Differential Expression of Plasticity-Related Genes in Waking and Sleep and Their Regulation by the Noradrenergic System

Abstract

Behavioral studies indicate that the ability to acquire long-term memories is severely impaired during sleep. It is unclear, however, why the highly synchronous discharge of neurons during sleep should not be followed by the induction of enduring plastic changes. Here we show that the expression of phosphorylated CRE-binding protein, Arc, and BDNF, three genes whose induction is often associated with synaptic plasticity, is high during waking and low during sleep. We also show that the induction of these genes during waking depends on the activity of the noradrenergic system, which is high in waking and low in sleep. These molecular results complement behavioral evidence and provide a mechanism for the impairment of long-term memory acquisition during sleep.Key words: Arc; BDNF; neural plasticity; memory; norepinephrine; P-CREB; sleep; sleep deprivation; waking Behavioral studies have shown that sleep severely impairs the ability to acquire long-term memories . For example, a large number of studies have failed to demonstrate the transfer of any learning from sleep to consecutive waking (Simon and Emmons, 1956). The retention of new information is possible only when the subject is awake during the presentation of the stimulus or when this presentation induces activation in the electroencephalogram (EEG) (Portnoff et al., 1966;Koukkou and Lehmann, 1968). Animal studies have shown that the impairment in the acquisition of long-term memories during sleep is not merely caused by a reduction of brain activity or by the reduced response to sensory inputs. In non-rapid eye movement (non-REM) sleep, neurons in the cortex and thalamus fire in synchronous bursts at overall rates only slightly lower than those in waking (Steriade, 1999). Furthermore, even if the reduced response to external stimuli is bypassed by high-frequency stimulation, hippocampal long-term potentiation (LTP) can be produced during waking but not during non-REM sleep (Leonard et al., 1987;Bramham and Srebro, 1989).From an evolutionary perspective, the suppression of long-term memory acquisition during sleep would seem to serve an adaptive purpose. In general, plastic changes leading to the acquisition of new information should occur when neural activity is related to the environment, but not when the brain is active off-line . However, the molecular correlates of the impairment of long-term memory acquisition during sleep are unclear. For example, despite the behavioral evidence against sleep learning, it has been suggested that synchronous activity bursts during non-REM sleep may be associated with massive influx of calcium and may constitute an ideal trigger for the induction of plasticityrelated genes (Buzsáki, 1998). Thus, it is of interest to establish whether genes thought to be associated with the occurrence of plastic changes are preferentially induced during waking or during sleep and, if so, what the underlying neural mechanisms might be.In this study, we examined the brain expression in sleep and waking of three molecular markers whose i...

Mapping neuronal activation and the influence of adrenergic signaling during contextual memory retrieval

“…This is perhaps surprising because lesions of the locus coeruleus, which supplies much of the adrenergic innervation to the forebrain, cause reductions in Arc labeling (Cirelli and Tononi 2000). However, those experiments measured IEG expression following prolonged wakefulness with repeated novel object exposure, whereas our experiments examined short-term induction of Arc in response to a change in context.…”

Elevated Sleep Spindle Density after Learning or after Retrieval in Rats

“…We found a time window during SWS ϳ2 h after the rat learned the odorreward contingency when the noradrenergic neurons of the locus ceruleus, which are usually quiescent during SWS, show a surge of activity that is never seen in animals that have not been in the learning situation (Sara et al, 2005). Learning-related delayed release of noradrenaline in forebrain neurons (Tronel et al, 2004), which are potentially engaged in reactivation during sleep, would serve as an effective signal or "molecular switch" for gene expression during a subsequent REM episode (Ribeiro et al, 1999;Cirelli and Tononi, 2000).…”

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…There is now incontrovertible evidence that the expression of selected critical genes varies dramatically during sleep and waking events, which likely plays a major role in regulating various and long-term neuroplastic events. 176 mRNA differential display, microarray, and biochemical studies have shown that short-term sleep deprivation is associated with an immediate 1) increase in levels of pCREB (the active form of this transcription factor); 2) increase in expression of BDNF; and 3) increase in expression of BDNF's receptor, TrkB.…”

“…In an extension of the gene expression studies, Cirelli and Tononi 176 hypothesized that a key factor responsible for the induction of the plasticity genes might be the level of activity of the neuromodulatory noradrenergic and serotonergic systems. Both of these systems project diffusely to most of the brain, where they regulate gene expression, and are only quiescent during rapid eye movement (REM) sleep.…”