Extracellular signal-regulated kinase (ERK) activity during sleep consolidates cortical plasticity in vivo.

Ocular dominance plasticity (ODP) in the cat primary visual cortex (V1) is induced during waking by monocular deprivation (MD) and consolidated during subsequent sleep. The mechanisms underlying this process are incompletely understood. Extracellular signal-regulated kinase (ERK) is activated in V1 during sleep after MD, but it is unknown whether ERK activation during sleep is necessary for ODP consolidation. We investigated the role of ERK in sleep-dependent ODP consolidation by inhibiting the ERK-activating enzyme MEK in V1 (via U0126) during post-MD sleep. ODP consolidation was then measured with extracellular microelectrode recordings. Western blot analysis was used to confirm the efficacy of U0126 and to examine proteins downstream of ERK. U0126 abolished ODP consolidation and reduced both phosphorylation of eukaryotic initiation factor 4E (eIF4E) and levels of the synaptic marker PSD-95. Furthermore, interfering with ERK-mediated translation by inhibiting MAP kinase-interacting kinase 1 (Mnk1) with CGP57380 mimicked the effects of U0126. These results demonstrate that ODP consolidation requires sleep-dependent activation of the ERK-Mnk1 pathway.

Protein synthesis during sleep consolidates cortical plasticity in vivo.

Sleep consolidates experience-dependent brain plasticity, but the precise cellular mechanisms mediating this process are unknown [1]. De novo cortical protein synthesis is one possible mechanism. In support of this hypothesis, sleep is associated with increased brain protein synthesis [2, 3] and transcription of messenger RNAs (mRNAs) involved in protein synthesis regulation [4, 5]. Protein synthesis in turn is critical for memory consolidation and persistent forms of plasticity in vitro and in vivo [6, 7]. However, it is unknown whether cortical protein synthesis in sleep serves similar functions. We investigated the role of protein synthesis in the sleep-dependent consolidation of a classic form of cortical plasticity in vivo (ocular dominance plasticity, ODP; [8, 9]) in the cat visual cortex. We show that intracortical inhibition of mammalian target of rapamycin (mTOR)-dependent protein synthesis during sleep abolishes consolidation but has no effect on plasticity induced during wakefulness. Sleep also promotes phosphorylation of protein synthesis regulators (i.e., 4E-BP1 and eEF2) and the translation (but not transcription) of key plasticity related mRNAs (ARC and BDNF). These findings show that sleep promotes cortical mRNA translation. Interruption of this process has functional consequences, because it abolishes the consolidation of experience in the cortex.

The sedating antidepressant trazodone impairs sleep-dependent cortical plasticity.

BACKGROUND: Recent findings indicate that certain classes of hypnotics that target GABA(A) receptors impair sleep-dependent brain plasticity. However, the effects of hypnotics acting at monoamine receptors (e.g., the antidepressant trazodone) on this process are unknown. We therefore assessed the effects of commonly-prescribed medications for the treatment of insomnia (trazodone and the non-benzodiazepine GABA(A) receptor agonists zaleplon and eszopiclone) in a canonical model of sleep-dependent, in vivo synaptic plasticity in the primary visual cortex (V1) known as ocular dominance plasticity. METHODOLOGY/PRINCIPAL FINDINGS: After a 6-h baseline period of sleep/wake polysomnographic recording, cats underwent 6 h of continuous waking combined with monocular deprivation (MD) to trigger synaptic remodeling. Cats subsequently received an i.p. injection of either vehicle, trazodone (10 mg/kg), zaleplon (10 mg/kg), or eszopiclone (1-10 mg/kg), and were allowed an 8-h period of post-MD sleep before ocular dominance plasticity was assessed. We found that while zaleplon and eszopiclone had profound effects on sleeping cortical electroencephalographic (EEG) activity, only trazodone (which did not alter EEG activity) significantly impaired sleep-dependent consolidation of ocular dominance plasticity. This was associated with deficits in both the normal depression of V1 neuronal responses to deprived-eye stimulation, and potentiation of responses to non-deprived eye stimulation, which accompany ocular dominance plasticity. CONCLUSIONS/SIGNIFICANCE: Taken together, our data suggest that the monoamine receptors targeted by trazodone play an important role in sleep-dependent consolidation of synaptic plasticity. They also demonstrate that changes in sleep architecture are not necessarily reliable predictors of how hypnotics affect sleep-dependent neural functions.

The non-benzodiazepine hypnotic zolpidem impairs sleep-dependent cortical plasticity.

STUDY OBJECTIVES: The effects of hypnotics on sleep-dependent brain plasticity are unknown. We have shown that sleep enhances a canonical model of in vivo cortical plasticity, known as ocular dominance plasticity (ODP). We investigated the effects of 3 different classes of hypnotics on ODP. DESIGN: Polysomnographic recordings were performed during the entire experiment (20 h). After a baseline sleep/wake recording (6 h), cats received 6 h of monocular deprivation (MD) followed by an i.p. injection of triazolam (1-10 mg/kg i.p.), zolpidem (10 mg/kg i.p.), ramelteon (0.1-1 mg/kg i.p.), or vehicle (DMSO i.p.). They were then allowed to sleep ad lib for 8 h, after which they were prepared for optical imaging of intrinsic cortical signals and single-unit electrophysiology. SETTING: Basic neurophysiology laboratory PATIENTS OR PARTICIPANTS: Cats (male and female) in the critical period of visual development (postnatal days 28-41) INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Zolpidem reduced cortical plasticity by approximately 50% as assessed with optical imaging of intrinsic cortical signals. This was not due to abnormal sleep architecture because triazolam, which perturbed sleep architecture and sleep EEGs more profoundly than zolpidem, had no effect on plasticity. Ramelteon minimally altered sleep and had no effect on ODP. CONCLUSIONS: Our findings demonstrate that alterations in sleep architecture do not necessarily lead to impairments in sleep function. Conversely, hypnotics that produce more "physiological" sleep based on polysomnography may impair critical brain processes, depending on their pharmacology.

Automatic repositioning of single voxels in longitudinal 1H MRS studies.

An automatic procedure, allowing the prospective registration of brain MRI images and the acquisition of nearly identical brain volumes (coverage and orientation) in longitudinal exams, is presented. This procedure, based on a fast registration algorithm and a tailored pulse sequence, is used to reposition single voxels for 1H MRS data acquired in vivo. The impact of the repositioning method on the extent of voxel overlap and on the reproducibility of metabolite concentration measurements is studied. A statistically significant increase in voxel overlap and generally decreased short-term measurement variability (decreased coefficients of variation and increased reproducibility coefficients) are observed. Differences in the long-term variances of metabolite concentrations and concentration ratios measured using the eye and automatic repositioning scheme, however, do not reach statistical significance. The improved workflow associated with the use of the automatic repositioning process, which obviates the need for skilled operator intervention for voxel repositioning, suggests that approaches similar to the one presented here may be a standard element in tomorrow's longitudinal MRI and MRS exams.