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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.

Brain-derived neurotrophic factor (BDNF) signaling regulates synaptic plasticity in the hippocampus (HC) and prefrontal cortex (PFC), and has been extensively linked with fear memory expression in rodents. Notably, disrupting BDNF production from promoter IV-derived transcripts enhances fear expression in mice, and decreases fear-associated HC-PFC synchrony, suggesting that Bdnf transcription from promoter IV plays a key role in HC-PFC function during fear memory retrieval. To better understand how promoter IV-derived BDNF controls HC-PFC connectivity and fear expression, we generated a viral construct that selectively targets cells expressing promoter IV-derived Bdnf transcripts (“p4-cells”) for tamoxifen-inducible Cre-mediated recombination (AAV8-p4Bdnf-ER(T2)CreER(T2)-PEST). Using this construct, we found that ventral hippocampal (vHC) p4-cells are recruited during fear expression, and that activation of these cells causes exaggerated fear expression that co-occurs with disrupted vHC-PFC synchrony in mice. Our data highlight how this novel construct can be used to interrogate genetically defined cell types that selectively contribute to BDNF-dependent behaviors.

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.

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis.

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.

Working memory depends on communication between the hippocampus and the prefrontal cortex (PFC); however, the neural circuitry that mediates interactions between these brain areas has not been well characterized. Two candidate structures are the thalamic reuniens (RE) and rhomboid (Rh) nuclei, which are reciprocally connected with both the hippocampus and PFC. These known anatomical connections suggest that RE/Rh may be involved in mediating hippocampal-prefrontal communication, and therefore may be critical for working memory processing. To test the hypothesis that RE/Rh are necessary for working memory, we trained separate groups of rats to perform one of two tasks in a T-maze. The first task was a working memory-dependent conditional discrimination (CDWM) task, and the second task was a non-working memory-dependent conditional discrimination (CD) task. These tasks took place in the same maze, featured the same number of trials, and utilized the same cue (a tactile-visual maze insert). After rats had learned either task, RE/Rh were transiently inactivated with the GABAA receptor agonist muscimol, and performance was assessed. RE/Rh inactivation caused performance deficits on the CDWM task, but not the CD task. This result suggests that RE/Rh are a necessary component of working memory task performance, which is also thought to depend on the hippocampal-prefrontal circuit. RE/Rh inactivation did not cause a performance deficit on the CD task, suggesting that RE/Rh have dissociable contributions to working memory-dependent and non-working memory-dependent tasks, independently of the known contributions of these two thalamic nuclei to the sensorimotor and attention-related aspects of other memory tasks.

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.

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.

The medial prefrontal cortex (mPFC) is responsible for executive functions such as abstract rule coding, strategy switching, and behavioral flexibility; however, there is some debate regarding the extent to which mPFC is involved in reversal learning, especially in complex multisensory tasks such as conditional discrimination. Therefore, we investigated the effects of mPFC inactivation on the acquisition, retention, and reversal of a visuospatial conditional discrimination (CD) task. In experiment 1, muscimol was infused through bilateral cannulae on days 1, 2, and 3 to test the effects of mPFC inactivation on task acquisition and days 19, 20, and 21 to test the effects on retention of the task. For experiment 2, rats were trained on the CD task for 21 days with no infusions given, after which the reward contingency was reversed, with infusions given during the first six days of reversal. The results of experiment 1 showed that the muscimol and saline groups did not differ on acquisition or retention. However, experiment 2 showed that the muscimol group displayed significantly more performance errors than the control group during reversal. Compared to the control group, the muscimol group also showed a decreased tendency to use a side-bias strategy during the intermediate stages of reversal. The failure of the muscimol group to exhibit a side bias suggests that the mPFC is necessary for sampling strategies necessary for the reversal of a visuospatial CD task.