How the cerebellum may monitor sensory information for spatial representation.

The cerebellum has already been shown to participate in the navigation function. We propose here that this structure is involved in maintaining a sense of direction and location during self-motion by monitoring sensory information and interacting with navigation circuits to update the mental representation of space. To better understand the processing performed by the cerebellum in the navigation function, we have reviewed: the anatomical pathways that convey self-motion information to the cerebellum; the computational algorithm(s) thought to be performed by the cerebellum from these multi-source inputs; the cerebellar outputs directed toward navigation circuits and the influence of self-motion information on space-modulated cells receiving cerebellar outputs. This review highlights that the cerebellum is adequately wired to combine the diversity of sensory signals to be monitored during self-motion and fuel the navigation circuits. The direct anatomical projections of the cerebellum toward the head-direction cell system and the parietal cortex make those structures possible relays of the cerebellum influence on the hippocampal spatial map. We describe computational models of the cerebellar function showing that the cerebellum can filter out the components of the sensory signals that are predictable, and provides a novelty output. We finally speculate that this novelty output is taken into account by the navigation structures, which implement an update over time of position and stabilize perception during navigation.

Multiple presentations reduce the behavioral impact of protected predator exposure in rats.

Exposure of rats to a predator species, such as a cat, or stimuli associated with a predator species has been used to model the effects of traumatic stress. We further investigated this procedure to determine if the behavioral effects from such exposure could be increased by multiple exposures. In rats (n=8 for each treatment group), we evaluated single (1×) and multiple (1×/day for 3 consecutive days [3×] and 2×/day for 3 consecutive days [6×]) exposures using cats and soiled cat litter. All exposures were 15min in duration and the rats were directly exposed to the cats but in a protected fashion that did not allow the predator to physically injure the rat. Sham exposures were conducted using similar conditions without the presence of the predator or litter. The effects of the exposures were evaluated using an elevated plus maze (EPM). Sessions on the EPM were conducted before the exposures and at various times after the exposure. Difference scores (post-pre) were calculated for dependent measures from the EPM, and statistical analyses compared the slopes and intercept values derived from regression functions from these scores over the post-exposure sessions. During the first 30 days after exposure, a significant reduction in activity on the EPM was observed for the 1× treatment and a smaller reduction was observed for the 3× treatment, but no reduction was observed for the 6× and sham control treatments. Thus, increasing the number of exposures did not increase the magnitude of the effect but, instead, resulted in a decrease. These results show that adaptation to the effects of the predator exposure occurred with repeated sessions.

Complementary Roles of the Hippocampus and the Dorsomedial Striatum during Spatial and Sequence-Based Navigation Behavior.

We investigated the neural bases of navigation based on spatial or sequential egocentric representation during the completion of the starmaze, a complex goal-directed navigation task. In this maze, mice had to swim along a path composed of three choice points to find a hidden platform. As reported previously, this task can be solved by using two hippocampal-dependent strategies encoded in parallel i) the allocentric strategy requiring encoding of the contextual information, and ii) the sequential egocentric strategy requiring temporal encoding of a sequence of successive body movements associated to specific choice points. Mice were trained during one day and tested the following day in a single probe trial to reveal which of the two strategies was spontaneously preferred by each animal. Imaging of the activity-dependent gene c-fos revealed that both strategies are supported by an overlapping network involving the dorsal hippocampus, the dorsomedial striatum (DMS) and the medial prefrontal cortex. A significant higher activation of the ventral CA1 subregion was observed when mice used the sequential egocentric strategy. To investigate the potential different roles of the dorsal hippocampus and the DMS in both types of navigation, we performed region-specific excitotoxic lesions of each of these two structures. Dorsal hippocampus lesioned mice were unable to optimally learn the sequence but improved their performances by developing a serial strategy instead. DMS lesioned mice were severely impaired, failing to learn the task. Our data support the view that the hippocampus organizes information into a spatio-temporal representation, which can then be used by the DMS to perform goal-directed navigation.

A look into the future: improving diabetes care by 2015.

Insulin initiation, which was traditionally the province of specialists, is increasingly undertaken by primary care. However, significant barriers to appropriate and timely initiation still exist. Whilst insulin is recognized as providing the most effective treatment in type 2 diabetes, it is also widely considered to be the most challenging and time consuming. This editorial identifies that the organization of existing healthcare services, the challenges faced by patients, and the treatments themselves contribute to suboptimal insulin management. In order to improve future diabetes care, it will be necessary to address all three problem areas: (1) re-think the best use of existing human and financial resources to promote and support patient self-management and adherence to treatment; (2) empower patients to participate more actively in treatment decision making; and (3) improve acceptance, persistence and adherence to therapy by continuing to refine insulin therapy and treatment regimens in terms of safety, simplicity and convenience. The principles discussed are also applicable to the successful management of any chronic medical illness.

Pregnenolone sulfate and its enantiomer: differential modulation of memory in a spatial discrimination task using forebrain NMDA receptor deficient mice.

This study examined the role of forebrain N-methyl-D-aspartate receptors (NMDA-Rs) in the promnesiant effects of natural (+) pregnenolone sulfate (PREGS) and its synthetic (-) enantiomer ent-PREGS in young adult mice. Using the two-trial arm discrimination task in a Y-maze, PREGS and ent-PREGS administration to control mice increased memory performances. In mice with a knock-out of the NR1 subunit of NMDA-Rs in the forebrain, the promnesiant effect of ent-PREGS was maintained whereas the activity of PREGS was lost. Memory enhancement by PREGS involves the NMDA-R activity in the hippocampal CA1 area and possibly in some locations of the cortical layers, whereas ent-PREGS acts independently of NMDA-R function.

A new approach for modeling episodic memory from rodents to humans: the temporal order memory.

One of the crucial issues in actual research on memory disorders and particularly in Alzheimer's disease is the development of behavioral tasks accurately testing episodic memory, a type of memory sensitive to aging and altered early during neurodegenerative disorders. Translational research allowing comparison of similar memory properties between human and rodent models is a requirement for the finding of behavioral and cognitive biomarkers as well as molecular deficits associated to the pathology. In this review, we propose that the ability to remember an ordered sequence of choices during spatial navigation could be one of the episodic memory properties shared by human and rodent models. The ability to learn the correct sequence of choices depends on the hippocampus, requires flexibility and is particularly sensitive to age-related decline in rodents as in humans. In an innovative approach, we took advantage of a well characterized rodent navigation task, the starmaze, to develop a new model of episodic allowing creating and objective experimental testing of a personal past experience without requiring verbal report which can be transferred to human.

Impaired sequential egocentric and allocentric memories in forebrain-specific-NMDA receptor knock-out mice during a new task dissociating strategies of navigation.

The hippocampus is considered to play a role in allocentric but not in egocentric spatial learning. How does this view fit with the emerging evidence that the hippocampus and possibly related cortical areas are necessary for episodic-like memory, i.e., in all situations in which events need to be spatially or sequentially organized? Are NMDA receptor-dependent mechanisms crucial for the acquisition of spatiotemporal relationships? To address this issue, we used knock-out (KO) mice lacking hippocampal CA1 NMDA receptors and presenting a reduction of these receptors in the deep cortical layers (NR1-KO mice). A new task (the starmaze) was designed, allowing us to distinguish allocentric and sequential-egocentric memories. NR1-KO mice were impaired in acquiring both types of memory. Our findings suggest that memories composed of multiple spatiotemporal events require intact NMDA receptors-dependent mechanisms in CA1 and possibly in the deep cortical layers.

p53 inactivation leads to impaired motor synchronization in mice.

We have combined genetic and pharmacological approaches to investigate the behavioural consequences of inactivation of the murine p53 protein. Our behavioural analysis revealed that p53-null mice (p53KO) exhibit a very specific and significant motor deficit in rapid walking synchronization. This deficit, observed using the rotarod test, was the only behavioural defect of p53KO mice. We demonstrated that it was not due to an increase in neuronal number or abnormal connectivity in the olivo-cerebellar system, thought to control motor synchronization. In order to test the role of p53 in the central nervous system, we injected a pharmacological inhibitor of p53 activation, pifithrin-alpha, into the cerebellum of wild-type mice. This treatment mimicked the walking synchronization deficit of p53KO mice, suggesting that presence of p53 protein in the cerebellum is necessary to execute this synchronization of walking. Our investigation reveals a functional role of cerebellar p53 protein in adult walking synchronization.