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The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are bi-directionally connected with the hippocampus and the medial prefrontal cortex. They participate in a variety of cognitive functions, including information holding for seconds to minutes in working memory tasks. What about longer delays? To address this question, we used a spatial working memory task in which rats had to reach a platform submerged in water. The platform location was changed every 2-trial session and rats had to use allothetic cues to find it. Control rats received training in a typical response-memory task. We interposed a 6 h interval between instruction (locate platform) and evaluation (return to platform) trials in both tasks. After the last session, rats were killed for c-Fos imaging. A home-cage group was used as additional control of baseline levels of c-Fos expression. C-Fos expression was increased to comparable levels in the Re (not Rh) of both spatial memory and response-memory rats as compared to their home cage counterparts. However, in spatial memory rats, not in their response-memory controls, task performance was correlated with c-Fos expression in the Re: the higher this expression, the better the performance. Furthermore, we noticed an activation of hippocampal region CA1 and of the anteroventral nucleus of the rostral thalamus. This activation was specific to spatial memory. The data point to a possible performance-determinant participation of the Re nucleus in the delayed engagement of spatial information encoded in a temporary memory., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Episodic memory is a complex process requiring input from several regions of the brain. Emerging evidence suggests that coordinated activity between the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) is required for episodic memory consolidation. However, the mechanisms through which the DH and mPFC interact to promote memory consolidation remain poorly understood. A growing body of research suggests that the nucleus reuniens of the thalamus (RE) is one of several structures that facilitate communication between the DH and mPFC during memory and may do so through bidirectional excitatory projections to both regions. Furthermore, recent work from other labs indicates that the RE is necessary for spatial working memory. However, it is not clear to what extent the RE is necessary for memory of object locations. The goal of this study was to determine whether activity in the RE is necessary for spatial memory as measured by the object placement (OP) task in female mice. A kappa-opioid receptor DREADD (KORD) virus was used to inactivate excitatory neurons in the RE pre- or post-training to establish a role for the RE in spatial memory acquisition and consolidation, respectively. RE inactivation prior to, or immediately after, object training blocked OP memory formation relative to chance and to control mice. Moreover, expression of the immediate early gene EGR-1 was reduced in the RE 1 hour after an object training trial, supporting the conclusion that reduced neuronal activity in the RE impairs the formation of object location memories. In summary, the findings of this study support a key role for the RE in spatial memory acquisition and consolidation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Working memory deficits are key cognitive symptoms of schizophrenia. Elevated delta oscillations, which are uniquely associated with the presence of the illness, may be the proximal cause of these deficits. Spatial working memory (SWM) is impaired by elevated delta oscillations projecting from thalamic nucleus reuniens (RE) to the hippocampus (HPC); these findings imply a role of the RE-HPC circuit in working memory deficits in schizophrenia, but questions remain as to whether the affected process is the encoding of working memory, recall, or both. Here, we answered this question by optogenetically inducing delta oscillations in the HPC terminals of RE axons in mice during either the encoding or retrieval phase (or both) of an SWM task., Methods: We transduced cells in RE to express channelrhodopsin-2 through bilateral injection of adeno-associated virus, and bilaterally implanted optical fibers dorsal to the hippocampus (HPC). While mice performed a spatial memory task on a Y-maze, the RE-HPC projections were optogenetically stimulated at delta frequency during distinct phases of the task., Results: Full-trial stimulation successfully impaired SWM performance, replicating the results of the previous study in a mouse model. Task-phase-specific stimulation significantly impaired performance during retrieval but not encoding., Conclusions: Our results indicate that perturbations in the RE-HPC circuit specifically impair the retrieval phase of working memory. This finding supports the hypothesis that abnormal delta frequency bursting in the thalamus could have a causal role in producing the WM deficits seen in schizophrenia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The ventral midline thalamus contributes to hippocampo-cortical interactions supporting systems-level consolidation of memories. Recent hippocampus-dependent memories rely on hippocampal connectivity remodeling. Remote memories are underpinned by neocortical connectivity remodeling. After a ventral midline thalamus lesion, recent spatial memories are formed normally but do not last. Why these memories do not endure after the lesion is unknown. We hypothesized that a lesion could interfere with hippocampal and/or neocortical connectivity remodeling. To test this hypothesis, in a first experiment male rats were subjected to lesion of the reuniens and rhomboid (ReRh) nuclei, trained in a water maze, and tested in a probe trial 5 or 25 days post-acquisition. Dendritic spines were counted in the dorsal hippocampus and medial prefrontal cortex. Spatial learning resulted in a significant increase of mushroom spines in region CA1. This modification persisted between 5 and 25 days post-acquisition in Sham rats, not in rats with ReRh lesion. Furthermore, 25 days after acquisition, the number of mushroom spines in the anterior cingulate cortex (ACC) had undergone a dramatic increase in Sham rats; ReRh lesion prevented this gain. In a second experiment, the increase of c-Fos expression in CA1 accompanying memory retrieval was not affected by the lesion, be it for recent or remote memory. However, in the ACC, the lesion had reduced the retrieval-triggered c-Fos expression observed 25 days post-acquisition. These observations suggest that a ReRh lesion might disrupt spatial remote memory formation by preventing persistence of early remodeled hippocampal connectivity, and spinogenesis in the ACC.

The ventral midline thalamus, consisting of the reuniens and rhomboid nuclei (RE/Rh), is a thalamic structure interconnected with the limbic systems including the hippocampus. Recently, many studies have revealed that this structure plays distinctive roles in spatial learning and memory in collaboration with hippocampal functions. However, what aspects of spatial information process are influenced by the RE/Rh is not clearly known. To elucidate the roles of RE/Rh in spatial information processing and its effects on hippocampal activity, specifically with the manipulation of spatial contents, we measured hippocampal-dependent spatial memory performance and hippocampal place cell activities after RE/Rh lesion using male C57BL/6J × 129/SvJae hybrid mice. We found that the lesion altered the behavioral aptitude in recognizing locational changes of an object. Furthermore, CA1 place cells in the lesion group showed different spatial representation patterns in recognizing the environment with cue locational changes compared with the control group. Interestingly, the patterns of CA1 place cells in recognizing the same environment previously visited were not disrupted in the lesion group compared with the control group. These findings demonstrate that the ventral midline thalamus (RE/Rh) is important in recognizing the spatial relationships, especially when spatial rearrangement of cue position was introduced. SIGNIFICANCE STATEMENT The ventral midline thalamic nuclei (reuniens and rhomboid) interact with the hippocampus to influence various cognitive functions requiring spatial memories, yet what aspects of spatial information process are influenced by these nuclei is not clearly known. Here, we reveal that these nuclei play a crucial role in modulating hippocampal properties only with locational rearrangement of cues, not with the familiar arrangement. These nuclei are distinctively involved in cue-dependent spatial information processes of CA1 place cells. In particular, we suggest that these nuclei modulate spatial information processing on discrete components, especially when the spatial cue relationship is modified., (Copyright © 2019 the authors 0270-6474/19/392276-15$15.00/0.)

The nucleus reuniens (RE) is a ventral midline thalamic nucleus that interconnects the medial prefrontal cortex (mPFC) and hippocampus (HPC). Considerable data indicate that HPC-mPFC circuits are involved in contextual and spatial memory; however, it is not clear whether the RE mediates the acquisition or retrieval of these memories. To examine this question, we inactivated the RE with muscimol before either the acquisition or retrieval of pavlovian fear conditioning in rats; freezing served as the index of fear. We found that RE inactivation before conditioning impaired the acquisition of contextual freezing, whereas inactivation of the RE before retrieval testing increased the generalization of freezing to a novel context; inactivation of the RE did not affect either the acquisition or expression of auditory fear conditioning. Interestingly, contextual conditioning impairments were absent when retrieval testing was also conducted after RE inactivation. Contextual memories acquired under RE inactivation were hippocampal independent, insofar as contextual freezing in rats conditioned under RE inactivation was insensitive to intrahippocampal infusions of the NMDA receptor antagonist aminophosphonovalerate. Together, these data reveal that the RE supports hippocampal-dependent encoding of precise contextual memories that allow discrimination of dangerous contexts from safe contexts. When the RE is inactive, however, alternate neural systems acquire an impoverished contextual memory that is expressed only when the RE is off-line. SIGNIFICANCE STATEMENT The midline thalamic nucleus reuniens (RE) coordinates communication between the hippocampus and medial prefrontal cortex, brain areas that are critical for contextual and spatial memory. Here we show that temporary pharmacological inactivation of RE impairs the acquisition and precision of contextual fear memories after pavlovian fear conditioning in rats. However, inactivating the RE before retrieval testing restored contextual memory in rats conditioned after RE inactivation. Critically, we show that imprecise contextual memories acquired under RE inactivation are learned independently of the hippocampus. These data reveal that the RE is required for hippocampal-dependent encoding of precise contextual memories to support the discrimination of safe and dangerous contexts., (Copyright © 2018 the authors 0270-6474/18/389925-09$15.00/0.)

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., (Copyright © 2018. Published by Elsevier Inc.)

Spatial navigation depends on the hippocampal function, but also requires bidirectional interactions between the hippocampus (HPC) and the prefrontal cortex (PFC). The cross-regional communication is typically regulated by critical nodes of a distributed brain network. The thalamic nucleus reuniens (RE) is reciprocally connected to both HPC and PFC and may coordinate the information flow within the HPC-PFC pathway. Here we examined if RE activity contributes to the spatial memory consolidation. Rats were trained to find reward following a complex trajectory on a crossword-like maze. Immediately after each of the five daily learning sessions the RE was reversibly inactivated by local injection of muscimol. The post-training RE inactivation affected neither the spatial task acquisition nor the memory retention, which was tested after a 20-d "forgetting" period. In contrast, the RE inactivation in well-trained rats prior to the maze exposure impaired the task performance without affecting locomotion or appetitive motivation. Our results support the role of the RE in memory retrieval and/or "online" processing of spatial information, but do not provide evidence for its engagement in "off-line" processing, at least within a time window immediately following learning experience., (© 2018 Mei et al.; Published by Cold Spring Harbor Laboratory Press.)

Lesions of the reuniens and rhomboid (ReRh) thalamic nuclei in rats do not alter spatial learning but shorten the period of memory persistence (Loureiro et al. 2012). Such persistence requires a hippocampo-cortical (prefrontal) dialog leading to memory consolidation at the systems level. Evidence for reciprocal connections with the hippocampus and the medial prefrontal cortex (mPFC) makes the ReRh a potential hub for regulating hippocampo-cortical interactions. As environmental enrichment (EE) fosters recovery of declarative-like memory functions after diencephalic lesions (e.g., anterior thalamus), we studied the possibility of triggering recovery of systems-level consolidation in ReRh lesioned rats using a 40-day postsurgical EE. Remote memory was tested 25days post-acquisition in a Morris water maze. The functional activity associated with retrieval was quantified using c-Fos imaging in the dorsal hippocampus, mPFC, intralaminar thalamic nuclei, and amygdala. EE enhanced remote memory in ReRh rats. Conversely, ReRh rats housed in standard conditions were impaired. C-Fos immunohistochemistry showed a higher recruitment of the mPFC in enriched vs. standard rats with ReRh lesions during retrieval. ReRh rats raised in standard conditions showed weaker c-Fos expression than their sham-operated counterparts. The reinstatement of memory capacity implicated an EE-triggered modification of functional connectivity: EE reduced a marked lesion-induced increase in baseline c-Fos expression in the amygdala. Thus, enriched housing conditions counteracted the negative impact of ReRh lesions on spatial memory persistence. These effects could be the EE-triggered consequence of an enhanced neuronal activation in the mPFC, along with an attenuation of a lesion-induced hyperactivity in the amygdala., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We summarize anatomical, electrophysiological and behavioral evidence that the rostral intralaminar (ILN) and the reuniens and rhomboid (ReRh) nuclei that belong to the nonspecific thalamus, might be part of a hippocampo-cortico-thalamic network underlying consolidation of enduring declarative(-like) memories at systems level. The first part of this review describes the anatomical and functional organization of these thalamic nuclei. The second part presents the theoretical models supporting the active systems-level consolidation, a process that relies upon sleep specific field-potential oscillations occurring during both slow-wave sleep (SWS) and rapid eye movement (REM) sleep. The last part presents data in the rat showing that the lesion of the rostral ILN or of the ReRh specifically hinders the formation of remote spatial memories without affecting task acquisition or retrieval of a recent memory. These results showing a critical role of the ILN and ReRh nuclei in the transformation of a recent memory into a remote one are discussed in the context of their control of cortical arousal (ARAS) and of thalamo-cortico-thalamic synchronization., (Copyright © 2014 Elsevier Ltd. All rights reserved.)