Synapse-Specific Modulation of Synaptic Responses by Brain States in Hippocampal Pathways.

Synaptic changes play a major role in memory processes. Modulation of synaptic responses by brain states remains, however, poorly understood in hippocampal networks, even in basal conditions. We recorded evoked synaptic responses at five hippocampal pathways in freely moving male rats. We showed that, at the perforant path to dentate gyrus (PP-DG) synapse, responses increase during wakefulness compared with sleep. At the Schaffer collaterals to CA1 (SC-CA1) synapse, responses increase during non-REM sleep (NREM) compared with the other states. During REM sleep (REM), responses decreased at the PP-DG and SC-CA1 synapses compared with NREM, while they increased at the fornix to nucleus accumbens synapse (Fx-NAc) during REM compared with the other states. In contrast, responses at the fornix to medial PFC synapse (Fx-PFC) and at the fornix to amygdala synapse (Fx-Amy) were weakly modulated by vigilance states. Extended sleep periods led to synaptic changes at PP-DG and Fx-Amy synapses but not at the other synapses. Synaptic responses were also linked to local oscillations and were highly correlated between Fx-PFC and Fx-NAc but not between Fx-Amy and these synapses. These results reveal synapse-specific modulations that may contribute to memory consolidation during the sleep-wake cycle.SIGNIFICANCE STATEMENT Surprisingly, the cortical network dynamics remains poorly known at the synaptic level. We tested the hypothesis that brain states would modulate synaptic changes in the same way at different cortical connections. To tackle this issue, we implemented an approach to explore the synaptic behavior of five connections upstream and downstream the rat hippocampus. Our study reveals that synaptic responses are modulated in a highly synapse-specific manner by wakefulness and sleep states as well as by local oscillations at these connections. Moreover, we found rapid synaptic changes during wake and sleep transitions as well as synaptic down and upregulations after extended periods of sleep. These synaptic changes are likely related to the mechanisms of sleep-dependent memory consolidation.

Highly Dynamic Spatiotemporal Organization of Low-Frequency Activities During Behavioral States in the Mouse Cerebral Cortex.

Although low-frequency (LF < 10 Hz) activities have been considered as a hallmark of nonrapid eye movement (NREM) sleep, several studies have recently reported LF activities in the membrane potential of cortical neurons from different areas in awake mice. However, little is known about the spatiotemporal organization of LF activities across cortical areas during wakefulness and to what extent it differs during NREM sleep. We have thus investigated the dynamics of LF activities across cortical areas in awake and sleeping mice using chronic simultaneous local field potential recordings. We found that LF activities had higher amplitude in somatosensory and motor areas during quiet wakefulness and decreased in most areas during active wakefulness, resulting in a global state change that was overall correlated with motor activity. However, we also observed transient desynchronization of cortical states between areas, indicating a more local state regulation. During NREM sleep, LF activities had higher amplitude in all areas but slow-wave activity was only poorly correlated across cortical areas. Despite a maximal amplitude during NREM sleep, the coherence of LF activities between areas that are not directly connected dropped from wakefulness to NREM sleep, potentially reflecting a breakdown of long-range cortical integration associated with loss of consciousness.

DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.

The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF-SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.

Brain-State-Dependent Modulation of Neuronal Firing and Membrane Potential Dynamics in the Somatosensory Thalamus during Natural Sleep.

The thalamus plays a central role in sleep rhythms in the mammalian brain and, yet, surprisingly little is known about its function and interaction with local cortical oscillations during NREM sleep (NREM). We investigated the neuronal correlates of cortical barrel activity in the two corresponding thalamic nuclei, the ventral posterior medial (VPM), and the posterior medial (Pom) nuclei during natural NREM in mice. Our data reveal (1) distinct modulations of VPM and Pom activity throughout NREM episodes, (2) a thalamic nucleus-specific phase-locking to cortical slow and spindle waves, (3) cell-specific subthreshold spindle oscillations in VPM neurons that only partially overlap with cortical spindles, and (4) that spindle features evolve throughout NREM episodes and vary according to the post-NREM state. Taken together, our results suggest that, during natural sleep, the barrel cortex exerts a leading role in the generation and transfer of slow rhythms to the somatosensory thalamus and reciprocally for spindle oscillations.

Reward-Based Learning Drives Rapid Sensory Signals in Medial Prefrontal Cortex and Dorsal Hippocampus Necessary for Goal-Directed Behavior.

The neural circuits underlying learning and execution of goal-directed behaviors remain to be determined. Here, through electrophysiological recordings, we investigated fast sensory processing across multiple cortical areas as mice learned to lick a reward spout in response to a brief deflection of a single whisker. Sensory-evoked signals were absent from medial prefrontal cortex and dorsal hippocampus in naive mice, but developed with task learning and correlated with behavioral performance in mice trained in the detection task. The sensory responses in medial prefrontal cortex and dorsal hippocampus occurred with short latencies of less than 50 ms after whisker deflection. Pharmacological and optogenetic inactivation of medial prefrontal cortex or dorsal hippocampus impaired behavioral performance. Neuronal activity in medial prefrontal cortex and dorsal hippocampus thus appears to contribute directly to task performance, perhaps providing top-down control of learned, context-dependent transformation of sensory input into goal-directed motor output.

Whisking-Related Changes in Neuronal Firing and Membrane Potential Dynamics in the Somatosensory Thalamus of Awake Mice.

The thalamus transmits sensory information to the neocortex and receives neocortical, subcortical, and neuromodulatory inputs. Despite its obvious importance, surprisingly little is known about thalamic function in awake animals. Here, using intracellular and extracellular recordings in awake head-restrained mice, we investigate membrane potential dynamics and action potential firing in the two major thalamic nuclei related to whisker sensation, the ventral posterior medial nucleus (VPM) and the posterior medial group (Pom), which receive distinct inputs from brainstem and neocortex. We find heterogeneous state-dependent dynamics in both nuclei, with an overall increase in action potential firing during active states. Whisking increased putative lemniscal and corticothalamic excitatory inputs onto VPM and Pom neurons, respectively. A subpopulation of VPM cells fired spikes phase-locked to the whisking cycle during free whisking, and these cells may therefore signal whisker position. Our results suggest differential processing of whisking comparing thalamic nuclei at both sub- and supra-threshold levels.

Density and frequency caudo-rostral gradients of sleep spindles recorded in the human cortex.

STUDY OBJECTIVE: This study aims at providing a quantitative description of intrinsic spindle frequency and density (number of spindles/min) in cortical areas using deep intracerebral recordings in humans. PATIENTS OR PARTICIPANTS: Thirteen patients suffering from pharmaco-resistant focal epilepsy and investigated through deep intracortical EEG in frontal, parietal, temporal, occipital, insular, and limbic cortices including the hippocampus were included. METHODS: Spindle waves were detected from the ongoing EEG during slow wave sleep (SWS) by performing a time-frequency analysis on filtered signals (band-pass filter: 10-16 Hz). Then, spindle intrinsic frequency was determined using a fast Fourier transform, and spindle density (number of spindles per minute) was computed. RESULTS: Firstly, we showed that sleep spindles were recorded in all explored cortical areas, except temporal neocortex. In particular, we observed the presence of spindles during SWS in areas such as the insular cortex, medial parietal cortex, occipital cortex, and cingulate gyrus. Secondly, we demonstrated that both spindle frequency and density smoothly change along the caudo-rostral axis, from fast frequent posterior spindles to slower and less frequent anterior spindles. Thirdly, we identified the presence of spindle frequency oscillations in the hippocampus and the entorhinal cortex. CONCLUSIONS: Spindling activity is widespread among cortical areas, which argues for the fundamental role of spindles in cortical functions. Mechanisms of caudo-rostral gradient modulation in spindle frequency and density may result from a complex interplay of intrinsic properties and extrinsic modulation of thalamocortical and corticothalamic neurons.

A vital role of tubulin-tyrosine-ligase for neuronal organization.

Tubulin is subject to a special cycle of detyrosination/tyrosination in which the C-terminal tyrosine of alpha-tubulin is cyclically removed by a carboxypeptidase and readded by a tubulin-tyrosine-ligase (TTL). This tyrosination cycle is conserved in evolution, yet its physiological importance is unknown. Here, we find that TTL suppression in mice causes perinatal death. A minor pool of tyrosinated (Tyr-)tubulin persists in TTL null tissues, being present mainly in dividing TTL null cells where it originates from tubulin synthesis, but it is lacking in postmitotic TTL null cells such as neurons, which is apparently deleterious because early death in TTL null mice is, at least in part, accounted for by a disorganization of neuronal networks, including a disruption of the cortico-thalamic loop. Correlatively, cultured TTL null neurons display morphogenetic anomalies including an accelerated and erratic time course of neurite outgrowth and a premature axonal differentiation. These anomalies may involve a mislocalization of CLIP170, which we find lacking in neurite extensions and growth cones of TTL null neurons. Our results demonstrate a vital role of TTL for neuronal organization and suggest a requirement of Tyr-tubulin for proper control of neurite extensions.

The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders.

Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP-/- mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP-/- mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP-/- mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.