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Upon stress exposure a broad network of structures comes into play in order to provide adequate responses and restore homeostasis. It has been known for decades that the main structures engaged during the stress response are the medial prefrontal cortex, the amygdala, the hippocampus, the hypothalamus, the monoaminergic systems (noradrenaline, dopamine, serotonin), and the periaqueductal gray. The lateral habenula (LHb) is an epithalamic structure directly connected to prefrontal cortical areas and to the amygdala, whereas it functionally interacts with the hippocampus. Also, it is a main modulator of monoaminergic systems. The LHb is activated upon exposure to basically all types of stressors, suggesting it is also involved in the stress response. However, it remains unknown if and how the LHb functionally interacts with the broad stress response network. In the current study we performed in rats a restraint stress procedure followed by immunohistochemical staining of the c-Fos protein throughout the brain. Using Graph Theory-based functional connectivity analyses, we confirm the principal hubs of the stress network (e.g. prefrontal cortex, amygdala, periventricular hypothalamus), and show that the LHb is engaged during stress exposure in close interaction with the medial prefrontal cortex, the lateral septum, and the medial habenula. In addition, we performed DREADD-induced LHb inactivation during the same restraint paradigm in order to explore its consequences on the stress response network. This last experiment gave contrasting results as the DREADD ligand alone, clozapine-N-oxide, was able to modify the network.GRAPHICAL ABSTRACTGRAPHICAL ABSTRACT TEXTIn this study, using immunohistochemical staining of the immediate early gene c-fos and graph theory-based functional correlational analyses, we aimed at unravelling the possible engagement of the lateral habenula (LHb) within the stress response network during acute stress exposure (10-min restraint) in rats. We found that the medial part of the LHb (LHbM) was preferentially engaged, and that this engagement was concomitant to this of structures such as the medial prefrontal cortex (mPFC), the insular cortex (Ins), hypothalamic (PVH) and thalamic (PVT) paraventricular nuclei, the extended amygdala, comprising the Bed nucleus of the stria terminalis (BNST) and the entire amygdala (AMG), as well as the dopaminergic ventral tegmental area (VTA) and the serotonergic dorsal raphe nucleus (RD). This suggests upon stressful situations the LHbM serves as a relay of cortical, thalamic, hypothalamic and temporal information, further transmitted to midbrain monoaminergic systems to probably initiate coping strategies.

International audience; Melatonin, a major signal of the circadian system, is also involved in brain functions such as learning and memory. Chronic melatonin treatment is known to improve memory performances, but the respective contribution of its central receptors, MT1 and MT2, is still unclear. Here, we used new single receptor deficient MT1-/and MT2-/mice to investigate the contribution of each receptor in the positive effect of chronic melatonin treatment on long-term recognition memory. The lack of MT2 receptor precluded memory-enhancing effect of melatonin in the object recognition task and to a lesser extent in the object location task, whereas the lack of MT1 receptor mitigated its effect in the object location task only. Our findings support a key role of MT2 in mediating melatonin's beneficial action on long-term object recognition memory, whereas MT1 may contribute to the effect on object location memory.

A critical challenge in current research on AD is to clarify the relationship between early neuropathology and network dysfunction associated to the emergence of subtle memory alterations which announce disease onset. In the present work, the new generation AppNL-F/MAPT double knock in (dKI) model was used to evaluate early stages of AD. The initial step of tau pathology was restricted to the perirhinal-entorhinal region, sparing the hippocampus. This discrete neuropathological sign was associated with deficits in the object-place associative memory, one of the earliest recognition memories affected in individuals at risk for developing AD. Analyses of task-dependent c-Fos activation was carried out in 22 brain regions across the medial prefrontal cortex, claustrum, retrosplenial cortex, and medial temporal lobe. Initial hyperactivity was detected in the entorhinal cortex and the claustrum of dKI mice. The retention phase was associated to reduced network efficiency especially across cingulate cortical regions, which may be caused by a disruption of information flow through the retrosplenial cortex. Moreover, the relationship between network global efficiency and memory performance in the WT could predict memory loss in the dKI, further linking reduced network efficiency to memory dysfunction. Our results suggest that early perirhinal-entorhinal pathology is associated with local hyperactivity which spreads towards connected regions such as the claustrum, the medial prefrontal cortex and ultimately the key retrosplenial hub which is needed to relay information flow from frontal to temporal lobes. The similarity between our findings and those reported in the earliest stages of AD suggests that the AppNL-F/MAPT dKI model has a high potential for generating key information on the initial stage of the disease.

Melatonin, a major signal of the circadian system, is also involved in brain functions such as learning and memory. Chronic melatonin treatment is known to improve memory performances, but the respective contribution of its central receptors, MT

International audience; Increasing evidence points to the engagement of the lateral habenula (LHb) in the selection of appropriate behavioral responses in aversive situations. However, very few data have been gathered with respect to its role in fear memory formation, especially in learning paradigms in which brain areas involved in cognitive processes like the hippocampus (HPC) and the medial prefrontal cortex (mPFC) are required. A paradigm of this sort is trace fear conditioning, in which an aversive event is preceded by a discrete stimulus, generally a tone, but without the close temporal contiguity allowing for their association based on amygdala-dependent information processing. In a first experiment, we analyzed cellular activations (c-Fos expression) induced by trace fear conditioning in subregions of the habenular complex, HPC, mPFC and amygdala using a factorial analysis to unravel functional networks through correlational analysis of data. This analysis suggested that distinct LHb subregions engaged in different aspects of conditioning, e.g. associative processes and onset of fear responses. In a second experiment, we performed chemogenetic LHb inactivation during the conditioning phase of the trace fear conditioning paradigm and subsequently assessed contextual and tone fear memories. Whereas LHb inactivation did not modify rat's behavior during conditioning, it induced contextual memory deficits and enhanced fear to the tone. These results demonstrate the involvement of the LHb in fear memory. They further suggest that the LHb is engaged in learning about threatening environments through the selection of relevant information predictive of a danger.

The lateral habenula (LHb) is involved in emotional and cognitive behaviors. Recently, we have shown in rats that blockade of excitatory inputs to the LHb not only induced deficits of memory retrieval in the water maze, but also altered swim strategies (i.e., induced excessive thigmotaxis). The latter observation, although consistent with the occurrence of memory deficits, could also possibly be the consequence of an excessive level of stress, further suggesting a role for the LHb in the stress response in our behavioral paradigm. To test this hypothesis we performed in rats intra-LHb infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 267 ng/side in 0.3 μL), or vehicle, and assessed the responsiveness of the hypothalamo-pituitary adrenal (HPA) axis to environmental stressful or non-stressful situations. We have measured plasma corticosterone (CORT) concentrations at different time points before and following intra-LHb infusion of CNQX – or of the same volume of vehicle – in three conditions: during the probe test of a water maze experiment; in an anxiety test, the elevated plus maze; and in a home cage condition. Whereas there were no differences in the home cage condition and in the elevated plus maze, in the water maze experiment we observed that CNQX-treated rats presented, along with memory deficits, a higher level of blood CORT than vehicle-treated rats. These results suggest that perturbations of the modulation of the HPA axis are consecutive to the alteration of LHb function, whether it is the result of a defective direct control of the LHb over the HPA axis, or the consequence of memory deficits.

DMSO has a widespread use as a vehicle for water-insoluble therapeutic drug candidates but may also exert disease-relevant pharmacological effects by itself. However, its influence on the CNS has hardly been addressed. Here we examined the brain structure and function following chronic exposure to low DMSO dose at a paradigm with flawed synaptic connectivity in a preclinical transgenic mouse model for Alzheimer's disease (APPSDL mice). DMSO treatment increased spine density in a region-specific manner in the hippocampus of APPSDL mice ex vivo and in vivo. Moreover, DMSO exhibited clear influence on the behavior of this mouse line by enhancing hippocampal-dependent spatial memory accuracy, modulating hippocampal-independent olfactory habituation and displaying anxiolytic effect. Despite that most of the action of DMSO was observed in animals with elevated Aβ levels, the drug did not exert its function via decreasing the oligomeric Aβ species. However, challenging organotypic hippocampal slice cultures with NMDA receptor antagonist MK-801 recapitulated the effect of DMSO on spine density, indicating a tuning influence of DMSO on receptor signalization. Our findings demonstrate that DMSO should be considered as a true bioactive compound, which has the potential to be a beneficial adjuvant to counteract Aβ-mediated synaptotoxicity and behavioral impairment.

In rats, some cognitive capabilities, like spatial learning and memory, are preserved from age-related decline by whole adult life enriched environment (EE) exposure. However, to which extent late EE contributes to such maintenance remains to be investigated. Here we assessed the impact of late housing condition (e.g., from the age of 18 months) on spatial learning and memory of aged rats (24 months) previously exposed or unexposed to EE from young adulthood. The results showed that late EE was not required for spatial memory maintenance in aged rats previously housed in EE. In contrast, late EE mitigates spatial memory deficit in aged rats previously unexposed to EE. These outcomes suggest that EE exposure up to middle age provides a "reserve"-like advantage which supports an enduring preservation of spatial capabilities in old age.

A number of animal models have been designed to reproduce some or the main pathophysiological and behavioural characteristics of Alzheimer's disease (AD), and to evaluate the potential of therapeutic targets and drug candidates. The object recognition paradigm played a significant role in the studies of these AD models, particularly with variants of this same paradigm taping in various forms and aspects of memory processes such as short- and long-term memory, spatial and nonspatial memory, episodic memory and consolidation and retrieval. In the present chapter, we summarized and evaluated the significant contributions of the object recognition test and some of its variants in the current animal models obtained through transgenic approaches and stereotaxic amyloid peptide Aβ injection, and in species naturally expressing age-dependent amyloid and tau pathologies. We also highlighted the clear advantages and possible limitations in the translational value of the object recognition paradigm.

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.

International audience; Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age-dependence which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets.

The chronic decrease of brain amyloid-β (Aβ) peptides is an emerging therapeutic for Alzheimer's disease, but no such treatment has achieved clinical validation yet. In vivo, some brain proteases, including neprilysin, possess the ability of degrading Aβ and experimental data suggest their exploitation in strategies to reduce cerebral Aβ concentration. Previous studies have shown that pharmacologic doses of gamma-hydroxybutyrate (sodium oxybate or Xyrem) induce histone deacetylases (HDACs) inhibition and neprilysin gene expression. Here, we demonstrate that brain neprilysin overexpression induced in vivo by repeated gamma-hydroxybutyrate autoadministration reduces cerebral Aβ contents and prevents cognitive deficits in APPSWE mice. Oral gamma-hydroxybutyrate also counteracted phosphoramidon-induced brain neprilysin inhibition and Aβ accumulation. HDACs activities in SH-SY5Y cells were inhibited by gamma-hydroxybutyrate which did not affect amyloid peptide precursor intracellular domain. Together, our results suggest that gamma-hydroxybutyrate, acting via HDAC inhibition, upregulates neprilysin to reduce Aβ level and related memory deficits. Because gamma-hydroxybutyrate doses used herein are clinically relevant, our data suggest that chronic oral administration of gamma-hydroxybutyrate or its analogs may be considered for strategies against presymptomatic or established Alzheimer's disease.

International audience; Notwithstanding tremendous research efforts, the cause of Alzheimer’s disease (AD) remains elusive and there is no curative treatment. The cholinergic hypothesis presented 35 years ago was the first major evidence-based hypothesis regarding AD etiology. It proposed that the depletion of brain acetylcholine was a primary cause of cognitive decline in advanced age and AD. It relied on a series of observations obtained in aged animals, elderly and AD patients which pointed to dysfunctions of cholinergic basal forebrain, similarities between cognitive impairments induced by anticholinergic drugs and those found in advanced age and AD, and beneficial effects of drugs stimulating cholinergic activity. This review comes back on these major results to show how this hypothesis provided the drive for the development of anticholinesterase inhibitor-based therapies of AD, the almost exclusive approved treatment in use despite transient and modest efficacy. New ideas for improving cholinergic therapies are also compared and discussed in light of the current revival of the cholinergic hypothesis based on two sets of evidence from new animal models and refined imagery techniques in humans. First, human and animal studies agree on detecting signs of cholinergic dysfunctions much earlier than initially thought. Second, alterations of the cholinergic system are deeply intertwined with its reactive responses providing the brain with efficient compensatory mechanisms to delay the conversion to AD. Active research in this field should give new insight to develop multi-therapies incorporating cholinergic manipulation, as well as early biomarkers of AD allowing earlier diagnostics. This is of prime importance to counteract a disease that is now recognized to start early in adult life.

Brain mechanisms compensating for cerebral lesions may mitigate the progression of chronic neurodegenerative disorders such as Alzheimer's disease (AD). Mild cognitive impairment (MCI), which often precedes AD, is characterized by neuronal loss in the entorhinal cortex (EC). This loss leads to a hippocampal disconnection syndrome that drives clinical progression. The concomitant sprouting of cholinergic terminals in the hippocampus has been proposed to compensate for reduced EC glutamatergic input. However, in absence of direct experimental evidence, the compensatory nature of the cholinergic sprouting and its putative mechanisms remain elusive. Transgenic mice expressing the humanAPOE4allele, the main genetic risk factor for sporadic MCI/AD, display impaired cholinergic sprouting after EC lesion. Using these mice as a tool to manipulate cholinergic sprouting in a disease-relevant way, we showed that this sprouting was necessary and sufficient for the acute compensation of EC lesion-induced spatial memory deficit before a slower glutamatergic reinnervation took place. We also found that partial EC lesion generates abnormal hyperactivity in EC/dentate networks. Dentate hyperactivity was abolished by optogenetic stimulation of cholinergic fibers. Therefore, control of dentate hyperactivity by cholinergic sprouting may be involved in functional compensation after entorhinal lesion. Our results also suggest that dentate hyperactivity in MCI patients may be directly related to EC neuronal loss. Impaired sprouting during the MCI stage may contribute to the faster cognitive decline reported inAPOE4carriers. Beyond the amyloid contribution, the potential role of both cholinergic sprouting and dentate hyperactivity in AD symptomatogenesis should be considered in designing new therapeutic approaches.SIGNIFICANCE STATEMENTCurrently, curative treatment trials for Alzheimer's disease (AD) have failed. The endogenous ability of the brain to cope with neuronal loss probably represents one of the most promising therapeutic targets, but the underlying mechanisms are still unclear. Here, we show that the mammalian brain is able to manage several deleterious consequences of the loss of entorhinal neurons on hippocampal activity and cognitive performance through a fast cholinergic sprouting followed by a slower glutamatergic reinnervation. The cholinergic sprouting is gender dependent and highly sensitive to the genetic risk factorAPOE4. Our findings highlight the specific impact of early loss of entorhinal input on hippocampal hyperactivity and cognitive deficits characterizing early stages of AD, especially inAPOE4carriers.

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.

International audience; 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.

Exposure of rodents to a stimulating environment has beneficial effects on some cognitive functions that are impaired during physiological aging, and especially spatial reference memory. The present study investigated whether environmental enrichment rescues these functions in already declining subjects and/or protects them from subsequent decline. Subgroups of 17-mo-old female rats with unimpaired versus impaired performance in a spatial reference memory task (Morris water maze) were housed until the age of 24 mo in standard or enriched environment. They were then trained in a second reference memory task, conducted in a different room than the first, and recent (1 d) and remote (10 d) memory were assessed. In unimpaired subgroups, spatial memory declined from 17 to 24 mo in rats housed in standard conditions; an enriched environment during this period allowed maintenance of accurate recent and remote spatial memory. At 24 mo, rats impaired at the age of 17 mo housed in enriched environment learned the task and displayed substantial recent memory, but their performance remained lower than that of unimpaired rats, showing that enrichment failed to rescue spatial memory in already cognitively declining rats. Controls indicated carryover effects of the first water maze training, especially in aged rats housed in standard condition, and confirmed the beneficial effect of enrichment on remote memory of aged rats even if they performed poorly than young adults housed for the same duration in standard or enriched condition.

International audience; G protein-coupled receptor (GPCR) associated sorting protein 1 (GASP-1) interacts with GPCRs and is implicated in their postendocytic sorting. Recently, GASP-1 has been shown to regulate dopamine (D2) and cannabinoid (CB1) receptor signalling, suggesting that preventing GASP-1 interaction with GPCRs might provide a means to limit the decrease in receptor signalling upon sustained agonist treatment. In order to test this hypothesis, we have generated and behaviourally characterized GASP-1 knockout (KO) mice and have examined the consequences of the absence of GASP-1 on chronic cocaine treatments. GASP-1 KO and wild-type (WT) mice were tested for sensitization to the locomotor effects of cocaine. Additional mice were trained to acquire intravenous self-administration of cocaine on a fixed ratio 1 schedule of reinforcement, and the motivational value of cocaine was then assessed using a progressive ratio schedule of reinforcement. The dopamine and muscarinic receptor densities were quantitatively evaluated in the striatum of WT and KO mice tested for sensitization and self-administration. Acute and sensitized cocaine-locomotor effects were attenuated in KO mice. A decrease in the percentage of animals that acquired cocaine self-administration was also observed in GASP-1-deficient mice, which was associated with pronounced down-regulation of dopamine and muscarinic receptors in the striatum. These data indicate that GASP-1 participates in acute and chronic behavioural responses induced by cocaine and are in agreement with a role of GASP-1 in postendocytic sorting of GPCRs. However, in contrast to previous studies, our data suggest that upon sustained receptor stimulation GASP-1 stimulates recycling rather than receptor degradation.

Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline.

In mammals, hippocampal and striatal regions are engaged in separable cognitive processes usually assessed through species-specific paradigms. To reconcile cognitive testing among species, translational advantages of the touchscreen-based automated method have been recently promoted. However, it remains undetermined whether similar neural substrates would be involved in such behavioral tasks both in humans and rodents. To address this question, the effects of hippocampal or dorso-striatal fiber-sparing lesions were first assessed in mice through a battery of tasks (experiment A) comprising the acquisition of two touchscreen paradigms, the Paired Associates Learning (dPAL) and Visuo-Motor Conditional Learning (VMCL) tasks, and a more classical T-maze alternation task. Additionally, we sought to determine whether post-acquisition hippocampal lesions would alter memory retrieval in the dPAL task (experiment B). Pre-training lesions of dorsal striatum caused major impairments in all paradigms. In contrast, pre-training hippocampal lesions disrupted the performance of animals trained in the T-maze assay, but spared the acquisition in touchscreen tasks. Nonetheless, post-training hippocampal lesions severely impacted the recall of the previously learned dPAL task. Altogether, our data show that, after having demonstrated their potential in genetically modified mice, touchscreens also reveal perfectly adapted to taxing functional implications of brain structures in mice by means of lesion approaches. Unlike its human counterpart requiring an intact hippocampus, the acquisition of the dPAL task requires the integrity of the dorsal striatum in mice. The hippocampus only later intervenes, when acquired information needs to be retrieved. Touchscreen assays may therefore be suited to study striatal- or hippocampal-dependent forms of learnings in mice.

Apolipoprotein E4 (apoE4), one of the three most common human apoE (h-apoE) isoforms, is a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. The biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent effect of h-apoE on cognitive performance was studied in gene-targeted mice, which show physiological expression levels and distribution of h-apoE3 or h-apoE4. Male and female h-apoE3 and h-apoE4, apoE-deficient and C57BL/6J mice (4-5 months) were subjected to tasks evaluating spatial memory and avoidance conditioning. Female h-apoE4 mice did not detect changes in the spatial configuration of objects as opposed to female h-apoE3 mice. Female h-apoE3 mice failed to improve their performance during training in a reference memory version of the spatial water-maze task, but performed well during the probe trial 24 h after the last training trial. Memory retention performances of h-apoE4 mice were impaired during this probe trial. Both h-apoE3 and h-apoE4 mice did not improve their performance in a water-maze delayed matching to place task. Finally, h-apoE3 mice showed mild perturbations in a Y-maze active avoidance task, whereas both h-apoE mouse lines performed well in a passive avoidance task. Thus, spatial memory performances appeared particularly sensitive to h-apoE-isoform-dependent effects. Deficits occurred predominantly in female h-apoE4 mice, which support the hypothesis that humans carrying h-apoE4, especially women, have impaired spatial memory compared to those carrying h-apoE3.

The beta-amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) and appears to be a multifunctional protein. Secreted forms of APP (sAPP) have memory-enhancing effects in certain behavioral paradigms. To investigate sAPP's role in spatial memory processes, we adapted a spatial recognition task and evaluated (1) the performance of OF1 mice after massed training (single 15-min acquisition session) and distributed training (three 5-min acquisition sessions), (2) the decline of spatial recognition performance by introducing different delays (5min, 1, 3, and 24h) between the acquisition and retention phases, and (3) the effects of sAPP(695) on spatial recognition memory. In the present study, mice selectively reacted to a change in the spatial configuration of five objects. Indeed, 3min post-acquisition, mice performed similarly in the massed and distributed versions of the task, by re-exploring the two displaced objects only, whereas mice exposed to the same spatial configuration did not. Additionally, all mice did react to a novel object in a subsequent object recognition phase. Mice detected object displacements 5min, 1h, or 3h post-acquisition, but no more at a 24h-delay. Finally, mice treated with sAPP(695) intracerebroventricularly at a dose of 0.5pg/4microL/mouse, 20-min pre-acquisition or 5-min post-acquisition, still reacted to a spatial change in objects position 24h post-acquisition, in marked contrast to NaCl-treated mice. Our data demonstrate that sAPP(695) significantly improves a form of spatial memory, and confirms the hypothesis of an action of this protein on early memory processes.

Small animal models that manifest many of the characteristic neuropathological and behavioral features of Alzheimer's disease (AD) have been developed and have proven of great value for studying the pathogenesis of this disorder at the molecular, cellular and behavioral levels. The great progress made in our understanding of the genetic factors that either cause or contribute to the risk of developing AD has prompted many laboratories to create transgenic (tg) mice that overexpress specific genes which cause familial forms of the disease. Several of these tg mice display neuropathological and behavioral features of AD including amyloid beta-peptide (A beta) and amyloid deposits, neuritic plaques, gliosis, synaptic alterations and signs of neurodegeneration as well as memory impairment. Despite these similarities, important differences in neuropathology and behavior between these tg mouse models and AD have also been observed, and to date no perfect animal model has emerged. Moreover, ascertaining which elements of the neuropathological and behavioral phenotype of these various strains of tg mice are relevant to that observed in AD continues to be a challenge. Here we provide a critical review of the AD-like neuropathology and behavioral phenotypes of several well-known and utilized tg mice that express human APP transgenes.

The superior colliculus is a hub for multisensory integration necessary for visuo-spatial orientation, control of gaze movements and attention. The multiple functions of the superior colliculus have prompted hypotheses about its involvement in neuropsychiatric conditions, but to date, this topic has not been addressed experimentally. We describe experiments on genetically modified mice, the Isl2-EphA3 knock-in line, that show a well-characterized duplication of the retino-collicular and cortico-collicular axonal projections leading to hyperstimulation of the superior colliculus. To explore the functional impact of collicular hyperstimulation, we compared the performance of homozygous knock-in, heterozygous knock-in and wild-type mice in several behavioral tasks requiring collicular activity. The light/dark box test and Go/No-Go conditioning task revealed that homozygous mutant mice exhibit defective response inhibition, a form of impulsivity. This defect was specific to attention as other tests showed no differences in visually driven behavior, motivation, visuo-spatial learning and sensorimotor abilities among the different groups of mice. Monoamine quantification and gene expression profiling demonstrated a specific enrichment of noradrenaline only in the superficial layers of the superior colliculus of Isl2-EphA3 knock-in mice, where the retinotopy is duplicated, whereas transcript levels of receptors, transporters and metabolic enzymes of the monoaminergic pathway were not affected. We demonstrate that the defect in response inhibition is a consequence of noradrenaline imbalance in the superficial layers of the superior colliculus caused by retinotopic map duplication. Our results suggest that structural abnormalities in the superior colliculus can cause defective response inhibition, a key feature of attention-deficit disorders. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0745-5) contains supplementary material, which is available to authorized users.

In the present study, we examined whether the relative levels of regional brain [ 14 C]2-deoxyglucose (2-DG) uptake are altered in a transgenic mouse model of Alzheimer's disease which overexpresses a mutated form of the human β-amyloid precursor protein (mutation V717F). We show that the relative levels of 2-DG uptake are significantly reduced in the septum, thalamus, dentate gyrus and parietal cortex of 3-month-old transgenic mice as compared with wild-type littermates. In 10-month-old transgenic mice, these alterations also extend to the CA3 hippocampal region, the cingulate, retrosplenial, occipital and temporal cortices, suggesting an age-dependent decrease in the regional 2-DG uptake. These results suggest that expression of a mutated APP gene induces an early regional cerebral hypometabolism independently of amyloid deposition per se.

The effects of immediate post-training administration of drugs interacting with group I and/or group II glutamate metabotropic receptors (mGluRs) were determined on the retention performance of a partially acquired lever-press learning task in mice. The antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) dose-dependently (0. 1-100 nmol/mouse, i.c.v.) impairs the retention performance evaluated 24 h post-training. The retention deficit induced by 100 nmol MCPG is related to the selective suppression of a time-dependent spontaneous improvement of performance between the two sessions. This phenomenon appears progressively within 24 h post-training in control mice and is thought to reflect post-training processing of memory traces. The coadministration of either (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), the group I mGluR agonist (R,S)3,5-dihydroxyphenylglycine (DHPG), or the group II mGluR agonist LY354740, completely blocked MCPG-induced deficits at a dose of 0.1 nmol for each agonist. These results suggest that selective activation of either group I or group II mGluRs is able to prevent the memory retention deficits induced by MCPG.

The effects of post-training administration of GF 109203X (5 and 50 ng i.c.v.), a selective inhibitor of protein kinase C, on retention performance were investigated in a positively reinforced lever press task, in male Swiss mice. Both doses of GF 109203X suppressed the spontaneous improvement of performance observed in control animals between the last 5 min of the acquisition session and the first 5 min of the retention session 24 h later. GF 109203X had no effect on food intake and locomotor activity. These data suggest that GF 109203X selectively interferes with mechanisms underlying post-training organization of information and that protein kinase C is involved in this memory process.

Le sulfate de dehydroepiandrosterone (S-DHEA) et le sulfate de pregnenolone (S-Preg) sont des steroides naturellement synthetises au niveau du cerveau. Ils ameliorent les performances de memoire a court terme et de memoire a long terme dans une grande variete d’apprentissages et de modeles d’amnesie chez les rongeurs. Par ailleurs, le S-DHEA et le S-Preg modulent la transmission synaptique GABAergique et glutamatergique en interagissant directement avec des recepteurs membranaires de type GABA-A, NMDA et/ou σ 1. De plus, ces deux neurosteroides ont une action facilitatrice sur la liberation d’acetylcholine et modulent des phenomenes de plasticite synaptique dans des structures cerebrales, telles que l’hippocampe, connues pour leur implication dans les processus mnesiques. Les liens possibles entre ces differentes actions du S-DHEA et du S-Preg et leurs effets promnesiants sont discutes dans la presente revue.

When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the β-amyloid precursor protein (APP s 751 and APP s 695 ) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APP s were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APP s antisera, and observed when APP s was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APP s had no effect on motor performance or exploratory activity. APP s 695 and APP s 751 were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APP s does not require the Kunitz protease inhibitor domain. These data suggest an important role for APP s s on memory processes.

The purpose of the present study was to design an object recognition task in mice and characterize the effects of scopolamine in this paradigm. This task consisted of exposing mice for 6 or 10 min to an object in an open field (trial 1) and, after a delay (1-24 h), testing mice for 10 min with the object and a novel object (trial 2). Mice explored the novel object more than the familiar object as the inter-trial delay decreased and/or the duration of trial 1 increased. Administration of scopolamine (0.3, 1 and 3 mg kg-1, s.c.) before trial 1 reduced recognition performance on trial 2 after a 3 h inter-trial delay and induced other behavioural effects, including an increase in locomotor activity on trial 1. Methylscopolamine (1 mg kg-1) had no effect on recognition performance. The present results show that this task is a useful model to test recognition memory in mice and that blocking the central cholinergic system impairs this form of memory.

By performing a whole genome screen in an F2 intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial “response to novelty” ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit1 16; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, >2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F2 population's phe-notypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences.

The cyclic nucleotide cGMP is an important intracellular messenger for synaptic plasticity and memory function in rodents. Therefore, inhibition of cGMP degrading phosphodiesterases, like PDE9A, has gained interest as potential target for treatment of cognition deficits in indications like Alzheimer's disease (AD). In fact, PDE9A inhibition results in increased hippocampal long-term potentiation and exhibits procognitive effects in rodents. To date, however, no evidence has been published linking PDE9A inhibition to the pathologic hallmarks of AD such as amyloid beta (Aβ) deposition. Therefore, we investigated the role of PDE9A inhibition in an AD relevant context by testing its effects on Aβ-related deficits in synaptic plasticity and cognition. The PDE9A inhibitor BAY 73-6691 was found to restore long-term potentiation impaired by Aβ42 oligomers. Furthermore, we demonstrated that BAY 73-6691 enhanced cGMP levels in the hippocampus of APP transgenic tg2576 mice and improved memory performance of these mice. Altogether, our results support the hypothesis that inhibition of PDE9A could be a beneficial approach for the treatment of memory impairment in AD patients.

Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small-molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex. Remarkably, CSP-TTK21 treatment promoted the formation of long and highly branched doublecortin-positive neurons in the subgranular zone of the dentate gyrus and reduced BrdU incorporation, suggesting that CBP/p300 activation favors maturation and differentiation of adult neuronal progenitors. In addition, mRNA levels of the neuroD1 differentiation marker and BDNF, a neurotrophin required for the terminal differentiation of newly generated neurons, were both increased in the hippocampus concomitantly with an enrichment of acetylated-histone on their proximal promoter. Finally, we found that CBP/p300 activation during a spatial training, while not improving retention of a recent memory, resulted in a significant extension of memory duration. This report is the first evidence for CBP/p300-mediated histone acetylation in the brain by an activator molecule, which has beneficial implications for the brain functions of adult neurogenesis and long-term memory. We propose that direct stimulation of acetyltransferase function could be useful in terms of therapeutic options for brain diseases.

Mild cognitive impairment (MCI) is a clinical condition that often precedes Alzheimer disease (AD). Compared with apolipoprotein E-e3 (APOE3), the apolipoprotein E-e4 (APOE4) allele is associated with an increased risk of developing MCI and spatial navigation impairments. In MCI, the entorhinal cortex (EC), which is the main innervation source of the dentate gyrus, displays partial neuronal loss. We show that bilateral partial EC lesions lead to marked spatial memory deficits and reduced synaptic density in the dentate gyrus of APOE4 mice compared with APOE3 mice. Genotype and lesion status did not affect the performance in non-navigational tasks. Thus, partial EC lesions in APOE4 mice were sufficient to induce severe spatial memory impairments and synaptic loss in the dentate gyrus. In addition, lesioned APOE4 mice showed no evidence of reactional increase in cholinergic terminals density as opposed to APOE3 mice, suggesting that APOE4 interferes with the ability of the cholinergic system to respond to EC input loss. These findings provide a possible mechanism underlying the aggravating effect of APOE4 on the cognitive outcome of MCI patients.

The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3-3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01-10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABAA receptors.

The neurosteroid pregnenolone sulfate (PREG-S) has been shown to modulate positively NMDA receptor activity and to have memory enhancing properties in mice. The present study was designed to evaluate the effects of post-training administration of PREG-S, alone or in combination with D-2-amino-5-phosphonovalerate (D-AP5), a competitive NMDA receptor antagonist, in Y-maze avoidance and appetitively motivated lever-press learning tasks and in a traction reflex test in mice. Intracerebroventricular (i.c.v.) administration of PREG-S (0.01-0.1 nmol/mouse) blocked the selective retention deficits induced by 0.02 nmol D-AP5 in the Y-maze avoidance task. PREG-S (0.1 nmol, i.c.v.) also blocked the retention deficits induced by 0.02 nmol D-AP5 in the lever-press task. Post-training administration of PREG-S alone (0.001-0.1 nmol, i.c.v.) had no effect on retention performance in the Y-maze and the lever-press tasks. PREG-S (1-10 nmol, i.c.v.) significantly reduced the impairment of the traction reflex induced by 2 nmol D-AP5. The ability of PREG-S to block retention performance deficits as well as motor impairment induced by D-AP5 is in agreement with its positive modulatory action at NMDA receptors.

The APOE-ɛ4 allele is associated with increased cognitive decline during normal aging and Alzheimer's disease. However, several studies intriguingly found a beneficial effect on cognition in young adult human APOE-ɛ4 carriers. Here, we show that 3-month old bigenic hAPP-Yac/apoE4-TR mice outperformed their hAPP-Yac/apoE3-TR counterparts on learning and memory performances in the highly hippocampus-dependent, hidden-platform version of the Morris water maze task. The two mouse lines did not differ in a non-spatial visible-platform version of the task. This hAPP-Yac/apoE-TR model may thus provide a useful tool to study the mechanisms involved in the antagonistic pleiotropic effects of APOE-ɛ4 on cognitive functions.

Recombinant inbred (RI) strains derived from the C57BL/6J and A/J mouse strains were used for behavioral studies designed to estimate the number and location of chromosomal loci responsible for anxiety-related behaviors and differential sensitivity to agonists and inverse agonists of the gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor complex. The phenotypes of the parental inbred strains and of 28 RI strains were characterized for the number of transitions in the light--dark exploratory model, anxiolytic response to diazepam, vertical and ambulatory activities in an open field, and sensitivity to the convulsant properties of methyl-beta-carboline-3-carboxylate (beta-CCM). The strain distribution patterns and estimates of the minimal number of loci obtained for each trait suggest that multiple chromosomal loci contribute to differences in anxiety-related behavioral phenotypes and the behavioral responses to diazepam and beta-CCM between C57BL/6J and A/J mice. The best probabilities of linkage were found between the variables characterizing response to diazepam and loci on chromosomes 1 (Xmv-41) and 10 (D10Mit2) and between the sensitivity to the convulsant actions of beta-CCM and locus D15Mit5 on chromosome 15.

The neurosteroid pregnenolone sulfate (PS) has been recently shown to positively modulate NMDA receptors and to have memory enhancing properties in mice. In the present study, we examined the ability of PS to increase retention performance and to reduce deficits induced by a competitive NMDA receptor antagonist, the 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), in a step-through passive avoidance task in rats. Pretraining administration of PS (0.84-1680 pmol, ICV) had minimal effects on retention performance assessed 24 h after training, while CPP significantly decreased retention performance at the doses of 1.2 and 1.6 nmol (ICV). However, when administered in combination with CPP (1.2 nmol), PS (0.84-840 pmol, ICV) dose-dependently blocked the deficit in passive avoidance response induced by the NMDA antagonist. At the dose of 840 nmol, PS also significantly reduced the motor impairment induced by CPP (1.2 nmol). The blockade of CPP-induced behavioral deficits by PS may result from its positive modulatory action at NMDA receptors.

Exploratory behaviors as well as pharmacological actions of gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor agonists and inverse agonists were characterized in C57BL/6J and A/J strains of mice. C57BL/6J mice displayed higher levels of exploratory behavior than A/J mice in the light in equilibrium with dark exploration model of anxiety and in an open-field test, suggesting that C57BL/6J mice are less "emotional" and more active than A/J mice, respectively. However, C57BL/6J mice were more sensitive than A/J mice to the anxiolytic effects of diazepam in the light in equilibrium with dark exploration model. In contrast, A/J mice were more sensitive than C57BL/6J mice to the convulsant effects of methyl-beta-carboline-3-carboxylate. C57BL/6J mice showed no evidence of acquisition of a passive avoidance task, while A/J readily acquired this memory task at low levels of footshock. C57BL/6J and A/J mice should be useful parental strains in recombinant inbred lines for investigating the genetic determinants of benzodiazepine-sensitive behaviors and sensitivity to drugs acting on the GABAA/benzodiazepine receptor complex.

G protein-coupled receptor (GPCR) associated sorting protein-1 (GASP-1) is suspected to play a key role in recycling and degradation of several GPCRs. In a previous study, we have shown that GASP-1-knock-out (GASP-1-KO) mice displayed deficits in acquiring a cocaine self-administration task, associated with an exacerbated down-regulation of striatal dopaminergic and cholinergic receptors. Among several possibilities, GASP-1 deficiency could have impaired memory processes underlying the acquisition of the operant conditioning task. Therefore, the present study investigated cognitive performances of GASP-1-KO mice and their wild-type littermates (WT) in a broad variety of memory tasks. Consistent with a deficit in procedural memory, GASP-1-KO mice showed delayed acquisition of a food-reinforced bar-press task. During water-maze training in hidden- or visible-platform paradigms, mutant and WT mice acquired the tasks at the same rate. However, GASP-1 mice exhibited persistent thigmotaxic swimming, longer distance to the platform, and reduced swim speed. There was no deficit in several tasks requiring simple behavioral responses (Barnes maze, object recognition and passive avoidance tasks). Thus, the ability to acquire and/or express complex responses seems affected in GASP-1-deficient mice. Hippocampal functions were preserved, as the retention of an acquired memory in spatial tasks remained unaffected. The pattern of behavioral deficits observed in GASP-1-KO mice is coherent with current knowledge on the role of striatal GPCRs in acquisition/expression of skilled behavior and in motivation. Together with the previous findings, the so far established phenotype of GASP-1-KO mice makes them a potentially exciting tool to study striatal functions.

We studied the effects of a selective inhibitor of protein kinase C (PKC), 2,6-diamino-N-[(1-(1-oxotridecyl)-2-piperidinyl]methyl)hexamide (NPC 15437), on acquisition and memory retention of a Y-maze avoidance task in mice. Post-training administration of NPC 15437 (0.1-10 mg/kg i.p.) induced a dose-dependent deficit in retention of the temporal but not the spatial component of the task. This selective amnesia does not reflect state dependence and NPC 15437 (1 mg/kg) had no effect on acquisition and memory retrieval. Our results suggest that this new PKC inhibitor interferes with mechanisms underlying memory consolidation. This is in agreement with recent findings suggesting that PKC is involved in memory processes.