Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease.

In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.

Evolution of hippocampal spatial representation over time in mice.

To investigate the intriguing and paradoxical contrast between the time-limited role of the hippocampus in memory consolidation and its permanent contribution to spatial memory as revealed by place cell activity, we carefully monitored the temporal evolution of the same set of place cells in normal naïve mice throughout their familiarization to a spatial context and their consolidation of memory about space. Over six daily recording sessions, despite their widely reported stability, we observed gradual changes in hippocampal place fields and cell firing patterns. These changes were interpreted in terms of both improvement and impoverishment of spatial codes: improvement due to intrinsic place cell plasticity, and impoverishment as a consequence of attentional filtering of allocentric spatial information reaching the hippocampus due to the procedural behavioral requirements of the task, or to hippocampal disengagement as learning progresses.

Kainate receptors act as conditional amplifiers of spike transmission at hippocampal mossy fiber synapses.

Hippocampal mossy fiber (Mf) synapses are viewed as conditional detonators, assisting CA3 cells in complex network functions. By analyzing mice deficient for GluK2 (GluR6), GluK3 (GluR7) and GluK5 (KA2) genes we show that kainate receptors (KARs) play a crucial role in the control of synaptic integration and spike transmission efficacy at Mf synapses. We dissected out the role of the different KAR functions at Mf synapses and we show that presynaptic and postsynaptic KARs concur to amplify unitary Mf synaptic inputs to trigger spike discharge within a wide range of frequencies (from 1 to 50 Hz). Moreover, KARs strongly favor spike transmission in response to patterns of presynaptic activity mimicking in vivo dentate granule cell activity. By amplifying spike transmission, KARs also facilitate the induction of associative long-term potentiation in CA3. Hence the actions of KARs as amplifiers of spike transmission contribute largely to the "conditional detonator" function of Mf synapses and are likely important for spatial information processing.

Differential involvement of prefrontal cortex, striatum, and hippocampus in DRL performance in mice.

Behavioral effects of neurotoxic lesions of the hippocampus, medial prefrontal (prelimbic, infralimbic and anterior cingulate) cortex or dorsal striatum were assessed using a DRL-10s schedule in mice. Post-operative acquisition data indicate that mice with hippocampal, but not prefrontal or striatal lesions received fewer reinforcements during daily 30-min sessions, and were less efficient in the timing of their responses. Additional analysis of inter-response-time (IRT) distributions revealed that the responses of hippocampal-lesioned mice exhibited undistinguishable responses for short IRTs (up to 9s). In addition, prefrontal-lesioned mice demonstrated a degradation of performance with further testing, and a flattened IRT distribution at late test phase, while striatal-lesioned mice behaved similarly to sham-lesioned mice. These results are interpreted in terms of known functions of the hippocampus in behavioral inhibition, and of the prefrontal cortex in executive control/decision making (and time production).

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington's Disease.

Huntington's disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep-wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep-wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

A new test for long-term spatial memory using an operant chamber in mice.

As part of ongoing efforts to develop fully automated and standardized behavioral tasks to probe cognitive and mnemonic capabilities of mice, we have constructed a new rectangular operant chamber. The chamber contains numerous nose poke holes, distributed over three of its inner walls that are identifiable by their spatial locations. Using this apparatus, we have developed a 'spatial' memory task using a successive reversal discrimination paradigm. Mice learn to discriminate, by trial and error, the position of a single valid hole during a Presentation session wherein they obtained a maximum of 20 reinforcements or 15 min time elapsed. Following a delay interval, they were resubmitted to the same task (Test) using the same reinforced hole. Results indicated that C57BL/6 mice exhibited a significant improvement during the Test, the magnitude of the improvement (memory savings) being dependent on the length of retention intervals ranging from 5 min to 24h. In addition, discrimination performance was sensitive to scopolamine in a dose dependent manner. The simplicity in task set up and the minimal labor and space requirements make this task suitable for high throughput behavioral characterization of genetically modified mice.

A long list visuo-spatial sequential learning in mice.

Sequential learning has been extensively studied in humans using the serial reaction time (SRT) paradigm, and has contributed significantly to the description of the neurobiological processes and substrates underlying different memory systems. More precisely, patients with basal ganglia, but not medial temporal lobe pathology exhibit selective deficits in this task, qualified as implicit learning, since this learning occurs without any conscious awareness of the subjects. While, the construction of transgenic mouse models of human neurological diseases has created a great need for developing mouse analogs of this or other types of human memory tasks, only a few studies exist in rodents, and more specifically in mice. The present study is aimed at examining a SRT protocol for mice using our new operant chamber designed to be polyvalent for different experimental conditions and uses. We provide data for learning by normal C57BL/6 mice of a repeating sequence of 12 nose poke responses, first, via the observation of increases in reaction times when repeated sequence is replaced by random sequence, and, second, by analysis of behavior during transfer trials in which one sequential element is discretely replaced by a new item. The potential of our protocol for dissecting the different neural systems of learning and memory is discussed as well as its usefulness for the validation of transgenic mouse models of human neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.

Item organization in three-dimensional space and their discriminability in a mouse operant behavioral task.

In order to study spatial cognition as well as operant/instrumental conditioning or attention processes in the same experimental context in mice, we have designed and constructed an operant chamber that contains a large number of nose poke holes distributed over its inner walls. The nose poke holes were placed three in a horizontal row on one left wall, five in a form of an X on the front wall, and three in a vertical column on one right wall in a hexagonal shaped chamber. This organization of nose poke holes was intended to provide mice with spatially structured environmental cues. Here, we report on an experiment in which providing additional structuring to the standard condition, favoring either further spatial grouping or perceptual/visual clustering of subsets of holes, tremendously facilitated nose poke discrimination learning in normal C57BL/6 mice. More interestingly, mice were able to use their (spatial or mental) representation of holes organization elaborated under spatially or visually structured environment, to improve their learning of a new discrimination under the standard less-structured environment. These findings support the idea that mice are sensitive to subtle visual background information, in addition to spatial information, to organize nose poke items, process similar to both pattern separation and chunking process, in order to minimize interference and to increase items discriminability and their capacity for (long-term) memory.

Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington's Disease Mice.

In hereditary neurodegenerative Huntington's disease (HD), there exists a growing consideration that sleep and circadian dysregulations may be important symptoms. It is not known, however, whether sleep abnormalities contribute to other behavioral deficits in HD patients and mouse models. To determine the precise chronology for sleep physiology alterations and other sensory, motor, psychiatric and cognitive symptoms of HD, the same R6/1 HD transgenics and their wild-type littermates were recorded monthly for sleep electroencephalogram (EEG) together with a wide range of behavioral tests according to a longitudinal plan. We found an early and progressive deterioration of both sleep architecture and EEG brain rhythms in R6/1 mice, which are correlated timely with their spatial working memory impairments. Sleep fragmentation and memory impairments were accompanied by the loss of delta (1-4 Hz) power in the transgenic mice, the magnitude of which increased with age and disease progression. These precocious sleep and cognitive impairments were followed by deficits in social behavior, sensory and motor abilities. Our data confirm the existence and importance of sleep physiology alterations in the widely used R6/1 mouse line and highlight their precedence over other plethoric phenotypic changes. The brainwave abnormalities, may represent a novel biomarker and point to innovative therapeutic interventions against HD.

Altered hippocampal information coding and network synchrony in APP-PS1 mice.

ß-amyloid is hypothesized to harm neural function and cognitive abilities by perturbing synaptic transmission and plasticity in Alzheimer's disease (AD). To assess the impact of this pathology on hippocampal neurons' ability to encode flexibly environmental information across learning, we performed electrophysiological recordings of CA1 hippocampal unit activity in AD transgenic mice as they acquired an action-reward association in a spatially defined environment; the behavioral task enabled the precise timing of discrete and intentional behaviors of the animal. We found that the proportion of behavioral task-sensitive cells in wild-type (WT) mice typically increased, whereas the proportion of place cells decreased with learning. In AD mice, this learning-dependent change of cell-discharge patterns was absent, and cells exhibited similar firings from the beginning to firings attained at the late learning stage in wild-type cells. These inflexible hippocampal representations of task and space throughout learning are accompanied by remarkable alterations of local oscillatory activity in the theta and ultra-fast ripple frequencies as well as learning abilities. The present data offer new insights into the in vivo cellular and network processes by which ß-amyloid and other AD mutations may exert its harmful effects to produce cognitive and behavioral impairments in early stage of AD.

Design of a twin tetrode microdrive and headstage for hippocampal single unit recordings in behaving mice.

A new, easy to construct electrode, microdrive and headstage for electrophysiological recording system which is specifically adapted for freely behaving mice is described. The system uses printed circuit boards and light, flexible cables to enable the animal's free movement for behavioral testing. A clip attachment system permits rapid and secure connection of the headstage and cables to the microdrive assembly on the animal's head. The current system provides eight recording channels, but the design can be modified to accommodate additional channels.

ß oscillation during slow wave sleep and rapid eye movement sleep in the electroencephalogram of a transgenic mouse model of Huntington's disease.

STUDY OBJECTIVES: To search for early abnormalities in electroencephalogram (EEG) during sleep which may precede motor symptoms in a transgenic mouse model of hereditary neurodegenerative Huntington's disease (HD). DESIGN: In the R6/1 transgenic mouse model of HD, rhythmic brain activity in EEG recordings was monitored longitudinally and across vigilance states through the onset and progression of disease. MEASUREMENTS AND RESULTS: Mice with chronic electrode implants were recorded monthly over wake-sleep cycles (4 hours), beginning at 9-11 weeks (presymptomatic period) through 6-7 months (symptomatic period). Recording data revealed a unique ß rhythm (20-35 Hz), present only in R6/1 transgenic mice, which evolves in close parallel with the disease. In addition, there was an unusual relationship between this ß oscillation and vigilance states: while nearly absent during the active waking state, the ß oscillation appeared with drowsiness and during slow wave sleep (SWS) and, interestingly, strengthened rather than dissipating when the brain returned to an activated state during rapid eye movement (REM) sleep. CONCLUSIONS: In addition to providing a new in vivo biomarker and insight into Huntington's disease pathophysiology, this serendipitous observation opens a window onto the rarely explored neurophysiology of the cortico-basal ganglia circuit during SWS and REM sleep.

Early temporal short-term memory deficits in double transgenic APP/PS1 mice.

We tested single APP (Tg2576) transgenic, PS1 (PS1dE9) transgenic, and double APP/PS1 transgenic mice at 3 and 6 months of age on the acquisition of a hippocampal-dependent operant "differential reinforcement of low rate schedule" (DRL) paradigm. In this task mice are required to wait for at least 10 seconds (DRL-10s) between 2 consecutive nose poke responses. Our data showed that while single APP and PS1 transgene expression did not affect DRL learning and performance, mice expressing double APP/PS1 transgenes were impaired in the acquisition of DRL-10s at 6 months, but not at 3 months of age. The same impaired double transgenic mice, however, were perfectly capable of normal acquisition of signaled DRL-10s (SDRL-10s) task, a hippocampal-independent task, wherein mice were required to emit responses when the end of the 10-second delay was signaled by a lighting of the chamber. The age-dependent and early deficits of APP/PS1 mice suggest that the appetitive DRL paradigm is sensitive to the amyloid pathology present in double APP/PS1 mice, and that this mouse line represents a good model with which to study the efficacy of therapeutic strategies against Alzheimer's disease.