Yannick Jeantet

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.

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.

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 animals 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 animals head. The current system provides eight recording channels, but the design can be modified to accommodate additional channels.

Facilitation of memory consolidation by post-training electrical stimulation of the medial septal nucleus: is it mediated by changes in rhythmic slow activity?

Sinusoidal (100 Hz) electrical stimulation was applied at a weak intensity (7.5 muA peak to peak) through bipolar electrodes located in the medial septal nucleus after partial acquisition of an appetitive operant conditioning task in a Skinner box. Analysis of performance in a retention test 24 hr later showed that (i) the presence of stimulation electrodes by itself impaired retention-test performance, and (ii) electrical stimulation applied 30 sec after the end of the acquisition session improves retention; this facilitatory effect disappeared when the treatment was delayed 15 min. Both impairment and facilitation were found to vary (considerably) among subjects. Electrodes located in the center of the medial septal nucleus led to both a greater impairment in unstimulated subjects and a greater facilitation in stimulated subjects than more anterior placements in the vicinity of the diagonal band. Finally, spectral analysis of hippocampal EEG showed that stimulation had no effect on rhythmic slow activity (RSA). These results are discussed in relation to studies showing that RSA is associated with memory-storage processes and our own hypothesis which underlines the importance of activation of septo-hippocampal cholinergic neurons in the early stages of these mnemonic processes.

Posttraining changes in excitability of the commissural path-CA1 pyramidal cell synapse in the hippocampus of mice

Mice were partially trained on a bar-press operant conditioning task on continuous reinforcement (CRF). The amplitude of population excitatory postsynaptic potentials (EPSPs) evoked by commissural stimulation of the Ca2 field of the dorsal hippocampus was found to significantly increase 1 h after training and then to decrease. This phenomenon was either not observed or much less evident in mice could not learn the task or which had already been trained on this task.

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).

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 (1-4Hz) 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.

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). Recording data revealed a unique β 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 β oscillation and vigilance states: while nearly absent during the active waking state, the β 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 Huntingtons disease pathophysiology, this serendipitous observation opens a window onto the rarely explored neurophysiology of the cortico-basal ganglia circuit during SWS and REM sleep.

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 Huntingtons disease and Alzheimers 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.