Spine plasticity of dentate gyrus parvalbumin-positive interneurons is regulated by experience.

Experience-driven alterations in neuronal activity are followed by structural-functional modifications allowing cells to adapt to these activity changes. Structural plasticity has been observed for cortical principal cells. However, how GABAergic interneurons respond to experience-dependent network activity changes is not well understood. We show that parvalbumin-expressing interneurons (PVIs) of the dentate gyrus (DG) possess dendritic spines, which undergo behaviorally induced structural dynamics. Glutamatergic inputs at PVI spines evoke signals with high spatial compartmentalization defined by neck length. Mice experiencing novel contexts form more PVI spines with elongated necks and exhibit enhanced network and PVI activity and cFOS expression. Enhanced green fluorescent protein reconstitution across synaptic partner-mediated synapse labeling shows that experience-driven PVI spine growth boosts targeting of PVI spines over shafts by glutamatergic synapses. Our findings propose a role for PVI spine dynamics in regulating PVI excitation by their inputs, which may allow PVIs to dynamically adjust their functional integration in the DG microcircuitry in relation to network computational demands.

Hemisphere-specific spatial representation by hippocampal granule cells.

The dentate gyrus (DG) output plays a key role in the emergence of spatial and contextual map representation within the hippocampus during learning. Differences in neuronal network activity have been observed between left and right CA1-3 areas, implying lateralization in spatial coding properties. Whether bilateral differences of DG granule cell (GC) assemblies encoding spatial and contextual information exist remains largely unexplored. Here, we employed two-photon calcium imaging of the left or the right DG to record the activity of GC populations over five consecutive days in head-fixed mice navigating through familiar and novel virtual environments. Imaging revealed similar mean GC activity on both sides. However, spatial tuning, context-selectivity and run-to-run place field reliability was markedly higher for DG place cells in the left than the right hemisphere. Moreover, the proportion of GCs reconfiguring their place fields between contexts was greater in the left DG. Thus, our data suggest that contextual information is differentially processed by GC populations depending on the hemisphere, with higher context discrimination in the left but a bias towards generalization in the right DG.

The hippocampus converts dynamic entorhinal inputs into stable spatial maps.

The medial entorhinal cortex (MEC)-hippocampal network plays a key role in the processing, storage, and recall of spatial information. However, how the spatial code provided by MEC inputs relates to spatial representations generated by principal cell assemblies within hippocampal subfields remains enigmatic. To investigate this coding relationship, we employed two-photon calcium imaging in mice navigating through dissimilar virtual environments. Imaging large MEC bouton populations revealed spatially tuned activity patterns. MEC inputs drastically changed their preferred spatial field locations between environments, whereas hippocampal cells showed lower levels of place field reconfiguration. Decoding analysis indicated that higher place field reliability and larger context-dependent activity-rate differences allow low numbers of principal cells, particularly in the DG and CA1, to provide information about location and context more accurately and rapidly than MEC inputs. Thus, conversion of dynamic MEC inputs into stable spatial hippocampal maps may enable fast encoding and efficient recall of spatio-contextual information.

The reuniens and rhomboid nuclei of the thalamus: A crossroads for cognition-relevant information processing?

Over the past twenty years, the reuniens and rhomboid (ReRh) nuclei, which constitute the ventral midline thalamus, have received constantly growing attention. Since our first review article about the functional contributions of ReRh nuclei (Cassel et al., 2013), numerous (>80) important papers have extended anatomical knowledge, including at a developmental level, introduced new and very original electrophysiological insights on ReRh functions, and brought novel results on cognitive and non-cognitive implications of the ReRh. The current review will cover these recent articles, more on Re than on Rh, and their contribution will be approached according to their affiliation with work before 2013. These neuroanatomical, electrophysiological or behavioral findings appear coherent and point to the ReRh nuclei as two major components of a multistructural system supporting numerous cognitive (and non-cognitive) functions. They gate the flow of information, perhaps especially from the medial prefrontal cortex to the hippocampus and back, and coordinate activity and processing across these two (and possibly other) brain regions of major cognitive relevance.

Ventral midline thalamus lesion prevents persistence of new (learning-triggered) hippocampal spines, delayed neocortical spinogenesis, and spatial memory durability.

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.

Using MRI to predict the fate of excitotoxic lesions in rats.

Excitotoxic lesions are frequently used to assess the role of cerebral structures in cognitive processes in rodents. However, the precise site and extent of these lesions remain unknown without histological verifications. Using a 7-Teslas MRI system and a T2-weighted turbo-RARE sequence, MR images were acquired at several time points following NMDA lesions (1h, 6h, 24h, 48h, 1 week and 2 weeks). NMDA infusions into the parenchyma induced a clear and delineable hyperintense signal from 1h up to 1-week post-surgery. Hyperintensity volumes were compared with NeuN and Cresyl violet histological quantifications of the lesion magnitude. NMDA-induced hypersignal is observed as soon as 1h post-injection and is a reliable estimate of the presence (or absence) of a lesion. Compared to NeuN, Cresyl violet staining underestimates the extent of the lesion in significant proportions. The MRI hyperintensity generated by NMDA instillation into the parenchyma can be used as a powerful tool to confirm the diffusion of the drug into the cerebral tissue, to ascertain the locus of injection and predict with a high success rate the fate of NMDA lesions as soon as 1h post-surgery. This approach could be very useful in a large variety of lesion studies in rodents.

Ventral Midline Thalamus Is Necessary for Hippocampal Place Field Stability and Cell Firing Modulation.

The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip-mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields.SIGNIFICANCE STATEMENT Growing evidence suggest that the ventral midline thalamic nuclei (reuniens and rhomboid) might play a substantial role in various cognitive tasks including spatial memory. In the present article, we show that the lesions of these nuclei impair the spatial representations encoded by CA1 place cells of both familiar and novel environments. First, reduced variability of place cell firing appears to indicate an impairment of attentional processes. Second, impaired stability of place cell representations could explain the long-term memory deficits observed in previous behavioral studies.

Environmental enrichment enhances systems-level consolidation of a spatial memory after lesions of the ventral midline thalamus.

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.

Dorsal hippocampus and medial prefrontal cortex each contribute to the retrieval of a recent spatial memory in rats.

Systems-level consolidation models propose that recent memories are initially hippocampus-dependent. When remote, they are partially or completely dependent upon the medial prefrontal cortex (mPFC). An implication of the mPFC in recent memory, however, is still debated. Different amounts of muscimol (MSCI 0, 30, 50, 80 and 250 ng in 1 µL PBS) were used to assess the impact of inactivation of the dorsal hippocampus (dHip) or the mPFC (targeting the prelimbic cortex) on a 24-h delayed retrieval of a platform location that rats had learned drug-free in a water maze. The two smallest amounts of MSCI (30 and 50 ng) did not affect recall, whatever the region. 80 ng MSCI infused into the dHip disrupted spatial memory retrieval, as did the larger amount. Infusion of MSCI into the mPFC did not alter performance in the 0-80 ng range. At 250 ng, it induced an as dramatic memory impairment as after efficient dHip inactivation. Stereological quantifications showed that 80 ng MSCI in the dHip and 250 ng MSCI in the mPFC induced a more than 80% reduction of c-Fos expression, suggesting that, beyond the amounts infused, it is the magnitude of the neuronal activity decrease which is determinant as to the functional outcome of the inactivation. Because, based on the literature, even 250 ng MSCI is a small amount, our results point to a contribution of the mPFC to the recall of a recently acquired spatial memory and thereby extend our knowledge about the functions of this major actor of cognition.

The reuniens and rhomboid nuclei: neuroanatomy, electrophysiological characteristics and behavioral implications.

The reuniens and rhomboid nuclei, located in the ventral midline of the thalamus, have long been regarded as having non-specific effects on the cortex, while other evidence suggests that they influence behavior related to the photoperiod, hunger, stress or anxiety. We summarise the recent anatomical, electrophysiological and behavioral evidence that these nuclei also influence cognitive processes. The first part of this review describes the reciprocal connections of the reuniens and rhomboid nuclei with the medial prefrontal cortex and the hippocampus. The connectivity pattern among these structures is consistent with the idea that these ventral midline nuclei represent a nodal hub to influence prefrontal-hippocampal interactions. The second part describes the effects of a stimulation or blockade of the ventral midline thalamus on cortical and hippocampal electrophysiological activity. The final part summarizes recent literature supporting the emerging view that the reuniens and rhomboid nuclei may contribute to learning, memory consolidation and behavioral flexibility, in addition to general behavior and aspects of metabolism.

The ventral midline thalamus contributes to strategy shifting in a memory task requiring both prefrontal cortical and hippocampal functions.

Electrophysiological and neuroanatomical evidence for reciprocal connections with the medial prefrontal cortex (mPFC) and the hippocampus make the reuniens and rhomboid (ReRh) thalamic nuclei a putatively major functional link for regulations of cortico-hippocampal interactions. In a first experiment using a new water escape device for rodents, the double-H maze, we demonstrated in rats that a bilateral muscimol (MSCI) inactivation (0.70 vs 0.26 and 0 nmol) of the mPFC or dorsal hippocampus (dHip) induces major deficits in a strategy shifting/spatial memory retrieval task. By way of comparison, only dHip inactivation impaired recall in a classical spatial memory task in the Morris water maze. In the second experiment, we showed that ReRh inactivation using 0.70 nmol of MSCI, which reduced performance without obliterating memory retrieval in the water maze, produces an as large strategy shifting/memory retrieval deficit as mPFC or dHip inactivation in the double-H maze. Thus, behavioral adaptations to task contingency modifications requiring a shift toward the use of a memory for place might operate in a distributed circuit encompassing the mPFC (as the potential set-shifting structure), the hippocampus (as the spatial memory substrate), and the ventral midline thalamus, and therein the ReRh (as the coordinator of this processing). The results of the current experiments provide a significant extension of our understanding of the involvement of ventral midline thalamic nuclei in cognitive processes: they point to a role of the ReRh in strategy shifting in a memory task requiring cortical and hippocampal functions and further elucidate the functional system underlying behavioral flexibility.

The ventral midline thalamus (reuniens and rhomboid nuclei) contributes to the persistence of spatial memory in rats.

The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: >500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks.