Sidney I. Wiener

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.

Inertial, Substratal and Landmark Cue Control of Hippocampal CA1 Place Cell Activity

Hippocampal ‘place cells’ discharge when a rat occupies a location that is fixed in relation to environmental landmarks. A principal goal of this study was to determine whether hippocampal place cell activity could be influenced by inertial cues. Water‐deprived rats were trained in a square‐walled open field in a dark room. The behavioural task required alternating visits to water reservoirs in the centre and in the four corners of the arena. The rat and arena were rotated in total darkness through ±90, 180 or 270°. The next water reward was then presented in the corner at the same position relative to the outside room as before the rotation. A cue card was later illuminated in this corner as a visual cue for the extra‐arena (room) reference frame. Fifteen out of 97 recorded hippocampal CA1 complex spike cells had spatially selective discharges in non‐central parts of the arena. After arena rotations, the firing fields of three units shifted between corners of the arena to maintain a fixed orientation relative to the room. This indicates that the hippocampus updated its representation of the position and heading direction of the rat using vestibular‐derived inputs concerning rotation angle. Other spatially selective discharges were guided to landmark cues (cue card or position of the reward: two units) or arena‐locked ‘substratal’ cues (eight units). In six cells, place cell activity suddenly ceased or appeared following rotations. These results provide evidence for contributions of inertial as well as substratal and landmark information to hippocampal spatial representations.

Fabrication technology for silicon-based microprobe arrays used in acute and sub-chronic neural recording

This work presents a new fabrication technology for silicon-based neural probe devices and their assembly into two-dimensional (2D) as well as three-dimensional (3D) microprobe arrays for neural recording. The fabrication is based on robust double-sided deep reactive ion etching of standard silicon wafers and allows full 3D control of the probe geometry. Wafer level electroplating of gold pads was performed to improve the 3D assembly into a platform. Lithography-based probe-tracking features for quality management were introduced. Probes for two different assembly methods, namely direct bonding to a flexible micro-cable and platform-based out-of-plane interconnection, were produced. Systems for acute and sub-chronic recordings were assembled and characterized. Recordings from rats demonstrated the recording capability of these devices.

Position and behavioral modulation of synchronization of hippocampal and accumbens neuronal discharges in freely moving rats.

To understand how hippocampal signals are processed by downstream neurons, we analyzed the relative timing between neuronal discharges in simultaneous recordings in the hippocampus and nucleus accumbens of rats performing in a plus maze. In all, 154 pairs of cells (composed of 65 hippocampal and 56 accumbens neurons) were examined during the 1 s period prior to reward delivery. Cross‐correlation analyses over a ±300‐ms window with 10‐ms bins revealed that 108 pairs had at least one significant histogram bin (P < 0.01). The most frequently occurring peaks of hippocampal firing prior to accumbens discharges appeared at latencies from −30–0 ms, corresponding to published values of the latency of the hippocampal pathway to the nucleus accumbens. Other peaks appeared most often at latencies multiples of about 110 ms prior to and after this, corresponding to theta rhythmicity. Since firing synchronization can result from several types of connectivity patterns (such as common inputs), a group of 18 hippocampus‐accumbens pairs was selected as those most likely to have monosynaptic connections. The criterion was the presence of at least one highly significant peak (P < 0.001) at latencies corresponding to field potentials evoked in the accumbens by hippocampal stimulation. A significant peak occurred on all four maze arms for only one of these cell pairs, indicating positional modulation for the others. In addition, behavior dependence of the synchrony between these nucleus accumbens and hippocampus neurons was examined by studying data in relation to three different synchronization points: reward box arrival, box departure, and arrival at the center of the maze. This indicates that the functional connectivity between hippocampal and accumbens neurons was stronger when the rat was near reward areas. Ten of the hippocampal neurons in these 18 cell pairs showed 9‐Hz (theta) rhythmic activity in autocorrelation analyses. Of these 10 cells, cross‐correlograms from eight hippocampal‐accumbens pairs also showed theta rhythmicity. Overall, these results indicate that the synchrony between hippocampus and nucleus accumbens neurons is modulated by spatial position and behavior, and theta rhythm may play an important role for this synchronization. Hippocampus 2000;10:717–728.

Multisensory processing in the elaboration of place and head direction responses by limbic system neurons.

This review explores the roles of several sensory modalities in the establishment and maintenance of discharges correlated with head position and orientation in neurons of the hippocampus and associated structures in the Papez circuit. Focus is placed on the integration of signals related to environmental cues and to displacement movements, both of external and internal origin. While the visual, vestibular and motor systems each exert influences, position and head direction signals are nevertheless maintained in the absence of any one of these respective inputs. Context-related changes in hippocampal discharge correlates are also highlighted. These characteristics provide these signals with robustness and flexibility, properties particularly suited for cognitive processes such as contextual processing, memory and planning.

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.

Lesions of the medial shell of the nucleus accumbens impair rats in finding larger rewards, but spare reward-seeking behavior.

The goal of this study was to help better understand the importance of the nucleus accumbens (Nacc) in the processing of position and reward value information for goal-directed orientation behaviors. Sixteen male Long-Evans rats, under partial water deprivation, were trained in a plus-maze to find water rewards in the respective arms which were lit in pseudo-random sequence (training trials). Each day one reward arm was selected to deliver six drops of water (at 1 s intervals) the others provided only one drop per visit. After 32 visits, probe trials were intermittently presented among training trials. Here, all four arms were lit and offered the previously assigned reward. The rats rapidly learned to go to the highly rewarded arm. Six trained rats were given bilateral electrolytic lesions in the Nacc shell, two others had unilateral lesions and eight had sham operations (with approved protocols). Field potentials evoked by fornix stimulation were recorded in lesion electrodes to guide placements. Only the lesioned rats showed significant impairments (P<0.05) in selecting the greater reward on probe trials. However on training trials, lesioned (and sham-operated) rats made only rare errors. While the motivation to drink and the capacity for cue-guided goal-directed orientation behavior was spared, lesioned rats were impaired in learning the location of the larger reward. The accumbens lesions apparently impaired integration of position and reward value information, consistent with anatomical and electrophysiological data showing the convergence of hippocampal, amygdalar, ventral tegmental area (VTA) and prefrontal cortical inputs there.

Position sensitivity in phasically discharging nucleus accumbens neurons of rats alternating between tasks requiring complementary types of spatial cues

To determine how hippocampal location-selective discharges might influence downstream structures for navigation, nucleus accumbens neurons were recorded in rats alternating between two tasks guided respectively by lit cues in the maze or by extramaze room cues. Of 144 phasically active neurons, 80 showed significant behavioral correlates including displacements, immobility prior to, or after reward delivery, as well as turning, similar to previous reports. Nine neurons were position-selective, 22 were sensitive to task and platform changes and 40 others were both. Although the accumbens neurons showed the same behavioral correlate in two or four functionally equivalent locations, these responses were stronger at some of these places, evidence for position sensitivity. To test whether position responses were selective for room versus platform cues, the experimental platform was rotated while the rat performed each of the two tasks. This revealed responses to changes in position relative to both platform and room cues, despite the fact that previous studies had shown that place responses of hippocampal neurons recorded in the same task are anchored to room cues only. After these manipulations and shifts between the two tasks, the responses varied among simultaneously recorded neurons, and even in single neurons in alternating visits to reward sites. Again this contrasts with the uniformity of place responses of hippocampal neurons recorded in this same task. Thus accumbens position responses may derive from hippocampal inputs, while responses to context changes are more likely to derive from other signals or intrinsic processing. Considering the accumbens as a limbic-motor interface, we conclude that position-modulated behavioral responses in the accumbens may be intermediate between the allocentric reference frame of position-selective discharges in the hippocampus and the egocentric coding required to organize movement control. The conflicting responses among simultaneously recorded neurons could reflect competition processes serving as substrates for action selection and learning.

Neurons in hippocampal afferent zones of rat striatum parse routes into multi-pace segments during maze navigation.

Hippocampal ‘place’ neurons discharge when rats occupy specific regions within an environment. This finding is a cornerstone of the theory of the hippocampus as a cognitive map of space. But for navigation, representations of current position must be implemented by signals concerning where to go next, and how to get there. In recordings in hippocampal output structures associated with the motor system (nucleus accumbens and ventromedial caudate nucleus) in rats solving a plus‐maze, neurons fired continuously from the moment the rat left one location until it arrived at the next goal site, or at an intermediate place, such as the maze centre. While other studies have shown discharges during reward approach behaviours, this is the first demonstration of activity corresponding to the parsing of complex routes into sequences of movements between landmarks, similar to the lists of instructions we often employ to communicate directions to follow between points on a map. As these cells fired during a series of several paces or re‐orientation movements, perhaps this is homologous to ‘chunking’. The temporal overlaps in the activity profiles of the individual neurons provide a possible substrate to successively trigger movements required to arrive at the goal. These hippocampally informed, and in some cases, spatially selective responses support the view of the ventral striatum as an interface between limbic and motor systems, permitting contextual representations to have an impact on fundamental action sequences for goal‐directed behaviour.

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.