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.

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

β-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.

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.

β 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).

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.

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.

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.

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).

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).

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.

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.

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.

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.