Optogenetic suppression of the medial septum impairs working memory maintenance.

Spatial working memory (SWM) is the ability to encode, maintain, and retrieve spatial information over a temporal gap, and relies on a network of structures including the medial septum (MS), which provides critical input to the hippocampus. Although the role of the MS in SWM is well-established, up until recently, we have been unable to use temporally precise circuit manipulation techniques to examine the specific role of the MS in SWM, particularly to distinguish between encoding, maintenance, and retrieval. Here, we test the hypothesis that the MS supports the maintenance of spatial information over a temporal gap using precisely timed optogenetic suppression delivered during specific portions of three different tasks, two of which rely on SWM and one that does not. In experiment 1, we found that MS optogenetic suppression impaired choice accuracy of a SWM dependent conditional discrimination task. Moreover, this deficit was only observed when MS suppression was delivered during the cue-sampling, but not the cue-retrieval, portion of the trial. There was also no deficit when MS neurons were optogenetically suppressed as rats performed a SWM-independent variant of the task. In experiment 2, we tested whether MS suppression affected choice accuracy on a delayed nonmatch to position (DNMP) task when suppression was limited to the sample, delay, and choice phases of the task. We found that MS suppression delivery during the delay phase of the DNMP task, but not during the sample or choice phases, impaired choice accuracy. Our results collectively suggest that the MS plays an important role in SWM by maintaining task-relevant information over a temporal delay.

The nucleus reuniens of the thalamus sits at the nexus of a hippocampus and medial prefrontal cortex circuit enabling memory and behavior.

The nucleus reuniens of the thalamus (RE) is a key component of an extensive network of hippocampal and cortical structures and is a fundamental substrate for cognition. A common misconception is that RE is a simple relay structure. Instead, a better conceptualization is that RE is a critical component of a canonical higher-order cortico-thalamo-cortical circuit that supports communication between the medial prefrontal cortex (mPFC) and the hippocampus (HC). RE dysfunction is implicated in several clinical disorders including, but not limited to Alzheimer's disease, schizophrenia, and epilepsy. Here, we review key anatomical and physiological features of the RE based primarily on studies in rodents. We present a conceptual model of RE circuitry within the mPFC-RE-HC system and speculate on the computations RE enables. We review the rapidly growing literature demonstrating that RE is critical to, and its neurons represent, aspects of behavioral tasks that place demands on memory focusing on its role in navigation, spatial working memory, the temporal organization of memory, and executive functions.

Optogenetic suppression of the nucleus reuniens selectively impairs encoding during spatial working memory.

The nucleus reuniens (Re) of the ventral midline thalamus is known to be a critical anatomical link between the hippocampus (HPC) and the medial prefrontal cortex (mPFC). Consistent with this anatomical connectivity, the Re has been shown to be crucial for HPC-mPFC oscillatory synchrony. Moreover, Re inhibition consistently results in spatial working memory (SWM) deficits. Together, these results suggest that SWM requires HPC-mPFC synchrony via the Re. In spite of these findings, an understanding of how the Re contributes to the encoding, maintenance, and retrieval of spatial information during a SWM task is lacking. To address this issue, we trained rats to perform a SWM-dependent delayed-non-match-to-position (DNMP) task in a T-maze. Using optogenetic inhibition of Re activity, we demonstrated that Re suppression during the sample phase, but not the delay or choice phase, significantly decreased choice accuracy. We conclude that the Re contributes to the encoding of spatial information during working memory.

Ventral Midline Thalamus Is Critical for Hippocampal-Prefrontal Synchrony and Spatial Working Memory.

UNLABELLED: Maintaining behaviorally relevant information in spatial working memory (SWM) requires functional synchrony between the dorsal hippocampus and medial prefrontal cortex (mPFC). However, the mechanism that regulates synchrony between these structures remains unknown. Here, we used a unique dual-task approach to compare hippocampal-prefrontal synchrony while rats switched between an SWM-dependent task and an SWM-independent task within a single behavioral session. We show that task-specific representations in mPFC neuronal populations are accompanied by SWM-specific oscillatory synchrony and directionality between the dorsal hippocampus and mPFC. We then demonstrate that transient inactivation of the reuniens and rhomboid (Re/Rh) nuclei of the ventral midline thalamus abolished only the SWM-specific activity patterns that were seen during dual-task sessions within the hippocampal-prefrontal circuit. These findings demonstrate that Re/Rh facilitate bidirectional communication between the dorsal hippocampus and mPFC during SWM, providing evidence for a causal role of Re/Rh in regulating hippocampal-prefrontal synchrony and SWM-directed behavior. SIGNIFICANCE STATEMENT: Hippocampal-prefrontal synchrony has long been thought to be critical for spatial working memory (SWM) and the ventral midline thalamic reuniens and rhomboid nuclei (Re/Rh) have long been considered a potential site for synchronizing the hippocampus and medial prefrontal cortex. However, the hypothesis that Re/Rh are critical for hippocampal-prefrontal synchrony and SWM has not been tested. We first used a dual-task approach to identify SWM-specific patterns of hippocampal-prefrontal synchrony. We then demonstrated that Re/Rh inactivation concurrently disrupted SWM-specific behavior and the SWM-specific patterns of hippocampal-prefrontal synchrony seen during dual-task performance. These results provide the first direct evidence that Re/Rh contribute to SWM by modulating hippocampal-prefrontal synchrony.

Inactivation of the nucleus reuniens/rhomboid causes a delay-dependent impairment of spatial working memory.

Inactivation of the rodent medial prefrontal cortex (mPFC) and hippocampus or disconnection of the hippocampus from the mPFC produces deficits in spatial working memory tasks. Previous studies have shown that delay length determines the extent to which mPFC and hippocampus functionally interact, with both structures being necessary for tasks with longer delays and either structure being sufficient for tasks with shorter delays. In addition, inactivation of the nucleus reuniens (Re)/rhomboid nucleus (Rh) of the thalamus, which has bidirectional connections with the mPFC and hippocampus, also produces deficits in these tasks. However, it is unknown how delay duration relates to the function of Re/Rh. If Re/Rh are critical in modulating mPFC-hippocampus interactions, inactivation of the RE/Rh should produce a delay-dependent impairment in spatial working memory performance. To investigate this question, groups of rats were trained on one of three different spatial working memory tasks: continuous alternation (CA), delayed alternation with a five-second delay (DA5), or with a thirty-second delay (DA30). The Re/Rh were inactivated with muscimol infusions prior to testing. The results demonstrate that inactivation of RE/Rh produces a deficit only on the two DA tasks, supporting the notion that the Re/Rh is a critical orchestrator of mPFC-HC interactions.

Dynamic coding of dorsal hippocampal neurons between tasks that differ in structure and memory demand.

Hippocampal place fields show remapping between environments that contain sufficiently different contextual features, a phenomenon that may reflect a mechanism for episodic memory formation. Previous studies have shown that place fields remap to changes in the configuration of visual landmarks in an environment. Other experiments have demonstrated that remapping can occur with experience, even when the visual features of an environment remain stable. A special case of remapping may be trajectory coding, the tendency for hippocampal neurons to exhibit different firing rates depending upon recently visited or upcoming spatial locations. To further delineate the conditions under which different task features elicit remapping, we recorded from place cells in dorsal CA1 of hippocampus while rats switched between tasks that differed in memory demand and task structure; continuous spatial alternation (CA), delayed spatial alternation (DA), and tactile-visual conditional discrimination (CD). Individual hippocampal neurons and populations of simultaneously recorded neurons showed coherent remapping between CA and CD. However, task remapping was rarely seen between DA and CD. Analysis of individual units revealed that even though the population retained a coherent representation of task structure across the DA and CD tasks, the majority of individual neurons consistently remapped at some point during recording sessions. In contrast with previous studies, trajectory coding on the stem of the T-maze was virtually absent during all of the tasks, suggesting that experience with multiple tasks in the same environment reduces the likelihood that hippocampal neurons will represent distinct trajectories. Trajectory coding was, however, observed during the delay period of DA. Whether place fields change in response to task or trial type or remain stable within the same environment may depend on which aspects of the context are most salient or relevant to behavior.

Dissociable roles of the dorsal striatum and dorsal hippocampus in conditional discrimination and spatial alternation T-maze tasks.

The roles of the dorsal hippocampus (DH) and dorsal striatum (DS) in the learning and retention of conditional discrimination (CD) rules is a subject of debate. Although previous studies have examined the relationship between the DH and DS and the performance of CD tasks in operant chambers, the relative contributions of these two brain regions to the retention of CD rules requiring an association between a cue and a spatial location have not been characterized. We designed an experiment to assess the roles of the DH and DS in the retention of a visuospatial CD task by transiently inactivating either structure with muscimol in separate groups of rats and measuring performance on a previously learned CD task. The performance of two other groups of rats on a previously learned delayed spatial alternation (DA) task was also measured following inactivation of either DS or DH, which allowed us to control for any possibly confounding effects of spatial cues present in the testing room, length of the intertrial interval period on the performance of the CD task, and muscimol on sensorimotor or motivational processing. Muscimol inactivation of dorsal striatum, but not dorsal hippocampus, impaired CD performance, while inactivation of dorsal hippocampus, but not dorsal striatum impaired DA performance. These results demonstrate a double dissociation between the roles of the DH and DS in these two tasks, and provide a systematic characterization of the relationship between these two brain areas and CD performance.

Pausing and reorienting behaviors enhance the performance of a spatial working memory task.

During spatial working memory tasks, animals need to retain information about a previous trial in order to successfully select their next trajectory. Specifically, the delayed non-match to position task requires rats to follow a cued sample trajectory, then select the opposite route after a delay period. When faced with this choice, rats will occasionally exhibit complex behaviors, such as pausing and sweeping their head back and forth. These behaviors, called vicarious trial and error (VTE), are thought to be a behavioral manifestation of deliberation. However, we identified similarly complex behaviors during sample-phase traversals, despite the fact that these laps do not require a decision. First, we identified that these behaviors occurred more often after incorrect trials than before them, indicating that rats are retaining information between trials. Next, we determined that these pause-and-reorient (PAR) behaviors increased the likelihood of the next choice being selected correctly, suggesting that these behaviors assist the rat in successful task performance. Finally, we identified similarities between PARs and choice-phase VTEs, suggesting that VTEs may not only be reflective of deliberation, but may also contribute to a strategy for successful performance of spatial working memory tasks.

Spatial representations in dorsal hippocampal neurons during a tactile-visual conditional discrimination task.

Trajectory-dependent coding in dorsal CA1 of hippocampus has been evident in various spatial memory tasks aiming to model episodic memory. Hippocampal neurons are considered to be trajectory-dependent if the neuron has a place field located on an overlapping segment of two trajectories and exhibits a reliable difference in firing rate between the two trajectories. It is unclear whether trajectory-dependent coding in hippocampus is a mechanism used by the rat to solve spatial memory tasks. A first step in answering this question is to compare results between studies using tasks that require spatial working memory and those that do not. We recorded single units from dorsal CA1 of hippocampus during performance of a discrete-trial, tactile-visual conditional discrimination (CD) task in a T-maze. In this task, removable floor inserts that differ in texture and appearance cue the rat to visit either the left or right goal arm to receive a food reward. Our goal was to assess whether trajectory coding would be evident in the CD task. Our results show that trajectory coding was rare in the CD task, with only 12 of 71 cells with place fields on the maze stem showing a significant firing rate difference between left and right trials. For comparison, we recorded from dorsal CA1 during the acquisition and performance of a continuous spatial alternation task identical to that used in previous studies and found a proportion of trajectory coding neurons similar to what has been previously reported. Our data suggest that trajectory coding is not a universal mechanism used by the hippocampus to disambiguate similar trajectories, and instead may be more likely to appear in tasks that require the animal to retrieve information about a past trajectory, particularly in tasks that are continuous rather than discrete in nature.

The ventral midline thalamus coordinates prefrontal-hippocampal neural synchrony during vicarious trial and error.

When faced with difficult choices, the possible outcomes are considered through a process known as deliberation. In rats, deliberation is thought to be reflected by pause-and-reorienting behaviors, better known as vicarious trial and errors (VTEs). While VTEs are thought to require medial prefrontal cortex (mPFC) and dorsal hippocampal (dHPC) interactions, no empirical evidence has yet demonstrated such a dual requirement. The nucleus reuniens (Re) of the ventral midline thalamus is anatomically connected with both the mPFC and dHPC, is required for HPC-dependent spatial memory tasks, and is critical for mPFC-dHPC neural synchronization. Currently, it is unclear if, or how, the Re is involved in deliberation. Therefore, by examining the role of the Re on VTE behaviors, we can better understand the anatomical and physiological mechanisms supporting deliberation. Here, we examined the impact of Re suppression on VTE behaviors and mPFC-dHPC theta synchrony during asymptotic performance of a HPC-dependent delayed alternation (DA) task. Pharmacological suppression of the Re increased VTE behaviors that occurred with repetitive choice errors. These errors were best characterized as perseverative behaviors, in which some rats repeatedly selected a goal arm that previously yielded no reward. We then examined the impact of Re suppression on mPFC-dHPC theta synchrony during VTEs. We found that during VTEs, Re inactivation was associated with a reduction in mPFC-dHPC theta coherence and mPFC-to-dHPC theta directionality. Our findings suggest that the Re contributes to deliberation by coordinating mPFC-dHPC neural interactions.

Eyeblink conditioning contingent on hippocampal theta enhances hippocampal and medial prefrontal responses.

Trace eyeblink classical conditioning (tEBCC) can be accelerated by making training trials contingent on the naturally generated hippocampal 3- to 7-Hz theta rhythm. However, it is not well-understood how the presence (or absence) of theta affects stimulus-driven changes within the hippocampus and how it correlates with patterns of neural activity in other essential trace conditioning structures, such as the medial prefrontal cortex (mPFC). In the present study, a brain-computer interface delivered paired or unpaired conditioning trials to rabbits during the explicit presence (T(+)) or absence (T(-)) of theta, yielding significantly faster behavioral learning in the T(+)-paired group. The stimulus-elicited hippocampal unit responses were larger and more rhythmic in the T(+)-paired group. This facilitation of unit responses was complemented by differences in the hippocampal local field potentials (LFP), with the T(+)-paired group demonstrating more coherent stimulus-evoked theta than T(-)-paired animals and both unpaired groups. mPFC unit responses in the rapid learning T(+)-paired group displayed a clear inhibitory/excitatory sequential pattern of response to the tone that was not seen in any other group. Furthermore, sustained mPFC unit excitation continued through the trace interval in T(+) animals but not in T(-) animals. Thus theta-contingent training is accompanied by 1) acceleration in behavioral learning, 2) enhancement of the hippocampal unit and LFP responses, and 3) enhancement of mPFC unit responses. Together, these data provide evidence that pretrial hippocampal state is related to enhanced neural activity in critical structures of the distributed network supporting the acquisition of tEBCC.

The nucleus reuniens orchestrates prefrontal-hippocampal synchrony during spatial working memory.

Spatial working memory, the ability to temporarily maintain an internal representation of spatial information for use in guiding upcoming decisions, has been shown to be dependent upon a network of brain structures that includes the hippocampus, a region known to be critical for spatial navigation and episodic memory, and the prefrontal cortex (PFC), a region known to be critical for executive function and goal directed behavior. Oscillatory synchronization between the hippocampus and the prefrontal cortex (PFC) is known to increase in situations of high working memory demand. Most of our knowledge about the anatomical connectivity between the PFC and hippocampus comes from the rodent literature. Thus, most of the findings that will be discussed here model human working memory using spatial working memory-dependent maze navigation tasks in rodents. It has been demonstrated that the ventral midline thalamic nucleus reuniens (Re) is reciprocally connected to both the infralimbic and prelimbic subregions of the PFC, collectively referred to as the medial PFC (mPFC), and the hippocampus. Given that the Re serves as a major anatomical route between the mPFC and hippocampus, it is perhaps not surprising that Re has been shown to be critical for spatial working memory. This review will describe the latest findings and ideas on how the Re contributes to prefrontal-hippocampal synchronization and spatial working memory in rodents. The review will conclude with possible future directions that will advance the understanding of the mechanisms that enable the Re to orchestrate long range synchrony in the prefrontal-hippocampal network.

Gradual translocation of spatial correlates of neuronal firing in the hippocampus toward prospective reward locations.

In a continuous T-maze alternation task, CA1 complex-spike neurons in the hippocampus differentially fire as the rat traverses overlapping segments of the maze (i.e., the stem) repeatedly via alternate routes. The temporal dynamics of this phenomenon were further investigated in the current study. Rats learned the alternation task from the first day of acquisition and the differential firing pattern in the stem was observed accordingly. More importantly, we report a phenomenon in which spatial correlates of CA1 neuronal ensembles gradually changed from their original firing locations, shifting toward prospective goal locations in the continuous T-maze alternation task. The relative locations of simultaneously recorded firing fields, however, were preserved within the ensemble spatial representation during this shifting. The within-session shifts in preferred firing locations in the absence of any changes in the environment suggest that certain cognitive factors can significantly alter the location-bound coding scheme of hippocampal neurons.

Representations of On-Going Behavior and Future Actions During a Spatial Working Memory Task by a High Firing-Rate Population of Medial Prefrontal Cortex Neurons.

Spatial working memory (SWM) requires the encoding, maintenance, and retrieval of spatially relevant information to guide decision-making. The medial prefrontal cortex (mPFC) has long been implicated in the ability of rodents to perform SWM tasks. While past studies have demonstrated that mPFC ensembles reflect past and future experiences, most findings are derived from tasks that have an experimental overlap between the encoding and retrieval of trajectory specific information. In this study, we recorded single units from the mPFC of rats as they performed a T-maze delayed non-match to position (DNMP) task. This task consists of an encoding dominant sample phase, a memory maintenance delay period, and retrieval dominant choice phase. Using a linear classifier, we investigated whether distinct ensembles collectively reflect various trajectory-dependent experiences. We find that a population of high-firing rate mPFC neurons both predict a future choice and reflect changes in trajectory-dependent behaviors. We then developed a modeling procedure that estimated the number of high and low-firing rate units required to dissociate between various experiences. We find that low firing rate ensembles weakly reflect the direction that rats were forced to turn on the sample phase. This was in contrast to the highly active population that could effectively predict both future decision-making on early stem traversals and trajectory-divergences at T-junction. Finally, we compared the ensemble size necessary to code a forced trajectory to the size required to predict a decision. We provide evidence to suggest that a larger number of highly active neurons are employed during decision-making processes when compared to rewarded forced behaviors. Together, our study provides important insight into how specific ensembles of mPFC units support upcoming choices and ongoing behavior during SWM.

Spatial representations of hippocampal CA1 neurons are modulated by behavioral context in a hippocampus-dependent memory task.

Although it is well known that hippocampal neurons code spatial information, it is less clear how these spatial representations are influenced by memory demands, especially in hippocampus-dependent tasks. Recently, our laboratory has demonstrated that hippocampal spatial representations are influenced by mnemonic factors in a T-maze continuous alternation task. Another unique experimental approach that might reveal the ways in which task-related factors impact hippocampal spatial representations is to compare firing patterns between events that require distinct episodic memory processes. Therefore, we recorded from CA1 single neurons during a discrete trial delayed-nonmatch-to-place task that allowed within-trial comparison between an encoding (sample) phase and a retrieval (choice) phase. A large subset of neurons that fired on the central stem of the maze showed dramatic selectivity for either the sample or choice phase of the trial. However, surprisingly, there were fewer neurons that showed differential firing rates between left- and right-bound trajectories. Our results suggest that trial-phase-selective coding is common in tasks that require rapid alternation between encoding and retrieval processes.

Hippocampal response patterns during discriminative eyeblink/jaw movement conditioning in the rabbit.

Rabbits were given concurrent training in eyeblink (EB) and jaw movement (JM) conditioning in which 1 tone predicted an airpuff and another tone predicted water. After 10 days of discrimination training, the animals were given 10 days of reversal training. In the discrimination phase, acquisition of the 2 conditioned responses was not significantly different; however JM discrimination errors were much more frequent than were EB errors. In the reversal phase, correct performance on EB trials increased gradually, as was expected, whereas there was immediate behavioral reversal on JM trials. Differences in size and topography of dorsal CA1 multiple-unit responses reflected the ability of the hippocampus to discriminate between stimuli in trained animals, corresponding to the performance of the behavioral discrimination. During JM trials, the rhythmicity of the neural response was further modulated by the type of the prior trial, suggesting the coding of sequential events by the hippocampus. Thus, hippocampal conditioned activity can rapidly change its magnitude and pattern depending on the specific trial type during a concurrent EB/JM discrimination task and its reversal. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

Informing geospatial toolset design: understanding the process of cancer data exploration and analysis.

There is an increasing need for new methods and tools that support knowledge construction from complex geospatial datasets related to public health. This study is part of a larger effort to develop, implement, and test such methods and tools. To be successful, the design of methods and tools must be grounded in a solid understanding of the work practices within the domain of use; the research reported here focuses on developing that understanding. We adopted a user-centered approach to toolset design where we investigated the work of cancer researchers and used the results of that investigation as inputs into the development of design guidelines for new geovisualization and spatial analysis tools. Specifically, we conducted key informant interviews focused on use, or potential use, of geographic information, methods, and tools and complemented this with a systematic analysis of published, peer-reviewed articles on geospatial cancer research. Results were used to characterize the typical process of analysis, to identify fundamental differences between intensive users of geospatial methods and infrequent users, and to outline key stages in analysis and tasks within the stages that methods and tools must support. Our findings inform design and implementation decisions for visual and analytic tools that support cancer prevention and control research and they provide insight into the processes used by cancer researchers for addressing the challenges of geographic factors in public health research and policy.

Role of the thalamic nucleus reuniens in mediating interactions between the hippocampus and medial prefrontal cortex during spatial working memory.

Despite decades of research, the neural mechanisms of spatial working memory remain poorly understood. Although the dorsal hippocampus is known to be critical for memory-guided behavior, experimental evidence suggests that spatial working memory depends not only on the hippocampus itself, but also on the circuit comprised of the hippocampus and the medial prefrontal cortex (mPFC). Disruption of hippocampal-mPFC interactions may result in failed transfer of spatial and contextual information processed by the hippocampus to the circuitry in mPFC responsible for decision making and goal-directed behavior. Oscillatory synchrony between the hippocampus and mPFC has been shown to increase in tasks with high spatial working memory demand. However, the mechanisms and circuitry supporting hippocampal-mPFC interactions during these tasks is unknown. The midline thalamic nucleus reuniens (RE) is reciprocally connected to both the hippocampus and the mPFC and has been shown to be critical for a variety of working memory tasks. Therefore, it is likely that hippocampal-mPFC oscillatory synchrony is modulated by RE activity. This article will review the anatomical connections between the hippocampus, mPFC and RE along with the behavioral studies that have investigated the effects of RE disruption on working memory task performance. The article will conclude with suggestions for future directions aimed at identifying the specific role of the RE in regulating functional interactions between the hippocampus and the PFC and investigating the degree to which these interactions contribute to spatial working memory.

Comparing Color and Leader Line Highlighting Strategies in Coordinated View Geovisualizations.

In most coordinated view geovisualization tools, a transient visual effect is used to highlight observations across views when brushed with a mouse or other input device. Most current geovisualization and information visualization systems use colored outlines or fills to highlight observations, but there remain a wide range of alternative visual strategies that can also be implemented and compared to color highlighting to evaluate user performance. This paper describes the results of an experiment designed to compare user performance with two highlighting methods; color and leader lines. Our study methodology uses eye-tracking to capture participant eye fixations while they answer questions that require attention to highlighted observations in multiple views. Our results show that participants extract information as efficiently from coordinated view displays that use leader line highlighting to link information as they do from those that use a specific color to highlight items. We also found no significant differences when changing the color of the highlighting effect from red to black. We conclude that leader lines show significant potential for use as an alternative highlighting method in coordinated multiple view visualizations, allowing color to be reserved for representing thematic attributes of data.

Integrating paid work and chronic illness in daily life: A space-time approach to understanding the challenges.

The upward trend of chronic illness in working age populations calls for better understanding of the difficulties chronically ill people face with workforce participation. Existing research focuses primarily on physical limitations and employer attitudes about chronic illness. Here we use a space-time approach to illuminate the importance of negotiating logistical challenges and embodied rhythms when balancing work and chronic illness. We draw from time geography and rhythmanalysis in analysing interviews from a qualitative case study of 26 individuals living with chronic kidney disease in Australia. Difficulties with paid work arise from: (1) competition for space-time resources by employers and health services; (2) arrhythmias between the body, work and health services; and (3) the absence of workplace rhythms on which to 'hook' health activities. Implications for workplaces and health services design are discussed.