruleus noradrenergic neurons phase-lock to prefrontal and hippocampal infra-slow rhythms that synchronize to behavioral events.

The locus coeruleus (LC) is the primary source of noradrenergic projections to the forebrain, and, in prefrontal cortex, is implicated in decision-making and executive function. LC neurons phase-lock to cortical infra-slow wave oscillations during sleep. Such infra-slow rhythms are rarely reported in awake states, despite their interest, since they correspond to the time scale of behavior. Thus, we investigated LC neuronal synchrony with infra-slow rhythms in awake rats performing an attentional set-shifting task. Local field potential (LFP) oscillation cycles in prefrontal cortex and hippocampus on the order of 0.4 Hz phase-locked to task events at crucial maze locations. Indeed, successive cycles of the infra-slow rhythms showed different wavelengths, as if they are periodic oscillations that can reset phase relative to salient events. Simultaneously recorded infra-slow rhythms in prefrontal cortex and hippocampus could show different cycle durations as well, suggesting independent control. Most LC neurons (including optogenetically identified noradrenergic neurons) recorded here were phase-locked to these infra-slow rhythms, as were hippocampal and prefrontal units recorded on the LFP probes. The infra-slow oscillations also phase-modulated gamma amplitude, linking these rhythms at the time scale of behavior to those coordinating neuronal synchrony. This would provide a potential mechanism where noradrenaline, released by LC neurons in concert with the infra-slow rhythm, would facilitate synchronization or reset of these brain networks, underlying behavioral adaptation.

Post-trauma behavioral phenotype predicts the degree of vulnerability to fear relapse after extinction in male rats.

Current treatments for trauma-related disorders remain ineffective for many patients.1,2 Fear extinction deficiency is a prominent feature of these diseases,3 and many behavioral treatments rely on extinction training.4,5 However, in many patients, therapy is followed by a relapse of symptoms, and the underpinnings of such interindividual variations in vulnerability to relapse remain unknown.6-8 Here, we modeled interindividual differences in post-therapy fear relapse with an ethologically relevant trauma recovery paradigm. After fear conditioning, male rats underwent fear extinction while foraging in a large enriched arena, permitting the expression of a wide spectrum of behaviors. An automated multidimensional behavioral assessment revealed that post-conditioning fear response profiles clustered into two groups: some animals expressed fear by freezing more, whereas others darted more, as if fleeing from danger. Remarkably, the tendency of an animal to dart or to freeze after CS presentation during the first extinction session was, respectively, associated with stronger or weaker fear renewal. Moreover, genome-wide transcriptional profiling revealed that these groups differentially regulated specific sets of genes, some of which were previously implicated in anxiety and trauma-related disorders. Our results suggest that post-trauma behavioral phenotypes and the associated gene expression landscapes can serve as markers of fear relapse susceptibility and thus may be instrumental for future development of more effective treatments for psychiatric patients.

Distributed cell assemblies spanning prefrontal cortex and striatum.

Highly synchronous neuronal assembly activity is deemed essential for cognitive brain function. In theory, such synchrony could coordinate multiple brain areas performing complementary processes. However, cell assemblies have been observed only in single structures, typically cortical areas, and little is known about their synchrony with downstream subcortical structures, such as the striatum. Here, we demonstrate distributed cell assemblies activated at high synchrony (∼10 ms) spanning prefrontal cortex and striatum. In addition to including neurons at different brain hierarchical levels, surprisingly, they synchronized functionally distinct limbic and associative sub-regions. These assembly activations occurred when members shifted their firing phase relative to ongoing 4 Hz and theta rhythms, in association with high gamma oscillations. This suggests that these rhythms could mediate the emergence of cross-structural assemblies. To test for the role of assemblies in behavior, we trained the rats to perform a task requiring cognitive flexibility, alternating between two different rules in a T-maze. Overall, assembly activations were correlated with task-relevant parameters, including impending choice, reward, rule, or rule order. Moreover, these behavioral correlates were more robustly expressed by assemblies than by their individual member neurons. Finally, to verify whether assemblies can be endogenously generated, we found that they were indeed spontaneously reactivated during sleep and quiet immobility. Thus, cell assemblies are a more general coding mechanism than previously envisioned, linking distributed neocortical and subcortical areas at high synchrony.

Time as the fourth dimension in the hippocampus.

Experiences of animal and human beings are structured by the continuity of space and time coupled with the uni-directionality of time. In addition to its pivotal position in spatial processing and navigation, the hippocampal system also plays a central, multiform role in several types of temporal processing. These include timing and sequence learning, at scales ranging from meso-scales of seconds to macro-scales of minutes, hours, days and beyond, encompassing the classical functions of short term memory, working memory, long term memory, and episodic memories (comprised of information about when, what, and where). This review article highlights the principal findings and behavioral contexts of experiments in rats showing: 1) timing: tracking time during delays by hippocampal 'time cells' and during free behavior by hippocampal-afferent lateral entorhinal cortex ramping cells; 2) 'online' sequence processing: activity coding sequences of events during active behavior; 3) 'off-line' sequence replay: during quiescence or sleep, orderly reactivation of neuronal assemblies coding awake sequences. Studies in humans show neurophysiological correlates of episodic memory comparable to awake replay. Neural mechanisms are discussed, including ion channel properties, plateau and ramping potentials, oscillations of excitation and inhibition of population activity, bursts of high amplitude discharges (sharp wave ripples), as well as short and long term synaptic modifications among and within cell assemblies. Specifically conceived neural network models will suggest processes supporting the emergence of scalar properties (Weber's law), and include different classes of feedforward and recurrent network models, with intrinsic hippocampal coding for 'transitions' (sequencing of events or places).

Dizziness and Convergence Insufficiency in Children: Screening and Management.

OBJECTIVE: In children screened for dizziness with vergence disorders, we tested short and long term efficacy of orthoptic vergence training (OVT) and instructions to reduce screen usage. METHODS: Prospective study: Of the 179 children referred for vertigo or dizziness (over 3 years) with ophthalmological disorder as the only problem after complete oto-neuro-vestibular testing, 69 presented vergence insufficiency, and 49 accepted to participate in this study. 109 healthy children served as controls. All subjects had classic orthoptic evaluation and video binocular movement recordings during various oculomotor tasks. Patients were evaluated before OVT (M0), 3 months after the end of OVT (M3) and 9 months after the end of OVT (M9). Statistics compared orthoptic and oculomotor parameters between patients and controls over time with one-way ANCOVA, and mixed models, controlling for age and gender. RESULTS: Patients reported vertigo that was usually rotatory, lasting <15 min, associated with or alternating with headache (50%). Their exposure to small video screens and TV was intensive (∼3.6 h per day). At M0, all orthoptic and oculomotor parameters were statistically different in patients relative to controls (p < 0.0001) except for divergence. At M3, vertigo symptoms had disappeared in all of the patients, and all eye movement parameters improved significantly (p < 0.0001). At M9, this improvement remained stable or continued. CONCLUSION: Vergence disorders (assessed by abnormal orthoptic and oculomotor parameters) can generate symptoms of dizziness in children. Orthoptic treatment and instruction to reduce screen usage has a significant and long term effect on vertigo symptoms as well as oculomotor performances. Dizzy children should be screened for vergence disorders. WHAT THIS STUDY ADDS: Dizziness in children can be associated exclusively with insufficient convergence. Orthoptic training and instructions to reduce screen exposure made dizziness symptoms disappear and improved all eye movement parameters for 6 months. Vergence disorders should be screened for in dizzy children.

Behavioral correlates of activity of optogenetically identified locus coeruleus noradrenergic neurons in rats performing T-maze tasks.

The nucleusLocus Coeruleus (LC) is the major source of forebrain norepinephrine. LC is implicated in arousal, response to novelty, and cognitive functions, including decision-making and behavioral flexibility. One hypothesis is that LC activation promotes rapid shifts in cortical attentional networks following changes in environmental contingencies. Recent recordings further suggest LC is critical for mobilizing resources to deal with challenging situations. In the present study optogenetically identified LC neuronal activity was recorded in rats in a self-paced T-maze. Rats were trained on visual discrimination; then place-reward contingencies were instated. In the session where the animal shifted tasks the first time, the LC firing rate after visual cue onset increased significantly, even as the animal adhered to the previous rule. Firing rate also increased prior to crossing photodetectors that controlled stimulus onset and offset, and this was positively correlated with accelerations, consistent with a role in mobilizing effort. The results contribute to the growing evidence that the noradrenergic LC is essential for behavioral adaptation by promoting cognitive flexibility and mobilizing effort in face of changing environmental contingencies.

Video Head Impulse Tests with a Remote Camera System: Normative Values of Semicircular Canal Vestibulo-Ocular Reflex Gain in Infants and Children.

The video head impulse test (VHIT) is widely used to identify semicircular canal function impairments in adults. But classical VHIT testing systems attach goggles tightly to the head, which is not tolerated by infants. Remote video detection of head and eye movements resolves this issue and, here, we report VHIT protocols and normative values for children. Vestibulo-ocular reflex (VOR) gain was measured for all canals of 303 healthy subjects, including 274 children (aged 2.6 months-15 years) and 26 adults (aged 16-67). We used the Synapsys® (Marseilles, France) VHIT Ulmer system whose remote camera measures head and eye movements. HITs were performed at high velocities. Testing typically lasts 5-10 min. In infants as young as 3 months old, VHIT yielded good inter-measure replicability. VOR gain increases rapidly until about the age of 6 years (with variation among canals), then progresses more slowly to reach adult values by the age of 16. Values are more variable among very young children and for the vertical canals, but showed no difference for right versus left head rotations. Normative values of VOR gain are presented to help detect vestibular impairment in patients. VHIT testing prior to cochlear implants could help prevent total vestibular loss and the resulting grave impairments of motor and cognitive development in patients with residual unilateral vestibular function.

Retrospectively and prospectively modulated hippocampal place responses are differentially distributed along a common path in a continuous T-maze.

Hippocampal place responses can be prospectively or retrospectively modulated by the animal's future or prior trajectory. Two main hypotheses explain this. The "multiple-map hypothesis" switches between different maps for different trajectories (rate remapping). In contrast, in the "buffer hypothesis," the hippocampus encodes an ongoing representation that includes the recent past and/or the impending future choice. This study examines the distribution of prospective and retrospective responses distributed along a common path in a continuous T-maze (providing all four combinations of provenance and destination) during a visual discrimination task. The multiple-map hypothesis predicts either uniform distributions or concerted shifts about a task-decision relevant point, whereas the buffer hypothesis predicts a time-limited overexpression around choice points (with retrospective responses after the central arm entry point and prospective responses nearer its exit). Here bilateral recordings in the dorsal CA1 region of the rat hippocampus show that retrospective responses were twice as prevalent as prospective responses. Furthermore, retrospective and prospective modulations have distinct spatial distributions, with retrospective primarily in the first two-thirds of the central arm and prospective restricted to the last third. To test for possible trial-by-trial remapping in relation to the two-thirds transition point, data from the first and second halves of the sessions were compared. Backward drift of path-modulated activity was significant only for retrospective, but not prospective, fields. Thus, these data are more consistent with the buffer hypothesis. Retrospective and prospective modulation would then participate in a single hippocampal representation of spatial and behavioral context.

Vestibular activity and cognitive development in children: perspectives.

Vestibular signals play an essential role in oculomotor and static and dynamic posturomotor functions. Increasing attention is now focusing on their impact on spatial and non-spatial cognitive functions. Movements of the head in space evoke vestibular signals that make important contributions during the development of brain representations of body parts relative to one another as well as representations of body orientation and position within the environment. A central nervous system pathway relays signals from the vestibular nuclei to the hippocampal system where this input is indispensable for neuronal responses selective for the position and orientation of the head in space. One aspect of the hippocampal systems' processing to create episodic and contextual memories is its role in spatial orientation and navigation behaviors that require processing of relations between background cues. These are also impaired in adult patients with vestibular deficits. However little is known about the impact of vestibular loss on cognitive development in children. This is investigated here with a particular emphasis upon the hypothetical mechanisms and potential impact of vestibular loss at critical ages on the development of respective spatial and non-spatial cognitive processes and their brain substrates.

Optic flow stimuli update anterodorsal thalamus head direction neuronal activity in rats.

Head direction (HD) neurons fire selectively according to head orientation in the yaw plane relative to environmental landmark cues. Head movements provoke optic field flow signals that enter the vestibular nuclei, indicating head velocity, and hence angular displacements. To test whether optic field flow alone affects the directional firing of HD neurons, rats walked about on a circular platform as a spot array was projected onto the surrounding floor-to-ceiling cylindrical black curtain. Directional responses in the anterodorsal thalamus of four rats remained stable as they moved about with the point field but in the absence of landmark cues. Then, the spherical projector was rotated about its yaw axis at 4.5°/s for ∼90 s. In 27 sessions the mean drift speed of the preferred directions (PDs) was 1.48°/s (SD=0.78°/s; range: 0.15 to 2.88°/s). Thus, optic flow stimulation entrained PDs, albeit at drift speeds slower than the field rotation. This could be due to conflicts with vestibular, motor command, and efferent copy signals. After field rotation ended, 20/27 PDs drifted back to within 45° of the initial values over several minutes, generally following the shortest path to return to the initial value. Poststimulation drifts could change speed and/or direction, with mean speeds of 0.68±0.64°/s (range 0 to 1.36°/s). Since the HD cell pathway (containing anterodorsal thalamus) is the only known projection of head direction information to entorhinal grid cells and hippocampal place cells, yaw plane optic flow signals likely influence representations in this spatial reference coordinate system for orientation and navigation.

Dynamics of decision-related activity in hippocampus.

Place-selective activity in hippocampal neurons can be modulated by the trajectory that will be taken in the immediate future ("prospective coding"), information that could be useful in neural processes elaborating choices in route planning. To determine if and how hippocampal prospective neurons participate in decision making, we measured the time course of the evolution of prospective activity by recording place responses in rats performing a T-maze alternation task. After five or seven alternation trials, the routine was unpredictably interrupted by a photodetector-triggered visual cue as the rat crossed the middle of central arm, signaling it to suddenly change its intended choice. Comparison of the delays between light cue presentation and the onset of prospective activity for neurons with firing fields at various locations after the trigger point revealed a 420 ms processing delay. This surprisingly long delay indicates that prospective activity in the hippocampus appears much too late to generate planning or decision signals. This provides yet another example of a prominent brain activity that is unlikely to play a functional role in the cognitive function that it appears to represent (planning future trajectories). Nonetheless, the hippocampus may provide other contextual information to areas active at the earliest stages of selecting future paths, which would then return signals that help establish hippocampal prospective activity.

The hippocampus: hub of brain network communication for memory.

A complex brain network, centered on the hippocampus, supports episodic memories throughout their lifetimes. Classically, upon memory encoding during active behavior, hippocampal activity is dominated by theta oscillations (6-10Hz). During inactivity, hippocampal neurons burst synchronously, constituting sharp waves, which can propagate to other structures, theoretically supporting memory consolidation. This 'two-stage' model has been updated by new data from high-density electrophysiological recordings in animals that shed light on how information is encoded and exchanged between hippocampus, neocortex and subcortical structures such as the striatum. Cell assemblies (tightly related groups of cells) discharge together and synchronize across brain structures orchestrated by theta, sharp waves and slow oscillations, to encode information. This evolving dynamical schema is key to extending our understanding of memory processes.

Coherent theta oscillations and reorganization of spike timing in the hippocampal- prefrontal network upon learning.

To study the interplay between hippocampus and medial prefrontal cortex (Pfc) and its importance for learning and memory consolidation, we measured the coherence in theta oscillations between these two structures in rats learning new rules on a Y maze. Coherence peaked at the choice point, most strongly after task rule acquisition. Simultaneously, Pfc pyramidal neurons reorganized their phase, concentrating at hippocampal theta trough, and synchronous cell assemblies emerged. This synchronous state may result from increased inhibition exerted by interneurons on pyramidal cells, as measured by cross-correlation, and could be modulated by dopamine: we found similar hippocampal-Pfc theta coherence increases and neuronal phase shifts following local administration of dopamine in Pfc of anesthetized rats. Pfc cell assemblies emerging during high coherence were preferentially replayed during subsequent sleep, concurrent with hippocampal sharp waves. Thus, hippocampal/prefrontal coherence could lead to synchronization of reward predicting activity in prefrontal networks, tagging it for subsequent memory consolidation.

Sequential Reinstatement of Neocortical Activity during Slow Oscillations Depends on Cells' Global Activity.

During Slow Wave Sleep (SWS), cortical activity is dominated by endogenous processes modulated by slow oscillations (0.1-1 Hz): cell ensembles fluctuate between states of sustained activity (UP states) and silent epochs (DOWN states). We investigate here the temporal structure of ensemble activity during UP states by means of multiple single unit recordings in the prefrontal cortex of naturally sleeping rats. As previously shown, the firing rate of each PFC cell peaks at a distinct time lag after the DOWN/UP transition in a consistent order. We show here that, conversely, the latency of the first spike after the UP state onset depends primarily on the session-averaged firing rates of cells (which can be considered as an indirect measure of their intrinsic excitability). This latency can be explained by a simple homogeneous process (Poisson model) of cell firing, with sleep averaged firing rates employed as parameters. Thus, at DOWN/UP transitions, neurons are affected both by a slow process, possibly originating in the cortical network, modulating the time course of firing for each cell, and by a fast, relatively stereotyped reinstatement of activity, related mostly to global activity levels.

Principal component analysis of ensemble recordings reveals cell assemblies at high temporal resolution.

Simultaneous recordings of many single neurons reveals unique insights into network processing spanning the timescale from single spikes to global oscillations. Neurons dynamically self-organize in subgroups of coactivated elements referred to as cell assemblies. Furthermore, these cell assemblies are reactivated, or replayed, preferentially during subsequent rest or sleep episodes, a proposed mechanism for memory trace consolidation. Here we employ Principal Component Analysis to isolate such patterns of neural activity. In addition, a measure is developed to quantify the similarity of instantaneous activity with a template pattern, and we derive theoretical distributions for the null hypothesis of no correlation between spike trains, allowing one to evaluate the statistical significance of instantaneous coactivations. Hence, when applied in an epoch different from the one where the patterns were identified, (e.g. subsequent sleep) this measure allows to identify times and intensities of reactivation. The distribution of this measure provides information on the dynamics of reactivation events: in sleep these occur as transients rather than as a continuous process.

Selective suppression of hippocampal ripples impairs spatial memory.

Sharp wave-ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.

Replay of rule-learning related neural patterns in the prefrontal cortex during sleep.

Slow-wave sleep (SWS) is important for memory consolidation. During sleep, neural patterns reflecting previously acquired information are replayed. One possible reason for this is that such replay exchanges information between hippocampus and neocortex, supporting consolidation. We recorded neuron ensembles in the rat medial prefrontal cortex (mPFC) to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts. In general, reactivation of learning-related patterns occurred in distinct, highly synchronized transient bouts, mostly simultaneous with hippocampal sharp wave/ripple complexes (SPWRs), when hippocampal ensemble reactivation and cortico-hippocampal interaction is enhanced. During sleep following learning of a new rule, mPFC neural patterns that appeared during response selection replayed prominently, coincident with hippocampal SPWRs. This was learning dependent, as the patterns appeared only after rule acquisition. Therefore, learning, or the resulting reliable reward, influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network.

Anticipatory reward signals in ventral striatal neurons of behaving rats.

It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of 'Actor-Critic' models of trial-and-error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model's adequacy for VS responses to multiple rewards in rats. The respective arms of a plus-maze provided rewards of varying magnitudes; multiple rewards were provided at 1-s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor-related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward-prediction profiles during reward consumption due to a temporal-order signal introduced to reproduce accurate timing in dopaminergic reward-prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal-order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD-learning architecture where different groups of neurons participate in solving the task based on varied input information.