Neural ensemble reactivation in rapid eye movement and slow-wave sleep coordinate with muscle activity to promote rapid motor skill learning.

Neural activity patterns of recent experiences are reactivated during sleep in structures critical for memory storage, including hippocampus and neocortex. This reactivation process is thought to aid memory consolidation. Although synaptic rearrangement dynamics following learning involve an interplay between slow-wave sleep (SWS) and rapid eye movement (REM) sleep, most physiological evidence implicates SWS directly following experience as a preferred window for reactivation. Here, we show that reactivation occurs in both REM and SWS and that coordination of REM and SWS activation on the same day is associated with rapid learning of a motor skill. We performed 6 h recordings from cells in rats' motor cortex as they were trained daily on a skilled reaching task. In addition to SWS following training, reactivation occurred in REM, primarily during the pre-task rest period, and REM and SWS reactivation occurred on the same day in rats that acquired the skill rapidly. Both pre-task REM and post-task SWS activation were coordinated with muscle activity during sleep, suggesting a functional role for reactivation in skill learning. Our results provide the first demonstration that reactivation in REM sleep occurs during motor skill learning and that coordinated reactivation in both sleep states on the same day, although at different times, is beneficial for skill learning. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

Rapid visual stimulation increases extrasynaptic glutamate receptor expression but not visual-evoked potentials in the adult rat primary visual cortex.

The model most used to study synaptic plasticity, long-term potentiation (LTP), typically employs electrical stimulation of afferent fibers to induce changes in synaptic strength. It would be beneficial for understanding the behavioral relevance of LTP if a model could be developed that used more naturalistic stimuli. Recent evidence suggests that the adult visual cortex, previously thought to have lost most of its plasticity once past the critical period, is in fact capable of LTP-like changes in synaptic strength in response to sensory manipulations alone. In a preliminary study, we used a photic tetanus (PT; flashing checkerboard stimulus) to induce an enhancement of the visual-evoked potential (VEP) in the primary visual cortex of anesthetised adult rats. In the present study, we sought to compare the mechanisms of this novel sensory LTP with those of traditional electrical LTP. Unexpectedly, we found that sensory LTP was not induced as reliably as we had observed previously, as manipulations of several parameters failed to lead to significant potentiation of the VEP. However, we did observe a significant increase in visual cortex glutamate receptor expression on the surface of isolated synapses following the PT. Both AMPA receptor expression and N-methyl-d-aspartate (NMDA) receptor subunit expression were increased, specifically in extrasynaptic regions of the membrane, in PT animals. These results provide biochemical confirmation of the lack of change in the VEP in response to PT, but suggest that PT may prime synapses for strengthening upon appropriate subsequent activation, through the trafficking of glutamate receptors to the cell surface.

PIDD orchestrates translesion DNA synthesis in response to UV irradiation.

PIDD has been implicated in survival and apoptotic pathways in response to DNA damage, and a role for PIDD was recently identified in non-homologous end-joining (NHEJ) repair induced by γ-irradiation. Here, we present an interaction of PIDD with PCNA, first identified in a proteomics screen. PCNA has essential functions in DNA replication and repair following UV irradiation. Translesion synthesis (TLS) is a process that prevents UV irradiation-induced replication blockage and is characterized by PCNA monoubiquitination and interaction with the TLS polymerase eta (polη). Both of these processes are inhibited by p21. We report that PIDD modulates p21-PCNA dissociation, and promotes PCNA monoubiquitination and interaction with polη in response to UV irradiation. Furthermore, PIDD deficiency leads to a defect in TLS that is associated, both in vitro and in vivo, with cellular sensitization to UV-induced apoptosis. Thus, PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-κB activation and cell death.

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90.

In response to DNA damage, p53-induced protein with a death domain (PIDD) forms a complex called the PIDDosome, which either consists of PIDD, RIP-associated protein with a death domain and caspase-2, forming a platform for the activation of caspase-2, or contains PIDD, RIP1 and NEMO, important for NF-κB activation. PIDDosome activation is dependent on auto-processing of PIDD at two different sites, generating the fragments PIDD-C and PIDD-CC. Despite constitutive cleavage, endogenous PIDD remains inactive. In this study, we screened for novel PIDD regulators and identified heat shock protein 90 (Hsp90) as a major effector in both PIDD protein maturation and activation. Hsp90, together with p23, binds PIDD and inhibition of Hsp90 activity with geldanamycin efficiently disrupts this association and impairs PIDD auto-processing. Consequently, both PIDD-mediated NF-κB and caspase-2 activation are abrogated. Interestingly, PIDDosome formation itself is associated with Hsp90 release. Characterisation of cytoplasmic and nuclear pools of PIDD showed that active PIDD accumulates in the nucleus and that only cytoplasmic PIDD is bound to Hsp90. Finally, heat shock induces Hsp90 release from PIDD and PIDD nuclear translocation. Thus, Hsp90 has a major role in controlling PIDD functional activity.

Long-term depression and associativity in rat primary motor cortex following thalamic stimulation.

Associativity is an attractive property of LTP in terms of its possible mechanism as a model for memory storage. In this study, we compare the effects of homosynaptic vs. associative stimulation on the induction of LTP and LTD in the neocortex of freely behaving rats. Using a callosal input to the motor cortex as a 'strong' input (one that potentiates reliably following homosynaptic stimulation), we paired activity of this pathway with a 'weak' thalamocortical pathway (one that does not potentiate when stimulated homosynaptically). Surprisingly, homosynaptic HFS caused a lasting depression of the field EPSP in the thalamocortical pathway. Analysis of this effect revealed that it was largely polysynaptic. Associative HFS (HFS applied to both pathways) not only failed to induce an LTP effect in the thalamocortical pathway, it increased the magnitude of the depression. Associative HFS did, however, facilitate LTP induction in the 'strong' callosal pathway. When comparing the effects of homosynaptic and associative LTD induction (HFS on one pathway anticorrelated with LFS on the other), we found that both protocols induced a similar magnitude of depression. These results show that HFS applied to the thalamocortical pathway causes a depression and this depression is enhanced, not reversed, by associative pairing with a strong input.

Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control.

BACKGROUND: A previous report showed that the open field behavior of rats sensitized to the dopamine agonist quinpirole satisfies 5 performance criteria for compulsive checking behavior. In an effort to extend the parallel between the drug-induced phenomenon and human obsessive-compulsive disorder (OCD), the present study investigated whether the checking behavior of quinpirole rats is subject to interruption, which is an attribute characteristic of OCD compulsions. For this purpose, the rat's home-cage was placed into the open field at the beginning or the middle of a 2-hr test. RESULTS: Introduction of the home-cage reduced checking behavior, as rats stayed inside the cage. After 40 min, checking resurfaced, as quinpirole rats exited the home-cage often. An unfamiliar cage had no such effects on quinpirole rats or saline controls. CONCLUSIONS: Checking behavior induced by quinpirole is not irrepressible but can be suspended. Results strengthen the quinpirole preparation as an animal model of OCD compulsive checking.