Marcos G. Frank

Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss

Astrocytes modulate neuronal activity by releasing chemical transmitters via a process termed gliotransmission. The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation. Inhibiting gliotransmission attenuated the accumulation of sleep pressure, assessed by measuring the slow wave activity of the EEG during NREM sleep, and prevented cognitive deficits associated with sleep loss. Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wild-type mice mimicked the transgenic phenotype, we conclude that astrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors.

Sleep enhances plasticity in the developing visual cortex.

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.

Cellular and molecular connections between sleep and synaptic plasticity.

The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca(2+) channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal-neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity.

Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo

Gliotransmission, the release of molecules from astrocytes, regulates neuronal excitability and synaptic transmission in situ. Whether this process affects neuronal network activity in vivo is not known. Using a combination of astrocyte-specific molecular genetics, with in vivo electrophysiology and pharmacology, we determined that gliotransmission modulates cortical slow oscillations, a rhythm characterizing nonrapid eye movement sleep. Inhibition of gliotransmission by the expression of a dominant negative SNARE domain in astrocytes affected cortical slow oscillations, reducing the duration of neuronal depolarizations and causing prolonged hyperpolarizations. These network effects result from the astrocytic modulation of intracortical synaptic transmission at two sites: a hypofunction of postsynaptic NMDA receptors, and by reducing extracellular adenosine, a loss of tonic A1 receptor-mediated inhibition. These results demonstrate that rhythmic brain activity is generated by the coordinated action of the neuronal and glial networks.

Mechanisms of sleep-dependent consolidation of cortical plasticity.

Sleep is thought to consolidate changes in synaptic strength, but the underlying mechanisms are unknown. We investigated the cellular events involved in this process during ocular dominance plasticity (ODP)-a canonical form of in vivo cortical plasticity triggered by monocular deprivation (MD) and consolidated by sleep via undetermined, activity-dependent mechanisms. We find that sleep consolidates ODP primarily by strengthening cortical responses to nondeprived eye stimulation. Consolidation is inhibited by reversible, intracortical antagonism of NMDA receptors (NMDARs) or cAMP-dependent protein kinase (PKA) during post-MD sleep. Consolidation is also associated with sleep-dependent increases in the activity of remodeling neurons and in the phosphorylation of proteins required for potentiation of glutamatergic synapses. These findings demonstrate that synaptic strengthening via NMDAR and PKA activity is a key step in sleep-dependent consolidation of ODP.

The Role of Sleep in Memory Consolidation and Brain Plasticity: Dream or Reality?

The notion that a good night of sleep improves memory is widely accepted by the general public. Among sleep scientists, however, the idea has been hotly debated for decades. In this review, the authors consider current evidence for and against the hypothesis that sleep facilitates memory consolidation and promotes plastic changes in the brain. They find that despite a steady accumulation of positive findings over the past decade, the precise role of sleep in memory and brain plasticity remains elusive. This impasse may be resolved by more integrated approaches that combine behavioral and neurophysiological measurements in well-described in vivo models of synaptic plasticity.

Sleep and Sleep Homeostasis in Mice Lacking the 5-HT2c Receptor

Studies in humans and rats indicate that serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in mammalian sleep expression. We investigated the contribution of the 5-HT2c receptor to sleep expression by examining sleep patterns in mice bearing a targeted null mutation of this receptor. 5-HT2c receptor knock-out mice had more wakefulness, several abnormalities in rapid eye movement sleep expression and an enhanced response to sleep deprivation compared with wild-type control mice. These findings suggest that 5HT2c receptors may mediate several effects on sleep that have been ascribed to serotonin.

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 ontogeny of mammalian sleep: A reappraisal of alternative hypotheses.

Newborn mammals spend as much as 90% or more of their time in a sleep state characterized by frequent twitches, rapid eye movements (REMs), and irregular respiratory cycles. These motor and respiratory patterns resemble the phasic motor/respiratory components of adult REM sleep, and as a consequence, this sleep state is traditionally viewed as an immature form of REM sleep. An alternative view is that a significant portion of what has been called REM sleep in these species is a form of spontaneous activity typical of the immature nervous system. In this review, we compare and contrast these two opposing views about the ontogenetic origins of REM sleep, and review the evidence most often cited to support the idea that REM sleep is present in newborn altricial mammals. Critical review of this evidence indicates that REM sleep may not be present at birth in these species; rather, it appears that all mammals early in development exhibit spontaneous, dissociated activity that progressively becomes organized into the distinct states of REM and non‐rapid eye movement sleep.

Sleep-Dependent Plasticity Requires Cortical Activity

Recent findings in humans and animals suggest that sleep promotes synaptic plasticity, but the underlying mechanisms have not been identified. We have demonstrated recently an important role for sleep in ocular dominance (OD) plasticity, a classic form of in vivo cortical remodeling triggered by monocular deprivation (MD) during a critical period of development. The mechanisms responsible for the effects of sleep on OD plasticity are unknown but may depend on neuronal activity in the sleeping brain. We investigated the role of cortical activity in sleep-dependent plasticity by reversibly inactivating the sleeping visual cortex (V1) after a period of MD. Critical period cats were bilaterally implanted with cannulas in V1 and standard EEG/EMG electrodes for polysomnographic recording. After a period of MD, visual cortices were infused with the sodium channel blocker lidocaine in vehicle or vehicle only during sleep. A third group of cats served as sham controls and were infused with lidocaine outside of V1 (into the CSF). Both optical imaging of intrinsic cortical signals and microelectrode recordings showed that OD plasticity was significantly reduced in cats whose visual cortices were reversibly silenced during sleep. These findings demonstrate that the mechanisms governing this form of sleep-dependent plasticity require cortical activity. They provide an important insight into how sleep modifies synaptic circuitry by narrowing the range of possible candidate mechanisms to those that are activity dependent.