Christopher J. Davis

Alzheimer’s disease (AD) is a complex neurodegenerative disorder where age, genetic factors and sleep disturbance significantly influence disease risk. Recent genome-wide association studies identified a C/T missense variant (rs141749679) in the sortilin (SORT1) gene linked to heightened AD risk, revealing SORT1’s role as a key player in the disease’s pathophysiology. This type I membrane glycoprotein is implicated in amyloid β (Aβ) accumulation and associated lipid dysregulation, particularly through its interaction with apolipoprotein E (ApoE). SORT1 facilitates the uptake of ApoE-bound polyunsaturated fatty acids (PUFAs), conversion to endocannabinoids (eCBs), and the regulation of anti-inflammatory pathways via peroxisome proliferator-activated receptors (PPARs). Notably, this neuroprotective signaling is contingent on the APOE allele, exhibiting functionality in presence of ApoE3 but disrupted with ApoE4. Additionally, the brain-type fatty acid binding protein, FABP7, mediates this signaling cascade, emphasizing its role in neuron-glia communication. FABP7 is known to regulate sleep across species and binds PUFAs and eCBs. Therefore, dysfunction of the ApoE-SORT1-FABP7 axis may underlie the neuroprotective loss observed in AD, linking sleep disruption and lipid homeostasis to disease progression. This perspective aims to elucidate the intricate neural-glial mechanisms governing the ApoE-SORT1-FABP7 interaction and their implications for targeting therapeutic interventions in Alzheimer’s disease.

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression.

In this perspectives piece we examine the role of dreaming in memory consolidation, the underlying neurobiological mechanisms of nightmares and the therapeutic potential of lucid dreaming for treating nightmares. Growing evidence suggests that dream content is shaped by both recent and remote memory sources, with non-rapid eye movement (NREM) sleep favoring the incorporation of recent declarative memories and REM sleep reflecting more remote experiences. When these dreams become pathological, we examine nightmares through the lens of the neurocognitive model, and focus on how nightmares affect mental health. We then explore lucid dreaming as a promising intervention to combat nightmares. Our conclusions claim that definitional ambiguity in dream research limits clinical progress, and we propose action to develop standardized definitions for dreaming and nightmares to guide cohesive research designs and enhance interstudy comparability.

Epileptic seizures often track with time of day and/or changes in vigilance state; however, specific molecular and cellular mechanisms driving the ictal and temporal associations are lacking. Astrocytes are a type of glial cell known to modulate neuronal excitability and circadian rhythms. These cells also abundantly express fatty acid–binding protein 7 (Fabp7), a clock-driven molecule necessary for normal sleep regulation, lipid signaling, and gene transcription. To determine whether Fabp7 influences time-of-day-dependent seizure susceptibility, we tested male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice using electroshock seizure threshold. Compared with WT mice, Fabp7 KO mice exhibited markedly higher general- and maximal-electroshock seizure thresholds (GESTs and MESTs, respectively) during the dark phase, but not the light phase. We used RNA-seq to determine the role of Fabp7 in activity-dependent gene expression in nocturnal seizures and compared genome-wide mRNA expression in cortical/hippocampal tissue collected from WT-MEST and Fabp7 KO-MEST mice with WT-SHAM and Fabp7 KO-SHAM mice during the dark period. Whereas significant differential expression of immediate early genes was observed in WT-MEST compared with WT-SHAM, this effect was blocked in the Fabp7 KO-MEST versus Fabp7 KO-SHAM. Gene ontology and pathway analysis of all groups revealed significant overlap between WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, suggesting basal mRNA levels of core molecular and cellular mechanisms in the brain of Fabp7 KO approximate postictal WT brain. Together, these data suggest that Fabp7 regulates time-of-day-dependent neural excitability and that neural activity likely interacts with astrocyte Fabp7-mediated signaling cascades to influence activity-dependent gene expression.

Epileptic seizures are often influenced by time-of-day and changes in vigilance state, yet the molecular and cellular mechanisms underpinning these associations remain poorly understood. Astrocytes, a pivotal type of glial cell, play a critical role in modulating neuronal excitability and circadian rhythms, and they express Fatty Acid Binding Protein 7 (Fabp7), a molecule vital for sleep regulation, lipid signaling, and gene transcription. This study investigates the role of Fabp7 in determining time-of-day dependent seizure susceptibility. We assessed electroshock seizure thresholds in male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice. Results demonstrated that, compared to WT mice, Fabp7 KO mice displayed significantly elevated general and maximal electroshock seizure thresholds (GEST and MEST) during the dark phase, but not during the light phase. To explore the impact of Fabp7 on activity-dependent gene expression during seizures, we conducted RNA sequencing (RNA-seq) on cortical and hippocampal tissues from WT and Fabp7 KO mice following MEST and SHAM procedures during the dark period. While immediate early genes (IEGs) showed considerable differential expression between WT-MEST and WT-SHAM, this expression was absent in Fabp7 KO-MEST compared to Fabp7 KO-SHAM. Gene ontology analyses revealed significant overlaps between the WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, indicating that the basal mRNA expression profiles in Fabp7 KO brains resemble those of WT brains in a post-ictal state. Collectively, these findings suggest that Fabp7 is a key regulator of time-of-day dependent neural excitability and that astrocyte-mediated signaling pathways involving Fabp7 interact with neuronal activity to influence gene expression in response to seizures. Significance Statement: Changes in sleep/wake state and/or circadian time-of-day are thought to influence neural excitability, which may confer seizure susceptibility. Here we describe a role for astrocytic Fabp7 in regulating nocturnal seizure threshold and gene expression associated with differences in seizure susceptibility, introducing an astrocyte factor that may represent a novel antiepileptic target for drug development.

Telomeres shorten with each cell division, serving as biomarkers of aging, with human tissues exhibiting short telomeres and restricted telomerase expression. In contrast, mice have longer telomeres and widespread telomerase activity, limiting their relevance as models for human telomere biology. To address this, we engineer a mouse strain with a humanized mTert gene (hmTert), replacing specific non-coding sequences with human counterparts. The hmTert gene, which is repressed in adult tissues except the gonads and thymus, closely mimics human TERT regulation. This modification rescues telomere dysfunction in mTert-knockout mice. Successive intercrosses of Tert^h/- mice stabilized telomere length below 10 kb, while Tert^h/h mice achieve a human-like average length of 10–12 kb, compared to 50 kb in wildtype mice. Despite shortened telomeres, Tert^h/h mice maintain normal body weight and cell homeostasis. These mice, with humanized telomere regulation, represent a valuable model to study human aging and cancer.

Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene. Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Tert^h/- mice, telomere length progressively declined, stabilizing below 10-kb. Tert^h/h mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert^h/h mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres. Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.

Corrigendum: Image discrimination reversal learning is impaired by sleep deprivation in rats: Cognitive rigidity or fatigue?

Introduction: Insufficient sleep is pervasive worldwide, and its toll on health and safety is recapitulated in many settings. It is thus important to understand how poor sleep affects the brain and decision making. A robust literature documents the adverse effects of sleep deprivation on cognitive processes including cognitive flexibility, which is the capacity to appraise new feedback and make behavioral adjustments to respond appropriately. Animal models are often used to unravel the molecules, genes and neural circuits that are altered by sleep loss. Herein we take a translational approach to model the effects of sleep deprivation on cognitive rigidity, i.e., impaired cognitive flexibility in rats.Methods: There are several approaches to assess cognitive rigidity; in the present study, we employ a pairwise discrimination reversal task. To our knowledge this is the first time this paradigm has been used to investigate sleep deprivation. In this touchscreen operant platform, we trained rats to select one of two images to claim a sucrose pellet reward. If the non-rewarded image was selected the rats proceeded to a correction trial where both images were presented in the same position as before. This image presentation continued until the rat selected the correct image. Once rats reached performance criteria, the reward contingencies were reversed. In one group of rats the initial reversal session was preceded by 10 h of sleep deprivation. We compared those rats to controls with undisturbed sleep on the number of sessions to reach performance criteria, number of trials per session, response latencies, correct responses, errors, perseverative errors and perseveration bouts in the initial training and reversal phases.Results: We report that on reversal session one, sleep deprived rats completed a fraction of the trials completed by controls. On subsequent reversal sessions, the sleep deprived rats struggled to adapt to the reversed contingencies despite completing a similar number of trials, suggesting an effect of cognitive rigidity separate from fatigue.Discussion: We discuss the delayed performance dynamics incurred by sleep loss in the context of fatigue and the implications of using pairwise discrimination reversal as a model to further examine the effects of sleep loss on adaptive decision making.