Dumoulin Bridi MC, Aton SJ, Seibt J, Renouard L, Coleman T, Frank MG (2015) Rapid eye movement sleep promotes cortical plasticity in the developing brain, Science Advances1(6)
Rapid eye movement sleep is maximal during early life, but its function in the developing brain is unknown. We investigated the role of rapid eye movement sleep in a canonical model of developmental plasticity in vivo (ocular dominance plasticity in the cat) induced by monocular deprivation. Preventing rapid eye movement sleep after monocular deprivation reduced ocular dominance plasticity and inhibited activation of a kinase critical for this plasticity (extracellular signal?regulated kinase). Chronic single-neuron recording in freely behaving cats further revealed that cortical activity during rapid eye movement sleep resembled activity present during monocular deprivation. This corresponded to times of maximal extracellular signal?regulated kinase activation. These findings indicate that rapid eye movement sleep promotes molecular and network adaptations that consolidate waking experience in the developing brain.
How sleep influences brain plasticity is not known. In particular, why certain electroencephalographic
(EEG) rhythms are linked to memory consolidation is poorly understood.
Calcium activity in dendrites is known to be necessary for structural plasticity changes, but
this has never been carefully examined during sleep. Here, we report that calcium activity in
populations of neocortical dendrites is increased and synchronised during oscillations in the
spindle range in naturally sleeping rodents. Remarkably, the same relationship is not found in
cell bodies of the same neurons and throughout the cortical column. Spindles during sleep
have been suggested to be important for brain development and plasticity. Our results
provide evidence for a physiological link of spindles in the cortex specific to dendrites, the
main site of synaptic plasticity.
Aton SJ, Seibt Julie, Frank MG (2009) Sleep and Memory,Encyclopedia of Life Sciences (ELS) ISBN: 9780470015902
Current behavioural evidence indicates that sleep plays a central role in memory
consolidation. Neural events during post-learning sleep share key features with both
early and late stages of memory consolidation. For example, recent studies have shown
neuronal changes during post-learning sleep which reflect early synaptic changes
associated with consolidation, including activation of shared intracellular pathways and
modifications of synaptic strength. Sleep may also play a role in later stages of
consolidation involving propagation of memory traces throughout the brain. However,
to date the precise molecular and physiological aspects of sleep required for this process
remain unknown. The behavioural effects of sleep may be mediated by the large-scale,
global changes in neuronal activity, synchrony and intracellular communication that
accompany this vigilance state, or by synapse-specific ?replay? of activity patterns
associated with prior learning.
Sleep consolidates experience-dependent brain plasticity,
but the precise cellular mechanisms mediating this process
are unknown . 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.
Many lines of evidence indicate that important traits of neuronal phenotype, such as cell body position and neurotransmitter expression, are specified through complex interactions between extrinsic and intrinsic genetic determinants. However, the molecular mechanisms specifying neuronal connectivity are less well understood at the transcriptional level. Here we demonstrate that the bHLH transcription factor Neurogenin2 cell autonomously specifies the projection of thalamic neurons to frontal cortical areas. Unexpectedly, Ngn2 determines the projection of thalamic neurons to specific cortical domains by specifying the responsiveness of their axons to cues encountered in an intermediate target, the ventral telencephalon. Our results thus demonstrate that in parallel to their well-documented proneural function, bHLH transcription factors also contribute to the specification of neuronal connectivity in the mammalian brain
Ocular dominance plasticity in the developing primary visual cortex is initiated by monocular deprivation (MD) and consolidated during subsequent sleep. To clarify how visual experience and sleep affect neuronal activity and plasticity, we continuously recorded extragranular visual cortex fast-spiking (FS) interneurons and putative principal (i.e., excitatory) neurons in freely behaving cats across periods of waking MD and post-MD sleep. Consistent with previous reports in mice, MD induces two related changes in FS interneurons: a response shift in favor of the closed eye and depression of firing. Spike-timing?dependent depression of open-eye?biased principal neuron inputs to FS interneurons may mediate these effects. During post-MD nonrapid eye movement sleep, principal neuron firing increases and becomes more phase-locked to slow wave and spindle oscillations. Ocular dominance (OD) shifts in favor of open-eye stimulation?evident only after post-MD sleep?are proportional to MD-induced changes in FS interneuron activity and to subsequent sleep-associated changes in principal neuron activity. OD shifts are greatest in principal neurons that fire 40?300 ms after neighboring FS interneurons during post-MD slow waves. Based on these data, we propose that MD-induced changes in FS interneurons play an instructive role in ocular dominance plasticity, causing disinhibition among open-eye?biased principal neurons, which drive plasticity throughout the visual cortex during subsequent sleep.
Dufour Audrey, Seibt Julie, Passante Lara, Depaepe Vanessa, Ciossek Thomas, Frisén Jonas, Kullander Klas, Flanagan John G, Polleux Franck, Vanderhaeghen Pierre (2003) Area Specificity and Topography
of Thalamocortical Projections
Are Controlled by ephrin/Eph Genes,Neuron39(3)pp. 453-465
The mechanisms generating precise connections between specific thalamic nuclei and cortical areas remain poorly understood. Using axon tracing analysis of ephrin/Eph mutant mice, we provide in vivo evidence that Eph receptors in the thalamus and ephrins in the cortex control intra-areal topographic mapping of thalamocortical (TC) axons. In addition, we show that the same ephrin/Eph genes unexpectedly control the inter-areal specificity of TC projections through the early topographic sorting of TC axons in an intermediate target, the ventral telencephalon. Our results constitute the first identification of guidance cues involved in inter-areal specificity of TC projections and demonstrate that the same set of mapping labels is used differentially for the generation of topographic specificity of TC projections between and within individual cortical areas.
Imprinting is an epigenetic mechanism that restrains the expression of about 100 genes to one allele depending on its
parental origin. Several imprinted genes are implicated in neurodevelopmental brain disorders, such as autism, Angelman,
and Prader-Willi syndromes. However, how expression of these imprinted genes is regulated during neural development is
poorly understood. Here, using single and double KO animals for the transcription factors Neurogenin2 (Ngn2) and Achaetescute
homolog 1 (Ascl1), we found that the expression of a specific subset of imprinted genes is controlled by these
proneural genes. Using in situ hybridization and quantitative PCR, we determined that five imprinted transcripts situated at
the Dlk1-Gtl2 locus (Dlk1, Gtl2, Mirg, Rian, Rtl1) are upregulated in the dorsal telencephalon of Ngn2 KO mice. This suggests
that Ngn2 influences the expression of the entire Dlk1-Gtl2 locus, independently of the parental origin of the transcripts.
Interestingly 14 other imprinted genes situated at other imprinted loci were not affected by the loss of Ngn2. Finally, using
Ngn2/Ascl1 double KO mice, we show that the upregulation of genes at the Dlk1-Gtl2 locus in Ngn2 KO animals requires
a functional copy of Ascl1. Our data suggest a complex interplay between proneural genes in the developing forebrain that
control the level of expression at the imprinted Dlk1-Gtl2 locus (but not of other imprinted genes). This raises the possibility
that the transcripts of this selective locus participate in the biological effects of proneural genes in the developing
Recent findings indicate that certain classes of hypnotics that target GABAA 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 GABAA 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.
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.
Schuurmans Carol, Armant Olivier, Nieto Marta, Stenman Jan M, Britz Olivier, Klenin Natalia, Brown Craig, Langevin Lisa-Marie, Seibt Julie, Tang Hua, Cunningham James M, Dyck Richard, Walsh Christopher, Campbell Kenny, Polleux Franck, Guillemot Francois (2004) Sequential phases of cortical specification
and -independent pathways,The EMBO Journal23(14)pp. 2892-2902
Neocortical projection neurons, which segregate into six
cortical layers according to their birthdate, have diverse
morphologies, axonal projections and molecular profiles,
yet they share a common cortical regional identity and
glutamatergic neurotransmission phenotype. Here we demonstrate
that distinct genetic programs operate at different
stages of corticogenesis to specify the properties shared
by all neocortical neurons. Ngn1 and Ngn2 are required to
specify the cortical (regional), glutamatergic (neurotransmitter)
and laminar (temporal) characters of early-born
(lower-layer) neurons, while simultaneously repressing an
alternative subcortical, GABAergic neuronal phenotype.
Subsequently, later-born (upper-layer) cortical neurons
are specified in an Ngn-independent manner, requiring
instead the synergistic activities of Pax6 and Tlx, which
also control a binary choice between cortical/glutamatergic
and subcortical/GABAergic fates. Our study thus reveals an
unanticipated heterogeneity in the genetic mechanisms
specifying the identity of neocortical projection neurons.
Sleep improves cognition and is necessary for normal brain plasticity, but the precise cellular and molecular mechanisms mediating these effects are unknown. At the molecular level, experience-dependent synaptic plasticity triggers new gene and protein expression necessary for long-lasting changes in synaptic strength.1 In particular, translation of mRNAs at remodeling synapses is emerging as an important mechanism in persistent forms of synaptic plasticity in vitro and certain forms of memory consolidation.2 We have previously shown that sleep is required for the consolidation of a canonical model of in vivo plasticity (i.e., ocular dominance plasticity [ODP] in the developing cat).3 Using this model, we recently showed that protein synthesis during sleep participates in the consolidation process. We demonstrate that activation of the mammalian target of rapamycin [mTOR] pathway, an important regulator of translation initiation,4 is necessary for sleep-dependent ODP consolidation and that sleep promotes translation (but not transcription) of proteins essential for synaptic plasticity (i.e., ARC and BDNF). Our study thus reveals a previously unknown mechanism operating during sleep that consolidates cortical plasticity in vivo.
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 laboratoryPatients or Participants:
Cats (male and female) in the critical period
of visual development (postnatal days 28-41)Interventions:
N/AMeasurements and Results:
Zolpidem reduced cortical plasticity by
~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.
Sleep is well known to benefit cognitive function. In particular, sleep has been shown to enhance learning and
memory in both humans and animals. While the underlying mechanisms are not fully understood, it has been
suggested that brain activity during sleep modulates neuronal communication through synaptic plasticity. These
insights were mostly gained using electrophysiology to monitor ongoing large scale and single cell activity.
While these efforts were instrumental in the characterisation of important network and cellular activity during
sleep, several aspects underlying cognition are beyond the reach of this technology. Neuronal circuit activity is
dynamically regulated via the precise interaction of different neuronal and non-neuronal cell types and relies on
subtle modifications of individual synapses. In contrast to established electrophysiological approaches, recent
advances in imaging techniques, mainly applied in rodents, provide unprecedented access to these aspects of
neuronal function in vivo.
In this review, we describe various techniques currently available for in vivo brain imaging, from single
synapse to large scale network activity. We discuss the advantages and limitations of these approaches in the
context of sleep research and describe which particular aspects related to cognition lend themselves to this kind
of investigation. Finally, we review the few studies that used in vivo imaging in rodents to investigate the
sleeping brain and discuss how the results have already significantly contributed to a better understanding on
the complex relation between sleep and plasticity across development and adulthood.
It is commonly accepted that brain plasticity occurs in wakefulness and sleep. However,
how these different brain states work in concert to create long-lasting changes in brain
circuitry is unclear. Considering that wakefulness and sleep are profoundly different
brain states on multiple levels (e.g., cellular, molecular and network activation), it is
unlikely that they operate exactly the same way. Rather it is probable that they engage
different, but coordinated, mechanisms. In this article we discuss how plasticity may be
divided across the sleep?wake cycle, and how synaptic changes in each brain state are
linked. Our working model proposes that waking experience triggers short-lived synaptic
events that are necessary for transient plastic changes and mark (i.e., ?prime?) circuits
and synapses for further processing in sleep. During sleep, synaptic protein synthesis
at primed synapses leads to structural changes necessary for long-term information
Spindles are ubiquitous oscillations during non-rapid eye movement (NREM) sleep. A growing body of evidence points to a possible link with learning and memory, and the underlying mechanisms are now starting to be unveiled. Specifically, spindles are associated with increased dendritic activity and high intracellular calcium levels, a situation favourable to plasticity, as well as with control of spiking output by feed-forward inhibition. During spindles, thalamocortical networks become unresponsive to inputs, thus potentially preventing interference between memory-related internal information processing and extrinsic signals. At the system level, spindles are co-modulated with other major NREM oscillations, including hippocampal sharp wave-ripples (SWRs) and neocortical slow waves, both previously shown to be associated with learning and memory. The sequential occurrence of reactivation at the time of SWRs followed by neuronal plasticity-promoting spindles is a possible mechanism to explain NREM sleep-dependent consolidation of memories.