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Alzheimer's disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenges as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early-stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxidative stress, astrocytes are particularly resistant to mitochondrial dysfunction and are therefore more resilient cells. In our study, we leveraged astrocytic mitochondrial uncoupling and examined neuronal function in the 3xTg AD mouse model. We overexpressed the mitochondrial uncoupling protein 4 (UCP4), which has been shown to improve neuronal survival in vitro. We found that this treatment efficiently prevented alterations of hippocampal metabolite levels observed in AD mice, along with hippocampal atrophy and reduction of basal dendrite arborization of subicular neurons. This approach also averted aberrant neuronal excitability observed in AD subicular neurons and preserved episodic-like memory in AD mice assessed in a spatial recognition task. These findings show that targeting astrocytes and their mitochondria is an effective strategy to prevent the decline of neurons facing AD-related stress at the early stages of the disease.

SummaryWith the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation ofatg5in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission andPV-atg5KOmice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory.

Parental behaviours are essential to secure survival and wellbeing of newborns1. Concomitantly, parenting also limits negative affective states in adults, which emerge when the coping with excessive neonatal distress becomes a challenge1–5. Whether neural circuits that process negative affect orchestrate components of parental behaviours remains, however, unknown. Here, we identify functional and transcriptional signatures of parental behaviours in neurons of the negative emotion center lateral habenula receiving bed nucleus of the stria terminalis innervation (BNSTLHb). Calcium imaging reveals that LHb neurons of virgin female mice increase their activity during pup retrieval to a nest, a behaviour that disappears following optogenetic LHb inactivation. Intersectional cell identification and transcriptional profiling of BNSTLHb neurons associates this neuronal population to parental behaviours and outlines gene expression in female virgins that is similar to mothers but divergent from virgin males. From a functional standpoint, optogenetic activation and inactivation of the BNSTLHb pathway maximizes and suppresses, respectively, the parental behaviour. Finally, tracking of single BNSTLHb cell activity demonstrates specificity of this neuronal subset for encoding negative stimuli and pup retrieval, but not sociability amongst conspecifics. Thus, BNSTLHb cells are operational for female parenting, demonstrating that neural circuit elements for negative affect contribute to specific social interactions.

Alzheimer’s disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenge as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxydative stress, astrocytes are particularly resistant to mitochondrial dysfunction and are therefore more resilient cells. In our study, we leveraged astrocytic mitochondrial uncoupling and examined neuronal function in the 3xTg AD mouse model. We overexpressed the mitochondrial uncoupling protein 4 (UCP4), which has been shown to improve neuronal survival in vitro. We found that this treatment efficiently prevented alterations of hippocampal metabolite levels observed in AD mice, along with hippocampal atrophy and reduction of basal dendrite arborization of subicular neurons. This approach also averted aberrant neuronal excitability observed in AD subicular neurons and preserved episodic-like memory in AD mice assessed in a spatial recognition task. These findings show that targeting astrocytes and their mitochondria is an effective strategy to prevent the decline of neurons facing AD-related stress at the early stages of the disease.

International audience; Academic Core Facilities are optimally situated to improve the quality of preclinical research by implementing quality control measures and offering these to their users.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e., performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

The discovery of a G-protein-coupled receptor for lactate named hydroxycarboxylic acid receptor 1 (HCAR1) in neurons has pointed to additional nonmetabolic effects of lactate for regulating neuronal network activity. In this study, we characterized the intracellular pathways engaged by HCAR1 activation, using mouse primary cortical neurons from wild-type (WT) and HCAR1 knock-out (KO) mice from both sexes. Using whole-cell patch clamp, we found that the activation of HCAR1 with 3-chloro-5-hydroxybenzoic acid (3Cl-HBA) decreased miniature EPSC frequency, increased paired-pulse ratio, decreased firing frequency, and modulated membrane intrinsic properties. Using fast calcium imaging, we show that HCAR1 agonists 3,5-dihydroxybenzoic acid, 3Cl-HBA, and lactate decreased by 40% spontaneous calcium spiking activity of primary cortical neurons from WT but not from HCAR1 KO mice. Notably, in neurons lacking HCAR1, the basal activity was increased compared with WT. HCAR1 mediates its effect in neurons through a G iα -protein. We observed that the adenylyl cyclase-cAMP-protein kinase A axis is involved in HCAR1 downmodulation of neuronal activity. We found that HCAR1 interacts with adenosine A1, GABA B , and α 2A -adrenergic receptors, through a mechanism involving both its G iα and G iβγ subunits, resulting in a complex modulation of neuronal network activity. We conclude that HCAR1 activation in neurons causes a downmodulation of neuronal activity through presynaptic mechanisms and by reducing neuronal excitability. HCAR1 activation engages both G iα and G iβγ intracellular pathways to functionally interact with other G i -coupled receptors for the fine tuning of neuronal activity.SIGNIFICANCE STATEMENT Expression of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) was recently described in neurons. Here, we describe the physiological role of this G-protein-coupled receptor (GPCR) and its activation in neurons, providing information on its expression and mechanism of action. We dissected out the intracellular pathway through which HCAR1 activation tunes down neuronal network activity. For the first time, we provide evidence for the functional cross talk of HCAR1 with other GPCRs, such as GABA B , adenosine A1- and α 2A -adrenergic receptors. These results set HCAR1 as a new player for the regulation of neuronal network activity acting in concert with other established receptors. Thus, HCAR1 represents a novel therapeutic target for pathologies characterized by network hyperexcitability dysfunction, such as epilepsy.

Memory is coded by patterns of neural activity in distinct circuits. Therefore, it should be possible to reverse engineer a memory by artificially creating these patterns of activity in the absence of a sensory experience. In olfactory conditioning, an odor conditioned stimulus (CS) is paired with an unconditioned stimulus (US; for example, a footshock), and the resulting CS–US association guides future behavior. Here we replaced the odor CS with optogenetic stimulation of a specific olfactory glomerulus and the US with optogenetic stimulation of distinct inputs into the ventral tegmental area that mediate either aversion or reward. In doing so, we created a fully artificial memory in mice. Similarly to a natural memory, this artificial memory depended on CS–US contingency during training, and the conditioned response was specific to the CS and reflected the US valence. Moreover, both real and implanted memories engaged overlapping brain circuits and depended on basolateral amygdala activity for expression. Pairing an odor conditioned stimulus (CS) with an unconditioned stimulus (US) induces memory formation. Vetere et al. replace the real CS and US with direct optogenetic stimulation of the brain and create a fully artificial odor memory in mice.

Summary Optimal selection of threat-driven defensive behaviors is paramount to an animal’s survival. The lateral habenula (LHb) is a key neuronal hub coordinating behavioral responses to aversive stimuli. Yet, how individual LHb neurons represent defensive behaviors in response to threats remains unknown. Here, we show that in mice, a visual threat promotes distinct defensive behaviors, namely runaway (escape) and action-locking (immobile-like). Fiber photometry of bulk LHb neuronal activity in behaving animals reveals an increase and a decrease in calcium signal time-locked with runaway and action-locking, respectively. Imaging single-cell calcium dynamics across distinct threat-driven behaviors identify independently active LHb neuronal clusters. These clusters participate during specific time epochs of defensive behaviors. Decoding analysis of this neuronal activity reveals that some LHb clusters either predict the upcoming selection of the defensive action or represent the selected action. Thus, heterogeneous neuronal clusters in LHb predict or reflect the selection of distinct threat-driven defensive behaviors., Graphical Abstract, Highlights • A threat promotes opposing and context-dependent behavioral responses • Habenular neurons encode looming-driven runaway and action-locking • Habenular clusters define different time epochs of defensive behaviors, Lecca et al. show that the lateral habenula (LHb) underlies threat-driven defensive behaviors in mice. LHb calcium dynamics increase when mice run away and decrease when mice remain immobile upon a threat presentation. Distinct cell clusters emerge in LHb during defensive strategies: some representing the action and others holding predictive power.

Structural synaptic changes occur in medial prefrontal cortex circuits during remote memory formation. Whether extinction reverts or further reshapes these circuits is, however, unknown. Here we show that the number and the size of spines were enhanced in anterior cingulate (aCC) and infralimbic (ILC) cortices 36 d following contextual fear conditioning. Upon extinction, aCC spine density returned to baseline, but the enhanced proportion of large spines did not. Differently, ILC spine density remained elevated, but the size of spines decreased dramatically. Thus, extinction partially erases the remote memory network, suggesting that the preserved network properties might sustain reactivation of extinguished conditioned fear.

Background Antidepressants (AD) need to be chronically administered (weeks to months) to provide beneficial effects. Evidence suggests that combined administration of inhibitors of monoamine reuptake and phosphodiesterase type 4 allows a highly effective therapeutic action. Also, this coadministration more rapidly boosts the cyclic adenosine monophosphate (cAMP) pathway, which is normally activated during chronic treatment of single compounds. Little is known, however, about how this augmentation therapy affects the core mechanism of glutamatergic plasticity. We therefore investigated how in vivo combinational subchronic rolipram and imipramine (scRI) treatment affects depressive behavior, cAMP-dependent transcription, and glutamatergic transmission in the hippocampus, a region critically implicated in depression. Methods Antidepressant properties of scRI were investigated through the forced swim test. Changes in cAMP-dependent transcription and synaptic transmission of CA1 pyramidal cells were explored with green fluorescent protein, enzyme-linked immunosorbent assay, electrophysiology recordings, and Golgi-Cox staining. Results We demonstrate that scRI displays robust antidepressant properties compared with single-drug treatments and increases hippocampal c-Fos expression and brain-derived neurotrophic factor protein levels. These effects are accompanied by a specific increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N -methyl-D-aspartate receptors in already existing synapses. Finally, both acute and subchronic treatments led to enhancement of long-term potentiation but differently affected spine density and morphology, with scRI administration specifically resulting in a large increase in stubby spines. Conclusions We conclude that scRI is highly effective in providing antidepressive effects, including the hippocampal transcriptional alterations normally observed with longer single-drug treatments. Furthermore, we identified scRI-induced modifications in glutamatergic transmission that probably underlie the beneficial action of this combinational therapy.

Synaptic activity-dependent phosphorylation of the transcription factor cAMP response element binding protein (CREB) leads to CREB-dependent gene transcription, a process thought to underlie long-term hippocampal synaptic plasticity and memory formation. We previously reported that increasing CREB activity in glutamatergic neurons enhances synaptic plasticity and neuronal excitability. Whether these modifications are sufficient to promote hippocampal-dependent memory formation was not determined. Here, we provide direct evidence that a brief increase in CREB-dependent transcription in either CA1 or DG neurons, using in vivo viral vectors, is sufficient to boost memory for contextual representations, as tested in the contextual fear conditioning task, without affecting motor, pain, or anxiety behaviors. © 2008 Wiley-Liss, Inc.

Tg2576 mice over-expressing human mutant APP (hAPPswe) show progressive impairments in hippocampal plasticity and episodic memory while fronto-striatal plasticity and procedural memory remain intact. Here we examine the status of synaptic connectivity in the hippocampus and the dorsolateral striatum (DLS) of 3- and 15-month-old Tg2576 and wild-type mice through the analysis of single dendritic spines microanatomy. We found that, in each region, all mice showed a global reduction in the size of spines as a function of age. Ageing mutants, however, exhibited smaller spines with shorter necks on CA1 pyramidal neurons but larger spines with longer necks on DLS spiny neurons compared to their age-matched wild-type controls. Our findings indicate that hippocampal and DLS dendritic spines in hAPPswe mutants undergo a different pattern of morphological changes over time and point to minor alterations in the microanatomy of DLS spines as a compensatory mechanism maintaining procedural abilities in the ageing mutants.

New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Although the addition of these new neurons may facilitate the formation of new memories, as they integrate, they provide additional excitatory drive to CA3 pyramidal neurons. During development, to maintain homeostasis, new neurons form preferential contacts with local inhibitory circuits. Using retroviral and transgenic approaches to label adult-generated granule cells, we first asked whether a comparable process occurs in the adult hippocampus in mice. Similar to development, we found that, during adulthood, new neurons form connections with inhibitory cells in the dentate gyrus, hilus, and CA3 regions as they integrate into hippocampal circuits. In particular, en passant bouton and filopodia connections with CA3 interneurons peak when adult-generated dentate granule cells (DGCs) are ∼4 weeks of age, a time point when these cells are most excitable. Consistent with this, optical stimulation of 4-week-old (but not 6- or 8-week-old) adult-generated DGCs strongly activated CA3 interneurons. Finally, we found that CA3 interneurons were activated robustly during learning and that their activity was strongly coupled with activity of 4-week-old (but not older) adult-generated DGCs. These data indicate that, as adult-generated neurons integrate into hippocampal circuits, they transiently form strong anatomical, effective, and functional connections with local inhibitory circuits in CA3. Significance statement: New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Understanding how these cells integrate within well formed circuits will increase our knowledge about the basic principles governing circuit assembly in the adult hippocampus. This study uses a combined connectivity analysis (anatomical, functional, and effective) of the output connections of adult-born hippocampal cells to show that, as these cells integrate into hippocampal circuits, they transiently form strong connections with local inhibitory circuits. This transient increase of connectivity may represent an homeostatic process necessary to accommodate changes in the excitation/inhibition balance induced by the addition of these new excitatory cells to the preexisting excitatory hippocampal circuits.

The progression of activity and structural changes in the anterior cingulate cortex during remote contextual fear memory formation was measured by imaging c-fos expression and dendritic spines following retrieval tests administered at six post-training time points (days 1, 5, 7, 14, 21, 36). Here we report that conditioned mice exhibit robust freezing at each time point. C-fos expression starts to augment on day 5, showing a monotonic increase over the successive time points, and then stabilized in relation to the higher freezing scores. The first significant increase in mean spine density emerges on day 7. By day 14, the net number of spines remained stable, yet the distribution of single neuron spine density becomes progressively more homogeneous. Our findings reveal that activity changes precede structural remodeling of neurons in the neocortex while remodeling coherence develops gradually in cortical neuron ensembles.

C57BL/6 and DBA/2 mice with cannulae inserted bilaterally in the dorsal hippocampus or the dorsolateral striatum were released from the south arm of a cross maze and trained to find food in the east arm. Probe trials on which mice were released from the north arm were given following short or prolonged training. Prior to the probe trials, mice received intra-hippocampal or intra-striatal injections of lidocaine or saline. Results show that saline-injected C57BL/6 were fundamentally place learners whereas saline-injected DBA/2 mice did not engage any predominant system. Inactivating the hippocampus or the dorsolateral striatum in C56BL/6 mice disrupted place learning without promoting response learning. Inactivating the same brain sites in DBA/2 mice did not affect their behaviour. Thus, contrary to that observed in rats, disrupting the neural substrate of one memory system can abolish learning in that system but does not promote the use of another system in these genotypes.

C57 and DBA mice were trained in a crossed maze to assess possible strain differences in place or response learning as a function of training duration (8 or 17 days) and extramaze cueing conditions. The first condition consisted of a diffuse visually cued environment (rich cueing). The second was the same plus an explicit visual cue marking the direction of the baited arm (rich cueing plus cue). The third was a featureless environment (poor cueing). During training, mice were released from the south arm and rewarded in the east arm. Probe trials on which mice were released from the north arm and allowed to choose either the east (place learning) or the west (response learning) arm were given either on the ninth (PT1) or the eighteenth (PT2) days. Strain x context differences in the activation of the dorsal hippocampus and the dorsolateral striatum were examined by analyzing Fos expression following each probe trial. Results first showed that C57 were essentially place-learners, whereas no learning modality was predominant in DBA, except on the PT2 run with the explicit cue available. Examination of Fos expression in C57 trained under "rich cueing" and "rich cueing plus cue" conditions revealed a strong and parallel increase of immunoreactivity in the hippocampus and dorsolateral striatum following PT1 that decreased under PT2. In that strain, the similar time-course variation of Fos expression in both areas suggests a simultaneous involvement of hippocampal- and striatal-based learning mechanisms, even if those controlled by the hippocampus were prevailing on those controlled by the dorsolateral striatum. In DBA mice, however, the absence of any preferential learning modality was associated with 1) a consistent hippocampal activation persistent across probe trials, and 2) a global superior activation of the dorsolateral striatum. Distinct patterns of Fos expression were therefore associated with every strain-specific learning modality. In each strain, however, each modality was found to be remarkably stable, whatever the training duration and the cueing conditions.

Latent inhibition (LI) consists of decreased associative strength between an elemental stimulus (CS: tone) paired with an unconditioned stimulus (US: footshock) following non-reinforced pre-exposure to the tone. In view of the differences shown by C57BL/6 (C57) and DBA/2 (DBA) mice in processing elemental vs. configural stimuli, the present experiments were designed (1) to assess whether these differences were likely to interfere with the capability of each strain to show LI, and (2) to verify the extent to which lesions of the nucleus accumbens, which have been reported to enhance attention towards contextual stimuli under certain conditions, might interfere with the development of LI. C57 and DBA mice with Nacc or sham lesions were given two periods (4 or 7 days) of pre-exposure to a CS (tone) then subjected to two CS-US pairings given on a single day. On the day after, freezing to the tone was examined in each group. Results show that, following the shorter period of pre-exposure, LI developed in sham-lesioned DBA but did not in sham-lesioned C57. Nacc lesions, however, were found (1) to block LI in DBA but (2) to promote LI in C57. After the longer period of pre-exposure LI was observed in both strain and lesion conditions. In general, these results confirm that strain differences in processing the tone as a single elemental cue (DBA) or, alternatively, as a part of a contextual configural stimulus (C57) can interfere with the development of LI. In addition, they indicate that Nacc lesions, that are susceptible to increase attention to the background, might modify the salience of the tone and produce opposite effect on LI according to the strain specialisation to show elemental or configural responding.

The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95. Of note, BC1 KO mice show aberrant structural plasticity in response to whisker deprivation, impaired texture novel object recognition and altered social behavior. Thus, our study highlights a role for BC1 RNA in experience-dependent plasticity and learning in the mammalian adult neocortex, and provides insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders., Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors.

New granule cells are continuously integrated into hippocampal circuits throughout adulthood, and the fine-tuning of this process is likely important for efficient hippocampal function. During development, this integration process is critically regulated by the α-calcium/calmodulin-dependent protein kinase II (α-CaMKII), and here we ask whether this role is conserved in the adult brain. To do this, we developed a transgenic strategy to conditionally delete α-CaMKII from neural progenitor cells and their progeny in adult mice. First, we found that the selective deletion of α-CaMKII from newly generated dentate granule cells led to an increase in dendritic complexity. Second, α-CaMKII deletion led to a reduction in number of mature synapses and cell survival. Third, consistent with altered morphological and synaptic development, acquisition of one-trial contextual fear conditioning was impaired after deletion of α-CaMKII from newly generated dentate granule cells. Previous work inXenopusidentified α-CaMKII as playing a key role in the stabilization of dendritic and synaptic structure during development. The current study indicates that α-CaMKII plays a plays a similar, cell-autonomous role in the adult hippocampus and, in addition, reveals that the loss of α-CaMKII from adult-generated granule cells is associated with impaired hippocampus-dependent learning.

Forget It! When examining the relationship between the production of new neurons in the hippocampus and memory, studies have generally first manipulated hippocampal neurogenesis and afterward investigated memory formation and found that new neurons help to encode new memories. However, when investigating how similar manipulations of neurogenesis impact established hippocampus-dependent memories, Akers et al. (p. 598 ; see the Perspective by Mongiat and Schinder ) uncovered a role for neurogenesis in memory clearance. Thus, the continuous addition of new neurons both degrades existing information stored in hippocampal circuits and simultaneously provides substrates for new learning.

Defective utilisation of background stimuli may result in a large range of cognitive impairments. We describe here three experimental paradigms taxing the processing of contextual information, (i) radial maze learning under distinct cueing conditions and successive context shifts; (ii) reactivity to spatial and object change; (iii) contextual versus cue fear conditioning with pre-test exposure to the experimental context. These paradigms have then been used to characterise the behaviour of null mutant and transgenic mice. In a first series of experiments, we assessed the effect of the null mutation of the gene encoding for Tissue Plasminogen Activator (tPA). Initial investigations pointed to a reduction of the late phase of long-term potentiation in tPA-knock out relative to wild type mice without any consistent performance impairment in several hippocampal-dependent tasks. When tested following our protocols, we found tPA knock out impaired in habituation of object exploration, reactivity to spatial change and contextual fear conditioning. The second example concerns mice overexpressing the mutant human Cu,Zn superoxide dismutase (SOD1) gene, that provide a murine model of amyotrophic lateral sclerosis. We found these mice exhibiting a paradoxical selective enhancement of reactivity to spatial change in comparison with mice overexpressing either the endogeneous murine Cu,Zn SOD1 or the wild type human Cu,Zn SOD1 genes. Our conclusion emphasises the view that experimental protocols involving contextual manipulations may be suitable for differentiating behavioural phenotypes.

The effect of nucleus accumbens lesions on radial maze performance of C57BL/6 and DBA/2 mice was assessed under distinct extra-maze cuing conditions. Among sham-lesioned mice, C57BL/6 performed better under rich than poor cuing conditions whereas DBA performed in the same fashion under both conditions. In C57BL/6, a disruptive effect of lesions was found only in mice tested under rich cuing. Conversely, in DBA/2, the lesions improved performance under poor cuing and disrupted performance under rich cuing. In that strain, a possible lesion-induced enhancement of attention to background stimuli improving performance under poor cuing but producing interference under rich cuing is suggested. In general, the lesions effect seemed to depend on the strain predisposition to implement configural or cue-based responding.

These experiments examine the influence of context manipulations on radial maze performance in C57BL/6 (C57) and DBA/2 (DBA) mice. Animals from each strain were trained in two distinct contexts—poor cuing vs rich cuing—that were sucessively switched. The results first show that C57 performed better when trained under rich cuing conditions than under poor ones, whereas DBA performed poorly under both conditions. In addition, contextual manipulations were found to produce more drastic effects in C57 than in DBA mice. That is, C57 showed a strong performance decrement following each context shift, whereas DBA mice did not. In particular, the fact that DBA mice performed similarly under rich and poor cuing conditions and also reacted mildly—or did not react—to context shifts suggests a deficit in processing contextual information, which places important constraints on their capability to form spatial representations.

Memory formation is thought to be mediated by dendritic-spine growth and restructuring. Myocyte enhancer factor 2 (MEF2) restricts spine growth in vitro, suggesting that this transcription factor negatively regulates the spine remodeling necessary for memory formation. Here we show that memory formation in adult mice was associated with changes in endogenous MEF2 levels and function. Locally and acutely increasing MEF2 function in the dentate gyrus blocked both learning-induced increases in spine density and spatial-memory formation. Increasing MEF2 function in amygdala disrupted fear-memory formation. We rescued MEF2-induced memory disruption by interfering with AMPA receptor endocytosis, suggesting that AMPA receptor trafficking is a key mechanism underlying the effects of MEF2. In contrast, decreasing MEF2 function in dentate gyrus and amygdala facilitated the formation of spatial and fear memory, respectively. These bidirectional effects indicate that MEF2 is a key regulator of plasticity and that relieving the suppressive effects of MEF2-mediated transcription permits memory formation.

Remodeling of cortical connectivity is thought to allow initially hippocampus-dependent memories to be expressed independently of the hippocampus at remote time points. Consistent with this, consolidation of a contextual fear memory is associated with dendritic spine growth in neurons of the anterior cingulate cortex (aCC). To directly test whether such cortical structural remodeling is necessary for memory consolidation, we disrupted spine growth in the aCC at different times following contextual fear conditioning in mice. We took advantage of previous studies showing that the transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis both in vitro and in vivo. We found that increasing MEF2-dependent transcription in the aCC during a critical posttraining window (but not at later time points) blocked both the consolidation-associated dendritic spine growth and subsequent memory expression. Together, these data strengthen the causal link between cortical structural remodeling and memory consolidation and, further, identify MEF2 as a key regulator of these processes.

International audience; Although hippocampal-cortical interactions are crucial for the formation of enduring declarative memories, synaptic events that govern long-term memory storage remain mostly unclear. We present evidence that neuronal structural changes, i.e., dendritic spine growth, develop sequentially in the hippocampus and anterior cingulate cortex (aCC) during the formation of recent and remote contextual fear memory. We found that mice placed in a conditioning chamber for one 7 min conditioning session and exposed to five footshocks (duration, 2 s; intensity, 0.7 mA; interstimulus interval, 60 s) delivered through the grid floor exhibited robust fear response when returned to the experimental context 24 h or 36 d after the conditioning. We then observed that their fear response at the recent, but not the remote, time point was associated with an increase in spine density on hippocampal neurons, whereas an inverse temporal pattern of spine density changes occurred on aCC neurons. At each time point, hippocampal or aCC structural alterations were achieved even in the absence of recent or remote memory tests, thus suggesting that they were not driven by retrieval processes. Furthermore, ibotenic lesions of the hippocampus impaired remote memory and prevented dendritic spine growth on aCC neurons when they were performed immediately after the conditioning, whereas they were ineffective when performed 24 d later. These findings reveal that gradual structural changes modifying connectivity in hippocampal-cortical networks underlie the formation and expression of remote memory, and that the hippocampus plays a crucial but time-limited role in driving structural plasticity in the cortex.

Pharmacological modulation of synaptic efficacy is a prominent target in the identification of promnesic compounds. Here, we report that pretraining administration of the serotonin 5-HT(4) receptors (5-HT(4)Rs) partial agonist SL65.0155 enhances simultaneous olfactory discrimination performance and potentiates learning-induced dendritic spine growth in the mouse hippocampus. SL65.0155 does not affect spine density in the pseudo-trained mice and, by itself, does not promote spine growth. Injecting the 5-HT(4) antagonist RS39604 prior to SL65.0155 prevents both the increase in performance and the additional formation of spines, thus confirming the 5-HT(4)Rs specificity of the observed effects. These findings provide evidence that 5-HT(4)Rs stimulation selectively increases experience-dependent structural plasticity in learning-activated hippocampal circuits.

This study examines the extent to which simultaneous olfactory discrimination learning increases spine density on hippocampal CA1 pyramidal neurons in C57BL/6J (C57) and DBA/2J (DBA) inbred mice, characterized by spontaneous differences in hippocampal plasticity and hippocampus-related learning. The behavioral data first showed a clear-cut difference in performance between the two strains. C57 mice learned to identify the positively reinforced olfactory cue whereas DBA did not. Both strains, however, similarly acquired the procedural aspects of the task. The morphological analysis performed 24 h post-training revealed that spine density was significantly increased along apical, oblique, and basal dendrites in trained C57 mice compared to trained DBA mice, and to pseudotrained as well as to control cage mice of both strains. These findings confirm the ability of C57 mice to solve hippocampal-dependent tasks and provide the first evidence that simultaneous olfactory discrimination learning elicits spine growth in the mouse hippocampus. In addition, the finding that DBA mice failed to discriminate between the two olfactory cues but were as efficient as C57 mice in learning the procedural aspects of the task outlines that the structural changes observed in the latter strain were independent from any procedural learning component. © 2006 Wiley-Liss, Inc.

We trained BALB/c Byllco (C), CD-1, SV 129/SvPasCr1 (129 SV), C57BL/6 (B6) and DBA/2J (D2) mice using the olfactory tubing maze with the hope of gaining insight into behavioral genetics related to learning and memory processes. All strains of mice acquired the odor-reward associations using this new task except the D2 strain. The C, CD-1, and 129 SV consistently remembered the associations from the sixth 20-trial training session, reaching 80% +/- 5 correct responses in session seven. The B6 mice required one more session to reach 76%, while the D2 mice never learned the correct odor-reward associations. All mice learned the paradigm and the timing of the task, although the 129 SV mice decreased slower the inter-trial intervals across sessions. With this new task, D2 mice, with a deficit totally devoted to an impairment on learning and memory, can be used as a model of hippocampal dysfunction, in some respects like that observed in human amnesic patients whose selective hippocampal-dependent memory is deeply impaired. The high-scoring strains (C, CD-1, and 129 SV) seem to be ideal in this task to study a gene-targeting mutation postulated to reduce behavioral performance, and inversely, for D2 mice. The moderate-scoring strain, B6, should be ideal for allowing gene-targeting to go either way. In addition, this new task, which enables automated training of odor associations, could be used for studying the phenomenon of transitivity in mice, as described in rats.

Fragile X syndrome, the most frequent form of hereditary mental retardation, is due to a mutation of the fragile X mental retardation 1 ( FMR1 ) gene on the X chromosome. Like fragile X patients, FMR1 -knockout ( FMR1 -KO) mice lack the normal fragile X mental retardation protein (FMRP) and show both cognitive alterations and an immature neuronal morphology. We reared FMR1 -KO mice in a C57BL/6 background in enriched environmental conditions to examine the possibility that experience-dependent stimulation alleviates their behavioral and neuronal abnormalities. FMR1 -KO mice kept in standard cages were hyperactive, displayed an altered pattern of open field exploration, and did not show habituation. Quantitative morphological analyses revealed a reduction in basal dendrite length and branching together with more immature-appearing spines along apical dendrites of layer five pyramidal neurons in the visual cortex. Enrichment largely rescued these behavioral and neuronal abnormalities while increasing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit 1 (GluR1) levels in both genotypes. Enrichment did not, however, affect FMRP levels in the WT mice. These data suggest that FMRP-independent pathways activating glutamatergic signaling are preserved in FMR1 -KO mice and that they can be elicited by environmental stimulation.

Gerbils subjected to global ischemia or sham-ischemia received electro-acupuncture (EA) or sham EA at points 26 Du (Renzhong) and 8 Du (Junsuo). All animals were then tested for motor activity in an open field, and for spontaneous alternation in a T maze. Results show that EA alone did not affect any behavioral parameter. Ischemia alone increased motor activity without significantly interfering with spontaneous alternation. EA in ischemic gerbils potentiated the increase of motor activity and elicited a decrease in spontaneous alternation. Thus, our data show an interaction between global ischemia and EA applied at specific acupoints which, however, consists of a potentiation rather than an alleviation of the behavioral alterations consecutive to the ischemic insult.

Wistar rats receiving intracerebroventricular infusion of the beta-amyloid protein (Abeta1-42) or of the inactive fragment (Abeta1-42) were subjected to the cross-maze task. According to the standard protocol, rats were released from the south arm and trained to collect food at the end of the east arm. After a 5-day training period, they were given a probe trial during which they were released from the north arm and allowed to choose either the east arm (place learning) or the west arm (response learning). Control rats showed predominant place learning whereas all rats receiving (Abeta1-42) showed response learning. These data indicate that exposure to (Abeta1-42) does not only impair cognitive responding but elicits strong procedural (motor-based) responding.