Impaired Fear Extinction Due to a Deficit in Ca2+ Influx Through L-Type Voltage-Gated Ca2+ Channels in Mice Deficient for Tenascin-C.

Mice deficient in the extracellular matrix glycoprotein tenascin-C (TNC-/-) express a deficit in specific forms of hippocampal synaptic plasticity, which involve the L-type voltage-gated Ca2+ channels (L-VGCCs). The mechanisms underlying this deficit and its functional implications for learning and memory have not been investigated. In line with previous findings, we report on impairment in theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in TNC-/- mice in the CA1 hippocampal region and its rescue by the L-VGCC activator Bay K-8644. We further found that the overall pattern of L-VGCC expression in the hippocampus in TNC-/- mice was normal, but Western blot analysis results uncovered upregulated expression of the Cav1.2 and Cav1.3 α-subunits of L-VGCCs. However, these L-VGCCs were not fully functional in TNC-/- mice, as demonstrated by Ca2+ imaging, which revealed a reduction of nifedipine-sensitive Ca2+ transients in CA1 pyramidal neurons. TNC-/- mice showed normal learning and memory in the contextual fear conditioning paradigm but impaired extinction of conditioned fear responses. Systemic injection of the L-VGCC blockers nifedipine and diltiazem into wild-type mice mimicked the impairment of fear extinction observed in TNC-/- mice. The deficiency in TNC-/- mice substantially occluded the effects of these drugs. Our results suggest that TNC-mediated modulation of L-VGCC activity is essential for fear extinction.

Re-evaluating the PCP challenge as a pre-clinical model of impaired cognitive flexibility in schizophrenia.

NMDA-R antagonists are a popular translational pharmacological challenge to induce cognitive deficits associated with schizophrenia. Amongst their many cognitive and non-cognitive effects is an ability to impair cognitive flexibility in general, and reversal learning in particular. Here, we test the hypothesis that the NMDA-R antagonist phencyclidine when given acutely selectively effects reversal learning by simultaneously measuring reversal learning and baseline responding, or acquisition and baseline responding, under identical conditions. Animals were trained to simultaneously perform two different visual discriminations in a touch-screen equipped operant box. Accordingly the reward contingencies associated with one pair could be altered, while the second pair acted as an experimental control. As such, the effect of a manipulation on reversal learning, stimuli acquisition, or baseline responding can be more accurately evaluated through the use of a double visual discrimination. A similar approach was also used to investigate the influence of sub-chronic phencyclidine administration on cognitive flexibility. Phencyclidine (1mg/kg) given before testing caused a slowing in acquisition and reversal learning, while having a minimal effect on secondary measures. Sub-chronic phencyclidine administration had no significant effect on any of the measures used within this study. While acute phencyclidine impairs reversal learning, it is clear from these results that other aspects of cognition (learning/relearning) are also impaired, potentially questioning the specificity of acute phencyclidine in conjunction with reversal learning paradigms as a model of impaired cognitive flexibility.

A touch-screen based paired-associates learning (PAL) task for the rat may provide a translatable pharmacological model of human cognitive impairment.

The use of touch-screen equipped operant boxes is an increasingly popular approach for modeling human cognition in the rodent. However little data is currently available describing the effects of pharmacological manipulations on touch-screen based tasks. Owing to the relationship between performance on visual-spatial paired associates learning (PAL) with schizophrenia and Alzheimer's disease one task of specific interest is the touch-screen PAL task developed for rodents (J. Talpos et al., 2009). The goal of this study was to profile a range of the commonly used pharmacological models of schizophrenia and Alzheimer's disease to investigate the sensitivity of PAL to these models of disease. Male Lister hooded rats were trained on PAL until stable performance was obtained. The effects of PCP, ketamine, amphetamine, LSD, scopolamine, and biperiden (recently proposed as an alternative to scopolamine) were then tested on animals performing the PAL task. While all compounds influenced responding during PAL, only PCP and amphetamine impaired performance with minimal changes in secondary measures (response latencies, trials completed). Surprisingly ketamine did not cause a change in percent correct despite being an NMDA antagonist, indicating that not all NMDA antagonists are equal in the touch-screen platform. This finding is in agreement with existing literature showing differential effects of NMDA antagonists on a wide variety of behavioral assays include tasks of attention, memory, and cognitive flexibility (Gilmour et al., 2009; Dix et al., 2010; Smith et al., 2011). Moreover biperiden showed no benefit when compared to scopolamine, highlighting the current lack of an effective pharmacological model of cholinergic dysfunction in the touch-screen platform. These data demonstrate that performance on PAL can be disrupted by common pharmacological disease models, suggesting that PAL may have the sensitivity to serve as a translational test for the study of cognition in humans.

Mice create what-where-when hippocampus-dependent memories of unique experiences.

Episodic memory is relevant for auto-consciousness in humans. In nonhuman animals, episodic-like memory is defined when the "what-where-when" content of a unique event forms an integrated cognitive representation that is then deployed during memory retrieval. Here, we aimed at testing episodic-like memories of mice under experimental conditions that allow the analysis of whether and how mice process what-where-when information. Using an ecologically relevant paradigm for spontaneous learning and memory, we show that mice modulate their behavior based on the what, where, and when components of past unique episodes, specifically on previous encounters of conspecifics at a defined location and at a specific time of the day. We also show that learning during this paradigm activated Arc/Arg3.1 mRNA expression in the hippocampus and that stereotactic injection of anisomycin into this region impairs memory consolidation. Thus, hippocampus-dependent episodic-like memories of single experiences are spontaneously created in mice. These findings extend our knowledge of the cognitive capacities of the mouse and suggest that this species can be used as model for studying the mechanisms underlying human episodic memory and related neurological disorders.

NMDA receptors, cognition and schizophrenia--testing the validity of the NMDA receptor hypofunction hypothesis.

Cognitive dysfunction is core to schizophrenia, and remains poorly treated by existing therapies. A prominent hypothesis suggests that many symptoms arise from N-methyl-d-aspartate receptor (NMDAR) hypofunction. Subsequently, there has emerged a widespread use of many preclinical and clinical NMDAR antagonist models in the search for novel treatments. Clinically, ketamine is broadly purported to induce cognitive symptoms similar to those of schizophrenia. Preclinically, acute, subchronic and neonatal NMDAR antagonist administration models are all utilised in this context, as well as NMDAR transgenic animals. In this review, key strengths and weaknesses of each of these approaches are described with regard to their ability to recapitulate the deficits seen in patients. Given the breadth of literature and vogue for research in this topic, instances of NMDAR antagonist effects in the desired domains can readily be found preclinically. However, it is surprisingly difficult to identify any single aspect of cognitive function that possesses complete translational integrity. That is, there does not seem to be an NMDAR antagonist regimen proven to engage NMDARs equivalently in humans and animals that reliably produces the same cognitive effects in each species. This is likely due to the diverse range of techniques and models used by preclinical researchers, a paucity of research describing pharmacokinetic-pharmacodynamic relationships of NMDAR antagonist regimens, little capability to measure target engagement, and the lack of harmonized procedures between preclinical and clinical studies. Realizing the potential of the NMDAR hypofunction hypothesis to model cognitive impairment in schizophrenia will require some of these issues to be addressed.

Geometric information is required for allothetic navigation in mice.

In tasks for allothetic navigation, animals should orientate by means of distal cues. We have previously shown that mice use several forms of information to navigate, among which geometry, i.e. the shape of the environment, seems to play an important role. Here we investigated whether geometric features of the environment are necessary for allothetic navigation in mice. Mice were trained to navigate in a circular water maze by means of four distal landmarks distributed either symmetrically (symmetry group) or asymmetrically (asymmetry group) around the maze. Thus, mice could locate a hidden platform by either differentiating the landmarks based on their intrinsic features (symmetry group) or in addition by geometric information, i.e. based on the relative distances between landmarks (asymmetry group). Data indicated that place learning occurred only in the asymmetry group. The results support the idea that mice navigate by using the relational properties between distal landmarks and that geometric information is required for proper allothetic navigation in this species.

Expression of the snoRNA host gene gas5 in the hippocampus is upregulated by age and psychogenic stress and correlates with reduced novelty-induced behavior in C57BL/6 mice.

The growth arrest specific 5 (gas5) is a noncoding protein gene that hosts small nucleolar RNAs. Based on the observation that gas5 RNA level in the brain is highest in the hippocampus and remarkably enhanced in aged mice, we tested the hypothesis that gas5 is involved in functions controlled by the hippocampus and known to be affected by age, such as spatial learning and novelty-induced behaviors. We show that aged (22-month-old) C57BL/6 male mice have spatial-learning impairments, reduced novelty-induced exploration, and enhanced gas5 RNA levels in the hippocampus compared to young (3-month-old) mice. At both ages, levels of gas5 RNA in the hippocampus negatively correlated with novelty-induced exploration in the open field and elevated-plus maze tests. No correlations were found between gas5 RNA levels in the hippocampus and performance in the water maze test. The expression of gas5 RNA in the rest of the brain did not correlate with any behavioral parameter analyzed. Because variations in novelty-induced behaviors could be caused by stressfull experiences, we analyzed whether gas5 RNA levels in the hippocampus are regulated by acute stressors. We found that gas5 RNA levels in the hippocampus were upregulated by 50% 24 h after a psychogenic stressor (60-min olfactory contact with a rat) but were unchanged after exposure to an unfamiliar environment or after acquisition of new spatial information in a one-trial learning task. The present results suggest that strong psychogenic stressors upregulate gas5 RNA in the hippocampus, which in turn affects novelty-induced responses controlled by this region. We hypothesize that long-life exposure to stressors causes an age-dependent increase in hippocampal gas5 RNA levels, which could be responsible for age-related reduced novelty-induced behaviors, thus suggesting a new mechanism by which ageing and stress affect hippocampal function.

Pharmacological intervention of hippocampal CA3 NMDA receptors impairs acquisition and long-term memory retrieval of spatial pattern completion task.

Pattern completion is the ability to retrieve complete information on the basis of incomplete retrieval cues. Although it has been demonstrated that this cognitive capacity depends on the NMDA receptors (NMDA-Rs) of the hippocampal CA3 region, the role played by these glutamatergic receptors in the pattern completion process has not yet been specified. In the present study, we investigated the function of the CA3 NMDA-Rs during the different memory stages (acquisition, memory consolidation, and retrieval) in a spatial pattern completion task (when some visual cues were removed from the environment) in comparison to a standard spatial water maze task (when all visual cues were available in the environment). Thus, we coupled a massed training with the injection of NMDA-receptor antagonist (AP5) into the CA3 subfield of the dorsal hippocampus of C57BL/6 mice. Our results show that NMDA-Rs are not implicated in a standard situation but are crucial during both acquisition and long-term memory retrieval in pattern completion. This work provides the first evidence of a specific role of CA3 NMDA-Rs during memory process involved in the reactivation of incomplete memory trace, particularly when the amount of environmental information available is strongly limited.

Reactivation with a simple exposure to the experimental environment is sufficient to induce reconsolidation requiring protein synthesis in the hippocampal CA3 region in mice.

Our understanding of the memory reconsolidation process is at an earlier stage than that of consolidation. For example, it is unclear if, as for memory consolidation, reconsolidation of a memory trace necessitates protein synthesis. In fact, conflicting results appear in the literature and this discrepancy may be due to differences in the experimental reactivation procedure. Here, we addressed the question of whether protein synthesis in the CA3 hippocampal region is crucial in memory consolidation and reconsolidation of allocentric knowledge after reactivation in different experimental conditions in the Morris water maze. We showed (1) that an injection of the protein synthesis inhibitor anisomycin in the CA3 region during consolidation or after a single reactivation trial disrupted performance and (2) that protein synthesis is required even after a simple contextual reactivation without any learning trial and independently of the presence of the reinforcement. This work demonstrates that a simple exposure to the spatial environment is sufficient to reactivate the memory trace, to make it labile, and that reconsolidation of this trace requires de novo protein synthesis.

Adult but not aged C57BL/6 male mice are capable of using geometry for orientation.

Geometry, e.g., the shape of the environment, can be used by numerous animal species to orientate, but data concerning the mouse are lacking. We addressed the question of whether mice are capable of using geometry for navigating. To test whether aging could affect searching strategies, we compared adult (3- to 5-mo old) and aged (20- to 21-mo old) C57BL/6 male mice. We established a water maze task in which spatial information is provided by one landmark proximal to the target (featural information) and by the rectangular shape of the maze (geometric information). By means of probe trials in which we manipulated the presence of these two kinds of information, we show that adult mice can use both geometry and landmark to orientate. By contrast, aged mice do not use geometry and rely exclusively on the landmark to locate the platform. This study provides the first evidence that mice are capable of using geometric information for orientation and that this ability declines in aged animals.