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The ventral midline thalamus, including the reuniens and rhomboid (ReRh) nuclei, connects bidirectionally with the medial prefrontal cortex (mPFC) and hippocampus (Hip), both essential for memory processes. This review compiles and discusses studies on a role for the ReRh nuclei in the system consolidation of memories, also considering their potentially limited participation in memory retrieval or early phases of consolidation. It also examines scientific literature on short- and long-term plasticity in ReRh-mPFC and ReRh-Hip connections, emphasizing plasticity's importance in understanding these nuclei's role in memory. The idea that the two nuclei are at the crossroads of information exchange between the mPFC and the Hip is not new, but the relationship between this status and the plasticity of their connections remains elusive. Since this perspective is relatively recent, our concluding section suggests conceptual and practical avenues for future research, aiming perhaps to bring more order to the apparently multi-functional implication of the ventral midline thalamus in cognition., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease., Methods: We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females)., Results: Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions., Conclusions: This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease. At the epigenomic level, histone hyperacetylation was observed at neuronal enhancers associated with glutamatergic regulations only in the tauopathy. Lastly, a treatment of tau mice with the CSP-TTK21 epi-drug that restored expression of key cholesterol biosynthesis genes counteracted hyperacetylation at neuronal enhancers and restored object memory. As acetyl-CoA is the primary substrate of both pathways, these data suggest that the rate of the cholesterol biosynthesis in hippocampal neurons may trigger epigenetic-driven changes, that may compromise the functions of hippocampal neurons in pathological conditions., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The reuniens (Re) nucleus is located in the ventral midline thalamus. It has fostered increasing interest, not only for its participation in a variety of cognitive functions (e.g., spatial working memory, systemic consolidation, reconsolidation, extinction of fear or generalization), but also for its neuroanatomical positioning as a bidirectional relay between the prefrontal cortex (PFC) and the hippocampus (HIP). In this review we compile and discuss recent studies having tackled a possible implication of the Re nucleus in behavioral flexibility, a major PFC-dependent executive function controlling goal-directed behaviors. Experiments considered explored a possible role for the Re nucleus in perseveration, reversal learning, fear extinction, and set-shifting. They point to a contribution of this nucleus to behavioral flexibility, mainly by its connections with the PFC, but possibly also by those with the hippocampus, and even with the amygdala, at least for fear-related behavior. As such, the Re nucleus could be a crucial crossroad supporting a PFC-orchestrated ability to cope with new, potentially unpredictable environmental contingencies, and thus behavioral flexibility and adaption., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The thalamic reuniens (Re) and rhomboid (Rh) nuclei are bidirectionally connected with the medial prefrontal cortex (mPFC) and the hippocampus (Hip). Fiber-sparing N-methyl-D-aspartate lesions of the ReRh disrupt cognitive functions, including persistence of certain memories. Because such lesions irremediably damage neurons interconnecting the ReRh with the mPFC and the Hip, it is impossible to know if one or both pathways contribute to memory persistence. Addressing such an issue requires selective, pathway-restricted and direction-specific disconnections., New Method: A recent method associates a retrograde adeno-associated virus (AAV) expressing Cre recombinase with an anterograde AAV expressing a Cre-dependent caspase, making such disconnection feasible by caspase-triggered apoptosis when both constructs meet intracellularly. We injected an AAVrg-Cre-GFP into the ReRh and an AAV5-taCasp into the mPFC. As expected, part of mPFC neurons died, but massive neurotoxicity of the AAVrg-Cre-GFP was found in ReRh, contrasting with normal density of DAPI staining. Other stainings demonstrated increasing density of reactive astrocytes and microglia in the neurodegeneration site., Comparison With Existing Methods: Reducing the viral titer (by a 4-fold dilution) and injection volume (to half) attenuated toxicity substantially, still with evidence for partial disconnection between mPFC and ReRh., Conclusions: There is an imperative need to verify potential collateral damage inherent in this type of approach, which is likely to distort interpretation of experimental data. Therefore, controls allowing to distinguish collateral phenotypic effects from those linked to the desired disconnection is essential. It is also crucial to know for how long neurons expressing the Cre-GFP protein remain operational post-infection., Competing Interests: Declaration of Competing Interest none. Conflict of interest The authors have no conflict of interest to declare. Declaration of Generative (AI) and AI-assisted technologies in the Writing Process. No such technologies have been used in the writing process., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus ∆NLS/+ mice. Yet, the mechanisms linking FUS mislocalization to hippocampal function and memory formation are still not characterized. Herein, we show that in these mice, the hippocampus paradoxically displays nuclear FUS accumulation. Multi-omic analyses showed that FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus ∆NLS/+ mice. Furthermore, these mice lacked precision in a hippocampal-dependent spatial memory task and displayed decreased dendritic spine density. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. These data call for further investigation in the neurological phenotype of FUS-related diseases and open therapeutic strategies towards epigenetic drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Molecular mechanisms underlying cognitive deficits in Huntington's disease (HD), a striatal neurodegenerative disorder, are unknown. Here, we generated ChIPseq, 4Cseq and RNAseq data on striatal tissue of HD and control mice during striatum-dependent egocentric memory process. Multi-omics analyses showed altered activity-dependent epigenetic gene reprogramming of neuronal and glial genes regulating striatal plasticity in HD mice, which correlated with memory deficit. First, our data reveal that spatial chromatin re-organization and transcriptional induction of BDNF-related markers, regulating neuronal plasticity, were reduced since memory acquisition in the striatum of HD mice. Second, our data show that epigenetic memory implicating H3K9 acetylation, which established during late phase of memory process (e.g. during consolidation/recall) and contributed to glia-mediated, TGFβ-dependent plasticity, was compromised in HD mouse striatum. Specifically, memory-dependent regulation of H3K9 acetylation was impaired at genes controlling extracellular matrix and myelination. Our study investigating the interplay between epigenetics and memory identifies H3K9 acetylation and TGFβ signaling as new targets of striatal plasticity, which might offer innovative leads to improve HD., Competing Interests: Competing interests The authors declare no competing of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Working memory (WM) is a function operating in three successive phases: encoding (sample trial), holding (delay), and retrieval (test trial) of information. Studies point to a possible implication of the thalamic reuniens nucleus (Re) in spatial WM (SWM). In which of the aforementioned 3 phases the Re has a function is largely unknown. Recently, in a delayed SWM water-escape task, we found that performance during the retrieval trial correlated positively with c-Fos expression in the Re nucleus, suggesting participation in retrieval. Here, we used the same task and muscimol (MUSC) inhibition or DREADD(hM4Di)-mediated inhibition of the Re during information encoding, right thereafter (thereby affecting the holding phase), or during the retrieval trial. A 6-hour delay separated encoding from retrieval. Concerning SWM, MUSC in the Re nucleus did not alter performance, be it during or after encoding, or during evaluation. CNO administered before encoding in DREADD-expressing rats was also ineffective, although CNO-induced inhibition disrupted set shifting performance, as found previously (Quet et al., Brain Struct Function 225, 2020), thereby validating DREADD efficiency. These findings are the first that do not support an implication of the Re nucleus in SWM. As most previous studies used T-maze alternation tasks, which carry high proactive interference risks, an important question to resolve now is whether the Re nucleus is required in (T-maze alternation) tasks using very short information-holding delays (seconds to minutes), and less so in other short-term spatial memory tasks with longer information holding intervals (hours) and therefore reduced interference risks., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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.)

Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA ® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75 NTR ), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism., (© 2022. The Author(s).)

Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease., (© 2021. The Author(s).)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The most distant roots of neuroanatomy trace back to antiquity, with the first human dissections, but no document which would identify the thalamus as a brain structure has reached us. Claudius Galenus (Galen) gave to the thalamus the name 'thalamus nervorum opticorum', but later on, other names were used (e.g., anchae, or buttocks-like). In 1543, Andreas Vesalius provided the first quality illustrations of the thalamus. During the 19th century, tissue staining techniques and ablative studies contributed to the breakdown of the thalamus into subregions and nuclei. The next step was taken using radiomarkers to identify connections in the absence of lesions. Anterograde and retrograde tracing methods arose in the late 1960s, supporting extension, revision, or confirmation of previously established knowledge. The use of the first viral tracers introduced a new methodological breakthrough in the mid-1970s. Another important step was supported by advances in neuroimaging of the thalamus in the 21th century. The current review follows the history of the thalamus through these technical revolutions from Antiquity to the present day., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The consolidation of declarative memories is believed to occur mostly during sleep and involves a dialogue between two brain regions, the hippocampus and the medial prefrontal cortex. The information encoded during experience by neuronal assemblies is replayed during sleep leading to the progressive strengthening and integration of the memory trace in the prefrontal cortex. The gradual transfer of information from the hippocampus to the medial prefrontal cortex for long-term storage requires the synchronization of cortico-hippocampal networks by different oscillations, like ripples, spindles, and slow oscillations. Recent studies suggest the involvement of a third partner, the nucleus reuniens, in memory consolidation. Its bidirectional connections with the hippocampus and medial prefrontal cortex place the reuniens in a key position to relay information between the two structures. Indeed, many topical works reveal the original role that the nucleus reuniens occupies in different recent and remote memories consolidation. This review aimed to examine these contributions, as well as its functional embedment in this complex memory network, and provide some insights on the possible mechanisms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Our previous studies consistently showed that MDMA-induced locomotor hyperactivity is dramatically increased by coadministration of ethanol (EtOH) in rats, indicating possible potentiation of MDMA abuse liability. Thus, we aimed to identify the brain region(s) and neuropharmacological substrates involved in the pharmacodynamics of this potentiation. We first showed that potentiation of locomotor activity by the combination of ip administration of EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) is delay sensitive and maximal when both drugs are injected simultaneously. Then, we used the 2-deoxyglucose quantitative autoradiography technique to assess the impact of EtOH, MDMA, or their combination on local cerebral metabolic rates for glucose (CMRglcs). We showed a specific metabolic activation in the ventral striatum (VS) under MDMA + EtOH versus MDMA or EtOH alone. We next tested if reversible (tetrodotoxin, TTX) or permanent (6-hydrodoxyopamine, 6-OHDA) lesion of the VS could affect locomotor response to MDMA and MDMA + EtOH. Finally, we blocked dopamine D1 or glutamate NMDA receptors in the VS and measured the effects of MDMA and MDMA + EtOH on locomotor activity. We showed that bilateral reversible inactivation (TTX) or permanent lesion (6-OHDA) of the VS prevented the potentiation by EtOH of MDMA-induced locomotor hyperactivity. Likewise, blockade of D1 or NMDA receptors in the VS also reduced the potentiation of MDMA locomotor activity by EtOH. These data indicate that dopamine D1 and glutamate NMDA receptor-driven mechanisms in the VS play a key role in the pharmacodynamics of EtOH-induced potentiation of the locomotor effects of MDMA., (© 2020 Society for the Study of Addiction.)

Temporal dynamics and mechanisms underlying epigenetic changes in Huntington's disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.

Microglia are brain immune cells responsible for immune surveillance. Microglial activation is, however, closely associated with neuroinflammation, neurodegeneration, and obesity. Therefore, it is critical that microglial immune response appropriately adapts to different stressors. The circadian clock controls the cellular process that involves the regulation of inflammation and energy hemostasis. Here, we observed a significant circadian variation in the expression of markers related to inflammation, nutrient utilization, and antioxidation in microglial cells isolated from mice. Furthermore, we found that the core clock gene-Brain and Muscle Arnt-like 1 ( Bmal1 ) plays a role in regulating microglial immune function in mice and microglial BV-2 cells by using quantitative RT-PCR. Bmal1 deficiency decreased gene expression of pro-inflammatory cytokines, increased gene expression of antioxidative and anti-inflammatory factors in microglia. These changes were also observed in Bmal1 knock-down microglial BV-2 cells under lipopolysaccharide (LPS) and palmitic acid stimulations. Moreover, Bmal1 deficiency affected the expression of metabolic associated genes and metabolic processes, and increased phagocytic capacity in microglia. These findings suggest that Bmal1 is a key regulator in microglial immune response and cellular metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Wang, Wolff, Korpel, Milanova, Sandu, Rensen, Kooijman, Cassel, Kalsbeek, Boutillier and Yi.)

Background: CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBP KIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding., Results: We found that CBP KIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBP KIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBP KIX/KIX mice. CBP KIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBP KIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein., Conclusions: These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.

According to the standard theory of memory consolidation, recent memories are stored in the hippocampus before their transfer to cortical modules, a process called systemic consolidation. The ventral midline thalamus (reuniens and rhomboid nuclei, ReRh) takes part in this transfer as its lesion disrupts systemic consolidation of spatial and contextual fear memories. Here, we wondered whether ReRh lesions would also affect the systemic consolidation of another type of memory, namely an olfaction-based social memory. To address this question we focused on social transmission of food preference. Adult Long-Evans rats were subjected to N-methyl-d-aspartate-induced, fibre-sparing lesions of the ReRh nuclei or to a sham-operation, and subsequently trained in a social transmission of food preference paradigm. Retrieval was tested on the next day (recent memory, n Sham  = 10, n ReRh  = 12) or after a 25-day delay (remote memory, n Sham  = 10, n ReRh  = 10). All rats, whether sham-operated or subjected to ReRh lesions, learned and remembered the task normally, whatever the delay. Compared to our former results on spatial and contextual fear memories (Ali et al., 2017; Klein et al., 2019; Loureiro et al., 2012; Quet et al., 2020), the present findings indicate that the ReRh nuclei might not be part of a generic, systemic consolidation mechanism processing all kinds of memories in order to make them persistent. The difference between social transmission of food preference and spatial or contextual fear memories could be explained by the fact that social transmission of food preference is not hippocampus-dependent and that the persistence of social transmission of food preference memory relies on different circuits., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2020.)

Memory persistence refers to the process by which a temporary, labile memory is transformed into a stable and long-lasting state. This process involves a reorganization of brain networks at systems level, which requires functional interactions between the hippocampus (HP) and medial prefrontal cortex (mPFC). The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are bidirectionally connected with both regions, and we previously demonstrated their crucial role in spatial memory persistence. We now investigated, in male rats, whether specific manipulations of ReRh activity also affected contextual and cued fear memory persistence. We showed that the permanent ReRh lesion impaired remote, but not recent contextual fear memory. Tone-cued recent and remote fear memory were spared by the lesion. In intact rats, acute chemogenetic ReRh inhibition conducted before recall of either recent or remote contextual fear memories produced no effect, indicating that the ReRh nuclei are not required for retrieval of such memories. This was also suggested by a functional cellular imaging approach, as retrieval did not alter c-fos expression in the ReRh. Collectively, these data are compatible with a role for the ReRh in 'off-line' consolidation of a contextual fear memory and support the crucial importance of ventral midline thalamic nuclei in systems consolidation of memories.

Memory impairment is the main feature of Alzheimer's disease (AD). Initial impairments originate in the temporal lobe area and propagate throughout the brain in a sequential manner. Epigenetic mechanisms, especially histone acetylation, regulate plasticity and memory processes. These may be dismantled during the disease. The aim of this work was to establish changes in the acetylation-associated pathway in two key brain regions affected in AD: the hippocampus and the F2 area of frontal cortex in end-stage AD patients and age-matched controls. We found that the F2 area was more affected than the hippocampus. Indeed, CREB-Binding Protein (CBP), P300/CBP-associated protein (PCAF), Histone Deacetylase 1 (HDAC1) and HDAC2 (but not HDAC3) levels were strongly decreased in F2 area of AD compared to controls patients, whereas only HDAC1 was decreased and CBP showed a downward trend in the hippocampus. At the histone level, we detected a substantial increase in total (H3 and H2B) histone levels in the frontal cortex, but these were decreased in nuclear extracts, pointing to a dysregulation in histone trafficking/catabolism in this brain region. Histone H3 acetylation levels were increased in cell nuclei mainly in the frontal cortex. These findings provide evidence for acetylation dysfunctions at the level of associated enzymes and of histones in AD brains, which may underlie transcriptional dysregulations and AD-related cognitive impairments. They further point to stronger dysregulations in the F2 area of the frontal cortex than in the hippocampus at an end-stage of the disease, suggesting a differential vulnerability and/or compensatory mechanisms efficiency towards epigenetic alterations., Competing Interests: Conflict of interest All other authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Response and place memory systems have long been considered independent, encoding information in parallel, and involving the striatum and hippocampus, respectively. Most experimental studies supporting this view used simple, repetitive tasks, with unrestrained access to spatial cues. They did not give animals an opportunity to correct a response strategy by shifting to a place one, which would demonstrate dynamic, adaptive interactions between both memory systems in the navigation correction process. In a first experiment, rats were trained in the double-H maze for different durations (1, 6, or 14 days; 4 trials/day) to acquire a repetitive task in darkness (forcing a response memory-based strategy) or normal light (placing response and place memory systems in balance), or to acquire a place memory. All rats were given a misleading shifted-start probe trial 24-h post-training to test both their strategy and their ability to correct their navigation directly or in response to negative feedback. Additional analyses focused on the dorsal striatum and the dorsal hippocampus using c-Fos gene expression imaging and, in a second experiment, reversible muscimol inactivation. The results indicate that, depending on training protocol and duration, the striatum, which was unexpectedly the first to come into play in the dual strategy task, and the hippocampus are both required when rats have to correct their navigation after having acquired a repetitive task in a cued environment. Partly contradicting the model established by Packard and McGaugh (1996, Neurobiology of Learning and Memory, vol. 65), these data point to memory systems that interact in more complex ways than considered so far. To some extent, they also challenge the notion of hippocampus-independent response memory and striatum-independent place memory systems., (Copyright © 2019 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.

Previous work has shown that β-adrenergic and GABAergic systems in the basolateral amygdala (BLA) are involved in the acquisition of conditioned odor aversion (COA) learning. The involvement of α 2 -adrenoreceptors, however, is poorly documented. In a first experiment, male Long-Evans rats received infusions of 0.1 μg of the selective α 2 -antagonist dexefaroxan (Dex) in the BLA before being exposed to COA learning. In a second experiment, levels of norepinephrine (NE) were analyzed following Dex retrodialysis into the BLA. While microdialysis data showed a significant enhancement of NE release in the BLA with Dex, behavioral results showed that pre-CS infusion of Dex impaired, rather than facilitated, the acquisition of COA. Our results show that the NE system in the BLA is involved in the acquisition of COA, including a strong α 2 -receptor modulation until now unsuspected. Supported by the recent literature, the present data suggest moreover that the processes underlying this learning are probably mediated by the balanced effects of NE excitatory/inhibitory signaling in the BLA, in which interneurons are highly involved.

Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co-localizing at TSS and CBP enhancers. Importantly, CSP-TTK21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS, including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof-of-concept evidence that CBP/p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Pre-clinical deep-brain stimulation (DBS) research has observed a growing interest in the use of portable stimulation devices that can be carried by animals. Not only can such devices overcome many issues inherent with a cable tether, such as twisting or snagging, they can also be utilized in a greater variety of arenas, including enclosed or large mazes. However, these devices are not inherently designed for water-maze environments, and their use has been restricted to individually-housed rats in order to avoid damage from various social activities such as grooming, playing, or fighting. By taking advantage of 3D-printing techniques, this study demonstrates an ultra-small portable stimulator with an environmentally-protective device housing, that is suitable for both social-housing and water-maze environments. The miniature device offers 2 channels of charge-balanced biphasic pulses with a high compliance voltage (12 V), a magnetic switch, and a diverse range of programmable stimulus parameters and pulse modes. The device's capabilities have been verified in both chronic pair-housing and water-maze experiments that asses the effects of nucleus reuniens DBS. Theta-burst stimulation delivered during a reference-memory water-maze task (but not before) had induced performance deficits during both the acquisition and probe trials of a reference memory task. The results highlight a successful application of 3D-printing for expanding on the range of measurement modalities capable in DBS research.

Working memory is a cognitive ability allowing the temporary storage of information to solve problems or adjust behavior. While working memory is known to mainly depend on the medial prefrontal cortex (mPFC), very few is known about how cortical information are relayed subcortically. By its connectivity, the lateral habenula (lHb) might act as a subcortical relay for cortical information. Indeed, the lHb receives inputs from several mPFC subregions, and recent findings suggest a role for the lHb in online processing of spatial information, a fundamental aspect of working memory. In rats, in a delayed non-matching to position paradigm, using focal microinjections of the GABAA agonist muscimol we showed that inactivation of the lHb (16 ng in 0.2 µL per side), as well as disconnection between the prelimbic region of the mPFC (mPFC/PrL, 32 ng in 0.4 µL in one hemisphere) and the lHb (16 ng in 0.2 µL in the lHb in the contralateral hemisphere) impaired working memory. The deficits were unlikely to result from motivational or motor deficits as muscimol did not affect reward collection or cue responding latencies, and did not increase the number of omissions. These results show for the first time the implication of the lHb in mPFC-dependent memory processes, likely as a relay of mPFC/PrL information. They also open new perspectives in the understanding of the top-down processing of high-level cognitive functions., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Research methods in cognitive neuroscience using non-human primates have undergone notable changes over the last decades. Recently, several research groups have described freely accessible devices equipped with a touchscreen interface. Two characteristics of such systems are of particular interest: some apparatuses include automated identification of subjects, while others are mobile. Here, we designed, tested and validated an experimental system that, for the first time, combine automatization and mobility. Moreover, our system allows autonomous learning and testing of cognitive performance in group-living subjects, including follow-up assessments. The mobile apparatus is designed to be available 24h a day, 7days a week, in a typical confined primate breeding and housing facility. Here we present as proof of concept, the results of two pilot studies. We report that rhesus macaques (Macaca mulatta) learned the tasks rapidly and achieved high-level of stable performance. Approaches of this kind should be developed for future pharmacological and biomedical studies in non-human primates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The administration of lithium-pilocarpine (LiPilo) in adult rats is a validated model reproducing the main clinical and neuropathological features of temporal lobe epilepsy (TLE). Previous studies have shown that carisbamate (CRS) has the property of modifying epileptogenesis in this model. When treated with CRS, about 50% of rats undergoing LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of convulsive ones (commonly observed in TLE). The goal of this work was to determine some of the early changes that occur after CRS administration, as they could be involved in the insult- and epileptogenesis-modifying effects of CRS. Thus, we performed high-performance liquid chromatography (HPLC) to quantify levels of amino acids and monoamines, and c-Fos immunohistochemical labeling to map cerebral activation during seizures. Comparing rats treated one hour after SE onset with saline (CT), CRS, or diazepam (DZP), HPLC showed that 4 h after SE onset, dopamine (DA), norepinephrine (NE), and GABA levels were normal, whereas serotonin levels were increased. Using c-Fos labeling, we demonstrated increased activity in thalamic mediodorsal (MD) and laterodorsal (LD) nuclei in rats treated with CRS. In summary, at early times, CRS seems to modulate excitability by acting on some monoamine levels and increasing activity of MD and LD thalamic nuclei, suggesting a possible involvement of these nuclei in insult- and/or epileptogenesis-modifying effects of CRS., Competing Interests: The authors declare no conflict of interest.

In adult rats, the administration of lithium-pilocarpine (LiPilo) reproduces most clinical and neuropathological features of human temporal lobe epilepsy (TLE). Carisbamate (CRS) possesses the property of modifying epileptogenesis in this model. Indeed, about 50% of rats subjected to LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of motor seizures when treated with CRS. However, the mechanisms underlying these effects remain unknown. The aim of this study was to perform a proteomic analysis in the hippocampus of rats receiving LiPilo and developing motor seizures or NCS following CRS treatment. Fifteen adult male Sprague-Dawley rats were used. SE was induced by LiPilo injection. CRS treatment was initiated at 1 h and 9 h after SE onset and maintained for 7 days, twice daily. Four groups were studied after video-EEG control of the occurrence of motor seizures: a control group receiving saline (CT n = 3) and three groups that underwent SE: rats treated with diazepam (DZP n = 4), rats treated with CRS displaying NCS (CRS-NCS n = 4) or motor seizures (CRS-TLE n = 4). Proteomic analysis was conducted by 2D-SDS-PAGE. Twenty-four proteins were found altered. In the CRS-NCS group, proteins related to glycolysis and ATP synthesis were down-regulated while proteins associated with pyruvate catabolism were up-regulated. Moreover, among the other proteins differentially expressed, we found proteins related to inflammatory processes, protein folding, tissue regeneration, response to oxidative stress, gene expression, biogenesis of synaptic vesicles, signal transduction, axonal transport, microtubule formation, cell survival, and neuronal plasticity. Our results suggest a global reduction of glycolysis and cellular energy production that might affect brain excitability. In addition, CRS seems to modulate proteins related to many other pathways that could significantly participate in the epileptogenesis-modifying effect observed., Competing Interests: The authors declare no conflict of interest.

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.)

Epigenetic and transcriptional alterations are both implicated in Huntington's disease (HD), a progressive neurodegenerative disease resulting in degeneration of striatal neurons in the brain. However, how impaired epigenetic regulation leads to transcriptional dysregulation in HD is unclear. Here, we investigated enhancer RNAs (eRNAs), a class of long non-coding RNAs transcribed from active enhancers. We found that eRNAs are expressed from many enhancers of mouse striatum and showed that a subset of those eRNAs are deregulated in HD vs control mouse striatum. Enhancer regions producing eRNAs decreased in HD mouse striatum were associated with genes involved in striatal neuron identity. Consistently, they were enriched in striatal super-enhancers. Moreover, decreased eRNA expression in HD mouse striatum correlated with down-regulation of associated genes. Additionally, a significant number of RNA Polymerase II (RNAPII) binding sites were lost within enhancers associated with decreased eRNAs in HD vs control mouse striatum. Together, this indicates that loss of RNAPII at HD mouse enhancers contributes to reduced transcription of eRNAs, resulting in down-regulation of target genes. Thus, our data support the view that eRNA dysregulation in HD striatum is a key mechanism leading to altered transcription of striatal neuron identity genes, through reduced recruitment of RNAPII at super-enhancers.

Within cognitive and behavioural research, the 5-Choice Serial Reaction Time task is widely recognized as a valuable test of attention in rats. However, technical and methodological developments required for extending its usefulness are still at an early stage. In view of advances in knowledge about cognition and other areas of biology, issues surrounding attention are increasingly important, and appear to require new methodological approaches. These changes may concern (i) the evolution of the protocol itself, (ii) adaptations in how tasks are implemented (e.g. use of new technologies such as touchscreens), and (iii) applying existing tasks to species presenting an emerging potential. From a primarily methodological perspective, this review focuses on work that has successively built upon the original 5-CSRT task. We address the strengths and weaknesses of new approaches as well as some of the new possibilities they offer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although the elaborate combination of histone and non-histone protein complexes defines chromatin organization and hence regulates numerous nuclear processes, the role of chromatin organizing proteins remains unexplored at the organismal level. The highly abundant, multifunctional, chromatin-associated protein and transcriptional coactivator positive coactivator 4 (PC4/Sub1) is absolutely critical for life, because its absence leads to embryonic lethality. Here, we report results obtained with conditional PC4 knock-out (PC4(f/f) Nestin-Cre) mice where PC4 is knocked out specifically in the brain. Compared with the control (PC4(+/+) Nestin-Cre) mice, PC4(f/f) Nestin-Cre mice are smaller with decreased nocturnal activity but are fertile and show no motor dysfunction. Neurons in different areas of the brains of these mice show sensitivity to hypoxia/anoxia, and decreased adult neurogenesis was observed in the dentate gyrus. Interestingly, PC4(f/f) Nestin-Cre mice exhibit a severe deficit in spatial memory extinction, whereas acquisition and long term retention were unaffected. Gene expression analysis of the dorsal hippocampus of PC4(f/f) Nestin-Cre mice revealed dysregulated expression of several neural function-associated genes, and PC4 was consistently found to localize on the promoters of these genes, indicating that PC4 regulates their expression. These observations indicate that non-histone chromatin-associated proteins like PC4 play a significant role in neuronal plasticity., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Spatial reference memory in rodents represents a unique opportunity to study brain mechanisms responsible for encoding, storage and retrieval of a memory. Even though its reliance on hippocampal networks has long been established, the precise computations performed by different hippocampal subfields during spatial learning are still not clear. To study the evolution of electrophysiological activity in the CA1-dentate gyrus axis of the dorsal hippocampus over an iterative spatial learning paradigm, we recorded local field potentials in behaving mice using a newly designed appetitive version of the Barnes maze. We first showed that theta and gamma oscillations as well as theta-gamma coupling are differentially modulated in particular hippocampal subfields during the task. In addition, we show that dentate gyrus networks, but not CA1 networks, exhibit a transient learning-dependent increase in theta-gamma coupling specifically at the vicinity of the target area in the maze. In contrast to previous immediate early-gene studies, our results point to a long-lasting involvement of dentate networks in navigational memory in the Barnes maze. Based on these findings, we propose that theta-gamma coupling might represent a mechanism by which hippocampal areas compute relevant information., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Aging weakens memory functions. Exposing healthy rodents or pathological rodent models to environmental enrichment (EE) housing improves their cognitive functions by changing neuronal levels of excitation, cellular signaling, and plasticity, notably in the hippocampus. At the molecular level, brain derived-neurotrophic factor (BDNF) represents an important player that supports EE-associated changes. EE facilitation of learning was also shown to correlate with chromatin acetylation in the hippocampus. It is not known, however, whether such mechanisms are still into play during aging. In this study, we exposed a cohort of aged rats (18-month-old) to either a 6 month period of EE or standard housing conditions and investigated chromatin acetylation-associated events [histone acetyltranferase activity, gene expression, and histone 3 (H3) acetylation] and epigenetic modulation of the Bdnf gene under rest conditions and during learning. We show that EE leads to upregulation of acetylation-dependent mechanisms in aged rats, whether at rest or following a learning challenge. We found an increased expression of Bdnf through Exon-I-dependent transcription, associated with an enrichment of acetylated H3 at several sites of Bdnf promoter I, more particularly on a proximal nuclear factor κB (NF-κB) site under learning conditions. We further evidenced p65/NF-κB binding to chromatin at promoters of genes important for plasticity and hippocampus-dependent learning (e.g., Bdnf, CamK2D). Altogether, our findings demonstrate that aged rats respond to a belated period of EE by increasing hippocampal plasticity, together with activating sustained acetylation-associated mechanisms recruiting NF-κB and promoting related gene transcription. These responses are likely to trigger beneficial effects associated with EE during aging., Significance Statement: Aging weakens memory functions. Optimizing the neuronal circuitry required for normal brain function can be achieved by increasing sensory, motor, and cognitive stimuli resulting from interactions with the environment (behavioral therapy). This can be experimentally modeled by exposing rodents to environmental enrichment (EE), as with large cages, numerous and varied toys, and interaction with other rodents. However, EE effects in aged rodents has been poorly studied, and it is not known whether beneficial mechanisms evidenced in the young adults can still be recruited during aging. Our study shows that aged rats respond to a belated period of EE by activating specific epigenetic and transcriptional signaling that promotes gene expression likely to facilitate plasticity and learning behaviors., (Copyright © 2016 the authors 0270-6474/16/364352-11$15.00/0.)

Objective: Even if considered benign, absence epilepsy may alter memory and attention, sometimes subtly. Very little is known on behavior and cognitive functions in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model of absence epilepsy. We focused on different memory systems and sustained visual attention, using Non Epileptic Controls (NECs) and Wistars as controls., Methods: A battery of cognitive/behavioral tests was used. The functionality of reference, working, and procedural memory was assessed in the Morris water maze (MWM), 8-arm radial maze, T-maze and/or double-H maze. Sustained visual attention was evaluated in the 5-choice serial reaction time task., Results: In the MWM, GAERS showed delayed learning and less efficient working memory. In the 8-arm radial maze and T-maze tests, working memory performance was normal in GAERS, although most GAERS preferred an egocentric strategy (based on proprioceptive/kinesthetic information) to solve the task, but could efficiently shift to an allocentric strategy (based on spatial cues) after protocol alteration. Procedural memory and visual attention were mostly unimpaired., Significance: Absence epilepsy has been associated with some learning problems in children. In GAERS, the differences in water maze performance (slower learning of the reference memory task and weak impairment of working memory) and in radial arm maze strategies suggest that cognitive alterations may be subtle, task-specific, and that normal performance can be a matter of strategy adaptation. Altogether, these results strengthen the "face validity" of the GAERS model: in humans with absence epilepsy, cognitive alterations are not easily detectable, which is compatible with subtle deficits., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

With the continued miniaturisation of portable embedded systems, wireless EEG recording techniques are becoming increasingly prevalent in animal behavioural research. However, in spite of their versatility and portability, they have seldom been used inside water-maze tasks designed for rats. As such, a novel 3D printed implant and waterproof connector is presented, which can facilitate wireless water-maze EEG recordings in freely-moving rats, using a commercial wireless recording system (W32; Multichannel Systems). As well as waterproofing the wireless system, battery, and electrode connector, the implant serves to reduce movement-related artefacts by redistributing movement-related forces away from the electrode connector. This implant/connector was able to successfully record high-quality LFP in the hippocampo-striatal brain regions of rats as they undertook a procedural-learning variant of the double-H water-maze task. Notably, there were no significant performance deficits through its use when compared with a control group across a number of metrics including number of errors and speed of task completion. Taken together, this method can expand the range of measurements that are currently possible in this diverse area of behavioural neuroscience, whilst paving the way for integration with more complex behaviours.

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.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia accounting for 50-80% of all age-related dementia. This pathology is characterized by the progressive and irreversible alteration of cognitive functions, such as memory, leading inexorably to the loss of autonomy for patients with AD. The pathology is linked with aging and occurs most commonly around 65 years old. Its prevalence (5% over 65 years of age and 20% after 80 years) constitutes an economic and social burden for AD patients and their family. At the present, there is still no cure for AD, actual treatments being moderately effective only in early stages of the pathology. A lot of efforts have been deployed with the aim of defining new AD biomarkers. Successful early detection of mild cognitive impairment (MCI) linked to AD requires the identification of biomarkers capable of distinguishing individuals with early stages of AD from other pathologies impacting cognition such as depression. In this article, we will review recent evidence suggesting that electroencephalographic (EEG) recordings, coupled with behavioral assessments, could be a useful approach and easily implementable for a precocious detection of AD.

The lateral habenula (LHb) is viewed as a relay between the limbic system, the basal ganglia (BG), and monoaminergic neurons of the midbrain. If a prominent role has been evidenced in BG-mediated functions such as value-based decision-making, very little is known about the involvement of the LHb in limbic functions such as memory processing. In the present study, we used two pharmacological approaches-LHb reversible inactivation with intra-LHb infusion of muscimol, an agonist of the GABA-A receptor, or blockade of excitatory inputs with intra-LHb infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the glutamatergic AMPA receptor-to investigate the involvement of the LHb in encoding, consolidation, and retrieval of spatial memory in the water maze (WM) in rats. We found that intra-LHb infusion of muscimol or CNQX prevented encoding and retrieval, but not consolidation of spatial information. In addition, muscimol but not CNQX induced impairments during a cued version of the WM task, and marked anxiety in the elevated plus maze. These results confirm the involvement of the LHb in higher cognitive functions. They further suggest a dichotomy between the role of glutamatergic and other inputs to the LHb in hippocampus-dependent memory processing, as well as in emotional aspects of goal-directed behaviors.

Environmental enrichment is a powerful way to stimulate brain and behavioral plasticity. However the required exposure duration to reach such changes has not been substantially analyzed. We aimed to assess the time-course of appearance of the beneficial effects of enriched environment. Thus, different behavioral tests and neurobiological parameters (such as neurogenesis, brain monoamines levels, and stress-related hormones) were concomitantly realized after different durations of enriched environment (24 h, 1, 3, or 5 weeks). While short enrichment exposure (24 h) was sufficient to improve object recognition memory performances, a 3-week exposure was required to improve aversive stimulus-based memory performances and to reduce anxiety-like behavior; effects that were not observed with longer duration. The onset of behavioral changes after a 3-week exposure might be supported by higher serotonin levels in the frontal cortex, but seems independent of neurogenesis phenomenon. Additionally, the benefit of 3-week exposure on memory was not observed 3 weeks after cessation of enrichment. Thus, the 3-week exposure appears as an optimal duration in order to induce the most significant behavioral effects and to assess the underlying mechanisms. Altogether, these results suggest that the duration of exposure is a keystone of the beneficial behavioral and neurobiological effects of environmental enrichment., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Spatial cognition research in rodents typically employs the use of maze tasks, whose attributes vary from one maze to the next. These tasks vary by their behavioral flexibility and required memory duration, the number of goals and pathways, and also the overall task complexity. A confounding feature in many of these tasks is the lack of control over the strategy employed by the rodents to reach the goal, e.g., allocentric (declarative-like) or egocentric (procedural) based strategies. The double-H maze is a novel water-escape memory task that addresses this issue, by allowing the experimenter to direct the type of strategy learned during the training period. The double-H maze is a transparent device, which consists of a central alleyway with three arms protruding on both sides, along with an escape platform submerged at the extremity of one of these arms. Rats can be trained using an allocentric strategy by alternating the start position in the maze in an unpredictable manner (see protocol 1; §4.7), thus requiring them to learn the location of the platform based on the available allothetic cues. Alternatively, an egocentric learning strategy (protocol 2; §4.8) can be employed by releasing the rats from the same position during each trial, until they learn the procedural pattern required to reach the goal. This task has been proven to allow for the formation of stable memory traces. Memory can be probed following the training period in a misleading probe trial, in which the starting position for the rats alternates. Following an egocentric learning paradigm, rats typically resort to an allocentric-based strategy, but only when their initial view on the extra-maze cues differs markedly from their original position. This task is ideally suited to explore the effects of drugs/perturbations on allocentric/egocentric memory performance, as well as the interactions between these two memory systems.