bioRxiv Subject Collection: Neuroscience's Journal

Investigating the role of cortical microglia in a mouse model of viral infection-induced seizures
Microglia, resident immune sentinels in the brain, are crucial in responding to tissue damage, infection, damage signals like purines (ATP/ ADP), and clearing cellular debris. It is currently unknown how microglial reactivity progresses and contributes to seizure development following Theilers Murine Encephalomyelitis Virus (TMEV) infection. Previously, our group has demonstrated that purinergic signaling in microglia is disrupted in the hippocampus of TMEV-infected mice. However, whether reactive cortical microglia also exhibit changes in purinergic signaling, cytokine levels, and purinergic receptors are unknown. Thus, we seek to evaluate region-based differences in microglial reactivity in the TMEV model. We employed a custom triple transgenic mouse line expressing tdTomato and GCaMP6f under a CX3CR1 Cre promoter and exogenously applied ATP/ADP to acute brain slice preparations from TMEV-infected mice and controls. Interestingly and in contrast to what is observed in hippocampus, we found that despite microglial reactivity in the cortex, microglia can respond to purinergic damage signals and engage calcium signaling pathways, comparable to PBS controls. Using a cytokine panel, we also found that pro-inflammatory cytokine levels (TNF-, IL-1 and IFN-{gamma}) are brain-region dependent in mice infected with TMEV. Using RNAScope-FISH, we observed increases in expression of purinergic receptors responsible for microglial motility (P2Y12R) and inflammation (P2X7R) in the cortex. Collectively our results suggest that following TMEV infection, microglial response to novel damage signals, as well as the production of proinflammatory cytokines, varies as a function of brain region.

Learning to blink strategically is crucial to performance in a predictable saccade task and varies across the lifespan
Humans blink their eyes 16-20 times each minute to spread tear film on the cornea, representing a substantial amount of waking time when one's eyes are closed. These spontaneous blinks are strategically timed to prioritize the processing of important visual input, balancing both stimulus characteristics and personal goals. Until now, the learning process underlying optimal blink timing has not been investigated in detail. Here, we present video-based eye-tracking data from 703 healthy participants (aged 5-91 years, 470 female) performing a structured interleaved pro-/anti-saccade task, in which we previously found that blink suppression occurs in anticipation of visual stimulus appearance (Pitigoi et al., 2024). Our goals are to understand (1) how participants modify their blink timing according to the temporal contingencies of the task; (2) whether the capacity to optimize blink timing impacts performance; and (3) whether this pattern varies with age. We found that participants quickly and strategically modified their blink distribution to optimize task performance. Blink probability decreased in periods that would compromise anti-saccade execution and increased when visual input was less critical. We also found significant differences in blink patterns and adaptive ability based on cognitive control capacity (indicated by participants' anti-saccade error rates). Furthermore, we demonstrated that blink optimization improves gradually from childhood to early adulthood, before declining with advanced age. This supports a possible link between regulation of blink behavior and age-related changes in learning capacity and inhibitory control across the lifespan.

ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation
Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including neural precursor hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.

PH sensitivity of cerebrospinal fluid-contacting neurons involves the modulation of phasic and tonic currents mediated by PKD2L1 channels located in the apical process.
Cerebrospinal fluid contacting neurons (CSFcNs) are GABAergic cells that surround the central canal (CC) of the spinal cord. Their soma is located sub-ependymally and they have a dendritic-like process that ends as a bulb (the so-called apical process; ApPr) inside the CC. It remains unclear how this unique anatomical organization, with the soma and the ApPr located in different extracellular environments, relates to their function as a multimodal sensor of cerebrospinal fluid (CSF) composition. One of the main physiological features of CSFcNs is a prominent spontaneous electrical activity mediated by PKD2L1 (or TRPP2) channels, a non-selective cation channel of the TRP family. PKD2L1 channels have a high single-channel conductance (around 200 pS) and can be modulated by protons and mechanical forces. In this work we investigate PKD2L1 channel sensitivity to pH and its effects on CSFcNs excitability. We demonstrate that PKD2L1 spontaneous activity generates not only phasic inward currents, but also a tonic current, both of which are modulated bidirectionally by pH with a high sensitivity around physiological values. By combining electrophysiology (direct recordings from intact and isolated ApPrs) with optical methods (laser-photolysis of protons) we further show that functional PKD2L1 channels are specifically localized in the ApPr. The spatial segregation of PKD2L1 channels, along with their biophysical properties (high single-channel conductance and pH sensitivity) and the ApPr's unique membrane properties (very high input resistance) renders CSFcN excitability exquisitely sensitive to PKD2L1 modulation. Altogether, our findings illustrate how the ApPr's properties are finely tuned to support its sensory role.

Decoding Amyloid Plaque Penetrability: Exploring Extracellular Space and Rheology2in Plaque-rich Cortex
A hallmark of Alzheimer's disease (AD) is the accumulation of amyloid plaques, primarily composed of misfolded amyloid {beta} (A{beta}) peptides. We employed complementary high-resolution imaging techniques to investigate the plaque penetrability and the extracellular space (ECS) rheology in a mouse model of AD. Two-photon shadow imaging in vivo confirmed that a dense ring of cells surrounds cortical amyloid plaques but highlighted the diffusional penetrability of the amyloid core. Quantum dot tracking unveiled that ECS diffusional parameters are heterogeneous in and around plaques, with an elevated diffusivity within and around plaques compared to WT-tissue. The amyloid core showed low nanoparticle density, varying by plaque phenotype. Carbon nanotube tracking confirmed these altered local rheological properties at the level of the whole cortex of AD mice. Finally, we found the extracellular matrix to be dysregulated within the amyloid plaque, which may account for the observed alterations in diffusivity. Our study provides fresh insights for understanding A{beta} plaque penetration, a prerequisite for therapeutic development

Multi-omics Profiling of the Lateral Ventricle Choroid Plexus Reveals Developmental Cellular Remodeling, Early Immune Gene Activation, and a Novel Epithelial Subtype
Healthy brain development and function highly depend on the choroid plexus. Temporal alterations in the cellular landscape and gene expression of choroid plexus cells can alter immune cell trafficking in the brain and cerebrospinal fluid composition, ultimately impacting brain dynamics. Here, we performed a comprehensive multi-omics analysis - including bulk and single-cell transcriptomics and epigenomics - of the lateral ventricle choroid plexus across early postnatal and adult stages in mice and rats. We uncovered striking changes in the choroid plexus cellular composition from neonatal to adult stages, accompanied by transcriptional remodeling of all main cell types. Immune cells were markedly increased in adulthood and immune cell profiling revealed an altered cell-type diversity through time. Surprisingly, we observed an early gene activation of host-defense genes in all choroid plexus main cell types, beginning in the neonatal period and progressively increasing into young adulthood. Moreover, some genes induced in epithelial cells in response to inflammation were found to be epigenetically primed, despite not being transcriptionally active. Epithelial cells exhibited subtype diversity and plasticity, with distinct gene expression programs and chromatin accessibility profiles emerging over time. Notably, we identified a novel epithelial cell subtype with unique gene markers suggesting a specialized function potentially linked to neuro-signaling. Ligand-receptor interaction analysis revealed a progressive remodeling of cellular crosstalk networks during choroid plexus maturation, suggesting dynamic intercellular signaling as the tissue develops. Our study offers a comprehensive atlas of transcriptional activity and chromatin accessibility in choroid plexus cells, providing a valuable resource to guide future efforts in targeting gene expression at the choroid plexus for therapeutical purposes.

Glia cells are selectively sensitive to nanosized titanium dioxide mineral forms
Nanosized titanium dioxide is widely used by the industry e.g. in pigments, suncreams and food colors. Its environmental and biological effects have been investigated in the past, however, few studies have focused on its crystal structure-specific effects. In our experiments, the toxicity of two types of nanoparticles was examined on primary neural cultures with different cell-compositions, using MTT and LDH assays. Primary murine cell cultures containing only astroglia cells originated from two brain regions, as well as mixed neurons and glia cells or microglia cells exclusively, were treated with anatase and rutile TiO2 nanoparticles at varying concentrations for 24 or 48 hours. Our results show that neither anatase nor rutile nanoparticles reduced viability in cell cultures containing a mixture of neurons and glial cells, independently of the applied concentration and treatment time. Rutile but not anatase form induced cell death in cortical astroglia cultures already at 24 hours of treatment above 10 g/mL, while hippocampus-derived glial cultures were much less sensitive to rutile. The rutile form also damaged microglia. These findings suggest that products containing rutile-form nano-titanium particles may pose a targeted risk to astroglia and microglial cells in the central nervous system.

Muscle transcriptome profiling reveals novel molecular pathways and biomarkers in laminin-α2 deficient patients
Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is caused by LAMA2 gene mutations, coding for laminin-211 (merosin) 2 subunit. LAMA2 mutations leading to complete laminin-211 absence result in an invariably severe clinical phenotype, with profound muscle weakness and respiratory insufficiency. Milder phenotypes are often associated with mutations allowing the production of a partially functional protein. While several dysregulated genes/pathways linked to LAMA2-RD muscle loss are known, an in-depth characterization of LAMA2-RD muscle gene expression profile in patients with mutations differentially affecting LAMA2 expression is lacking. We generated muscle transcriptomic data from patients with either complete or partial laminin-211 deficiency, and identified pathways linked to the most dysregulated processes. Genes related to fibrosis, inflammation and metabolism were similarly expressed in both patient cohorts. However, a subset of novel pro-fibrotic and pro-inflammatory genes were exclusively expressed in patients (and mice) completely lacking laminin-211, indicating aspects exacerbated in this cohort. Our work characterizes the main contributors of human LAMA2-RD pathology, providing insight into molecular pathways that could be used as disease biomarkers or as targets for therapeutic approaches.

The Contribution of Circulating Endocannabinoid Tone to Individual Differences in Human Pain Sensitivity: A Quantitative Sensory Testing Study
The endocannabinoid (eCB) system--comprising cannabinoid receptors, eCBs (anandamide--AEA, 2-arachidonoylglycerol--2-AG) and related N-acylethanolamines (NAEs; N-palmitoylethanolamide--PEA, and N-oleoylethanolamide--OEA), and metabolizing enzymes (e.g., fatty acid amide hydrolase; FAAH)--modulates nociceptive circuits in rodents. In humans, the FAAH C385A polymorphism is associated with reduced pain sensitivity, suggesting eCB tone influences individual pain differences, but this has yet to be tested. Here, we determined whether the eCB system is associated with somatosensory and pain sensitivity measured with quantitative sensory testing (QST) in 91 healthy participants (39 males, 52 females). We tested three hypotheses: (1) FAAH C385A polymorphism, cannabis use, and sex affect serum eCB/NAE concentrations; (2) FAAH C385A carriers show altered pain sensitivity versus non-carriers; and (3) baseline serum eCB/NAE concentrations are associated with QST measures. eCB/NAE concentrations were not statistically different based on sex (p > .05), based on FAAH genotype (p > .05), and based on cannabis use (p > .05). To address collinearity of AEA, OEA and PEA in linear regression analyses, we performed a factor analysis with principal components analysis, which identified a single component of FAAH substrates. Linear regressions found that FAAH genotype did not affect QST measures and that baseline 2-AG and FAAH substrate concentrations were not associated with QST measures, except pressure pain thresholds (PPT; p = 0.003), which were associated with AEA and OEA. Baseline eCB/NAE levels may not be a global predictor of QST somatosensory and pain tests in healthy adult humans; nonetheless, circulating FAAH substrate levels were associated with PPT.

Alpha-synuclein overexpression triggers divergent cellular responses and post-translational modifications in SH-SY5Y and ReNcell VM models
Alpha-synuclein (-syn) overexpression models are widely used to unravel the molecular mechanisms of Parkinsons disease (PD), particularly in light of the dose-dependent transition between its physiological and toxic roles. However, existing systems rely on inducible expression, lack robust dose stratification and comparative cellular contexts. Here, we developed and characterized a panel of stable neuronal cell lines in two human cellular models (SH-SY5Y neuroblastoma cells and ReNcell VM neural progenitors) overexpressing GFP-tagged wild-type (WT) or A53T mutant -syn at low and high overexpression levels. Utilizing this framework, we demonstrated that A53T consistently induces cytotoxicity, oxidative stress and mitochondrial dysfunction in both cell types. In contrast, WT -syn had divergent effects depending on the cellular context. In SH-SY5Y cells, it enhanced mitochondrial function and viability, whereas in ReNcell VM cells, the same protein triggered mitochondrial impairment and elevated oxidative stress. This opposing metabolic response was reflected in increased respiratory activity in SH-SY5Y cells and a marked decline across WT -syn overexpressing ReNcell VM. Importantly, post-translational modification (PTM) landscape of overexpressed WT -syn varied dramatically by cell type. ReNcell VM cells exhibited more robust modifications signatures, even in the absence of overt aggregation, which highlights a cell-type-specific PTM landscape that may contribute to differential vulnerability. Our findings underscore a complex interplay between -syn dosage, mutational status, cellular environment, and PTM profiles highlighting that neuronal vulnerability in PD is context-dependent. This work establishes a modular in vitro platform for dissecting -syn pathology and testing targeted therapeutic strategies grounded in cell-type specificity.

Multiplexed changes in synaptic transmission underlie stress-induced reduction of persistent firing in the parietal cortex
Repeated exposure to stress disrupts cognitive processes, including attention and working memory. A key mechanism supporting these functions is the ability of neurons to sustain action potential firing, even after a stimulus is no longer present. How stress impacts this persistent neuronal activity is currently unknown. We found that repeated exposure to multiple concurrent stressors during adolescence (aRMS) impedes the ability of layer 5 pyramidal neurons (L5 PNs) in the posterior parietal cortex (PPC) to produce persistent firing. To determine the mechanisms underlying this effect, we complemented computational modelling with whole-cell patch clamp electrophysiology in acute brain slices from male mice. Our model predicted that altered intrinsic excitability, reduced local connectivity, diminished glutamatergic transmission, or enhanced inhibition could explain diminished persistent activity. In ex vivo experiments, we found minimal effect of aRMS on excitability and recurrent connectivity. However, stress exposure altered the properties of excitatory connections between L5 PNs, specifically affecting decay kinetics and short-term synaptic dynamics. In addition, aRMS increased inhibitory tone in the PPC, altering both GABAa and GABAb receptor-mediated responses. Incorporating the observed physiological changes into our network model, we found that no single parameter was sufficient alone to reproduce the stress-induced reduction in persistent firing. Rather, a combination of altered excitatory and inhibitory synaptic transmission was necessary to impact sustained activity. These data suggest that a multitude of converging changes in neural and circuit function underpin the effects of stress on cognitive processes.

PINK1 regulates cholesterol homeostasis via SCAP phosphorylation in human dopaminergic neurons
Cholesterol is a key lipid enriched in neuronal membranes and essential for signaling and synaptic transmission. An imbalance in cholesterol levels may affect synaptic plasticity and contribute to neurodegeneration. Here, we identify in human dopaminergic neurons a mechanism linking loss of function of the Parkinson's disease (PD) gene PINK1 to altered cholesterol homeostasis. Loss of functional PINK1 impaired SCAP phosphorylation at Ser822 and Ser838, stabilizing SCAP and driving excess cholesterol biosynthesis. Cholesterol accumulated at the plasma membrane and in flotillin-rich lipid rafts, causing reduced neurotransmitter uptake and altering the distribution of dopamine transporter (DAT). Restoring PINK1 expression normalized cholesterol biosynthesis and levels. Moreover, the cholesterol-lowering drugs simvastatin and {beta}-cyclodextrin rescued DAT distribution and neurotransmitter uptake defects. These findings demonstrate that PINK1 influences cholesterol homeostasis through SCAP phosphorylation at Ser822 and Ser838 and that restoring cholesterol levels mitigates phenotypes observed in PINK1 PD neurons. These findings further highlight the cross-talk between mitochondria and lipid homeostasis in PD models, underscoring the relevance of cholesterol levels to dopaminergic functions.

Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity
The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.

The Role of Video Game Practice in Trial-by-Trial Adaptation, Consolidation, and Reinforcement Learning Biases
This study examined whether habitual video game play influences reinforcement learning dynamics, feedback adaptation, consolidation, and motivational biases. Two groups of participants (gamers and controls) completed a Probabilistic Selection Task assessing learning from positive and negative feedback across three phases: learning, test, and transfer. Mixed-effects modeling revealed that gamers showed enhanced learning trajectories, particularly under high-uncertainty conditions, greater sensitivity to accumulated rewards, and a more exploitative decision pattern compared to controls. In the test phase, gamers demonstrated higher accuracy, especially on difficult stimulus pairs, suggesting superior consolidation of probabilistic value representations. However, no group differences emerged in transfer-phase approach/avoidance biases or decision consistency. These findings suggest that habitual video game experience enhances dynamic feedback integration and value updating in uncertain contexts, but does not alter stable reinforcement learning biases. Results have implications for leveraging game-like environments to enhance adaptive learning strategies in educational and clinical settings.

Cyclin-dependent kinase-like 5 (CDKL5) binds to talin and is anchored at the postsynaptic density via direct interaction with PDZ domains
Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine kinase essential for brain development and function. Mutations in the CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe early-onset epileptic encephalopathy characterised by defects in synapse formation and function. Despite extensive research, the molecular mechanisms by which CDKL5 mutations disrupt synaptic function and lead to epilepsy remain unclear. Here, we report that the major neuronal isoform of CDKL5 contains a C-terminal PDZ domain-binding motif. We demonstrate that this motif mediates interactions with the PDZ domains of PSD-95 and SHANK proteins, facilitating the recruitment of CDKL5 to the postsynaptic density. Disruption of CDKL5's PDZ-binding motif results in its mislocalisation and impaired spine formation. Additionally, we show that CDKL5 directly interacts with the mechanosensitive synaptic scaffold protein talin, via the N-terminal kinase domain of CDKL5 and the R8 rod domain of talin. Our findings establish how CDKL5 is targeted to synapses and suggest that its activity may be spatially regulated through talin-mediated mechanical signalling. We propose that the spatial positioning of the CDKL5 kinase domain might be mechanically-operated and regulated by talin domain unfolding. As talin undergoes structural transitions in its force-dependent binary switch domains, the kinase domain bound to R8 would be moved up and down within the synaptic compartment as a function of the changing talin conformation. These insights enhance our understanding of the pathogenic mechanisms underlying CDKL5 variants with premature stop codons and highlight the need to re-evaluate studies that have used C-terminally tagged or the non-PDZ-binding isoform of CDKL5 to assess its neuronal function.

Sex-dependent interferon signaling drives female-biased vulnerability in Alzheimer's disease
Despite extensive efforts to understand Alzheimer's disease (AD), the biological basis for its greater burden in women remains unclear. We identified a sex-dependent activation of type I interferon (IFN-I) signaling as a contributor to this disparity. Transcriptomic profiling of brain from AD patients revealed selective enrichment of IFN-I pathway in females. This immune signature was mirrored in the APP/PS1 mouse model of AD, where females exhibited more pronounced amyloid accumulation, neuroinflammation, and neurodegeneration. Acute IFN-I activation reproduced pathological features of AD, whereas chronic IFN-I elevation in APP/PS1 mice aggravated disease progression. In contrast, pharmacological targeting of IFN-I response by inhibiting the cGAS-STING pathway in APP/PS1 female mice reduced neuropathological burden, and preserved cognitive performance. Together, these findings identify interferon signaling as a modifiable and sex-linked driver of AD pathology. Our study uncovers a critical neuroimmune mechanism contributing to female-biased vulnerability and highlights interferon modulation as a promising therapeutic strategy in AD.

Microglial activation and alpha-synuclein oligomers drive the early inflammatory phase of Parkinson's disease
Parkinson's disease (PD) is characterised by insoluble -synuclein (Syn) aggregates in Lewy bodies (LBs) within the substantia nigra, with cortical pathology appearing as the disease progresses. Late-stage LB deposition, cellular stress, and neuronal loss obscure disease-driving events, we therefore performed multi-regional transcriptomic and aggregate profiling in early-midstage PD brains (Braak 3-4), where cortical regions are pathologically unaffected. We report neuroimmune activation as an early PD feature, characterised by the expansion of a high-SNCA-expressing microglial state. This robust immune signature occurs prior to LB formation, but is associated with oligomeric Syn within cortical microglia. In hiPSC-derived microglia, both endogenous Syn oligomerisation, and exogenous oligomer uptake, trigger transcriptional reprogramming, characterised by interferon-driven inflammation, antigen presentation, and mitochondrial suppression, closely mirroring the early PD brain. These findings describe mechanisms by which Syn oligomerisation potently initiates early neuroinflammation, highlighting a critical interplay between proteinopathy and immune activation at the earliest stages of disease.

Brief sleep disruption following hippocampus-dependent learning downscales interneuron synapses within lateral entorhinal cortex
Brief sleep loss alters cognition and the activity and synaptic structures of both principal neurons and interneurons in hippocampus. However, although sleep-dependent coordination of activity between hippocampus and neocortex is essential for memory consolidation, much less is known about how sleep loss affects neocortical input to hippocampus, or excitatory-inhibitory balance within neocortical structures. We aimed to test how the synaptic structures of SST interneurons in lateral and medial entorhinal cortex (LEC and MEC), which are the major neocortical input to hippocampus, are affected by brief sleep disruption in the hours following learning. We used Brainbow 3.0 to label SST interneurons in the LEC or MEC of male SST-IRES-Cre transgenic mice. We then compared synaptic structures in labeled neurons after single trial contextual fear conditioning (CFC) followed by either a 6-h period of ad lib sleep, or gentle handling sleep deprivation (SD), focusing on cortical layers providing input to hippocampus. Dendritic spine density among EC SST interneurons was altered in a subregion-specific manner, with dramatic alterations in dendritic spine type distributions and reductions in spine size in LEC, but not MEC, after post-CFC SD. Our data suggest that the synaptic connectivity of SST interneurons is significantly reduced in LEC when learning is followed by sleep disruption. This suggests that post-learning sleep loss disrupts hippocampus-dependent memory processing in part through altered excitatory-inhibitory balance in neocortical structures providing input to hippocampus. They also provide more mechanistic insight into sleeps role in coordinating neocortical-hippocampal communication in the context of memory consolidation.