Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.(D) Representative spectra of LFPs recorded simultaneously from V1, SS1, CA1, and PFC. (E) Normalized group gamma power (see Figure S1C). n = 7 mice. Wilcoxon-Rank sum test; V1, Z = 5.9, p < 0.0001; SS1, Z = 2.4, p = 0.018; CA1, Z = 3.4, p < 0.0001; and PFC, Z = 3.3, p < 0.0001. (F) Raster plots of single CA1 units (labeled in different colors) with concurrently recorded LFP (band-pass filtered for 30-50 Hz) from two representative mice. (G) Spike probability of all isolated CA1 units across 40-Hz phase. (H) Phase locking strength of neuronal spikes to local LFP analyzed by mean resultant length (n = 24 cells from 4 mice. Wilcoxon-Rank sum, Z = 2.5, p = 0.011). Mean firing rate of single CA1 units did not differ between occluded (2.0 ± 0.12 Hz) and visible 40-Hz stimulation (2.1 ± 0.13 Hz) (Z = 0.55, p = 0.58). (I) LFP coherence between pairs of recording sites, as indicated, quantified using WPLI (n = 7 mice; 40-Hz visual stimulation occluded [blue] and visible [red]). (J) Group changes in low gamma band (30-50 Hz) WPLI, related to (I)

The epigenome and three-dimensional (3D) –genomic architecture are emerging as key factors in the dynamic regulation of different transcriptional programs required for neuronal functions. Here we utilize an activity-dependent tagging system in mice to determine the epigenetic state, 3D-genome architecture, and transcriptional landscape of engram cells over the lifespan of memory formation and recall. Our findings reveal that memory encoding leads to an epigenetic priming event, marked by increased accessibility of enhancers without corresponding transcriptional changes. Memory consolidation subsequently results in spatial reorganization of large chromatin segments and promoter-enhancer interactions. Finally, with reactivation, engram neurons utilize a subset of de novo long-range interactions, where primed enhancers were brought in contact with their respective promoters to up-regulate genes involved in local protein translation in synaptic compartments. Collectively, our work elucidates the comprehensive transcriptional and epigenomic landscape across the lifespan of memory formation and recall in the hippocampal engram ensemble. The formation and preservation of long-term memories depends on coordinated gene expression and synthesis of synaptic proteins 1 . These molecular processes act within a specific population of neurons, referred to as engram cells 2 – 4 . Recent approaches using activity-dependent expression of reporters, provided a framework for exploring the engram ensemble 5 – 8 , but the molecular mechanisms that govern memory storage and retrieval remain poorly understood. Specifically, epigenetic modifications and 3D -genomic architecture are emerging as a key factors in dynamic regulation of gene expression 9 – 17 , and there is an increasing appreciation of their importance in neuronal function, development and disease 14 , 16 , 18 Here, we utilized the Targeted Recombination in Active Populations (TRAP) mouse model 5 , 6 , in which activated neurons expressing the Activity Regulated Cytoskeleton Associated Protein, ( Arc ) gene, are permanently tagged in an inducible manner. Activated neurons during memory encoding, consolidation and recall were sorted and subjected to nuclear RNA sequencing (nRNA-seq), Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and chromosome conformation capture (Hi-C). Our data demonstrates that memory encoding leads to a genome-wide increase in chromatin accessibility, without expected changes in gene expression. Furthermore, we demonstrate that late phase of memory consolidation was associated with re-localization of large chromatin segments (sub-compartments) from...

Understanding the early factors affecting obesity development in males and females may help to prevent obesity and may lead to the discovery of more effective treatments for those already obese. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity is characterized by hyperphagia-induced obesity, due to a spontaneous lack of CCK(1) receptors. In the present study, we focused on the behavioral and physiological aspects of obesity development from weaning to adulthood. We examined body weight, feeding efficiency, fat pad [brown, retroperitoneal, inguinal and epydidimal (in males)] weight, inguinal adipocyte size and number, leptin and oxytocin levels, body mass index, waist circumference, and females' estrous cycle structure. In the males, central hypothalamic gene expression was also examined. OLETF rats presented overall higher fat and leptin levels, larger adipocytes, and increased waist circumference and BMI from weaning until adulthood, compared with controls. Analysis of developmental patterns of gene expression for hypothalamic neuropeptides revealed peptide-specific patterns that may underlie or be a consequence of the obesity development. Analysis of the developmental trajectories toward obesity within the OLETF strain revealed that OLETF females developed obesity in a more gradual manner than the males, presenting delayed obesity-related "turning points," with reduced adipocyte size but larger postweaning fat pads and increased adipocyte hyperplasia compared with the males. Intake decrease in estrus vs. proestrus was significantly less in OLETF vs. Long-Evans Tokushima Otsuka females. The findings highlight the importance of using different sex-appropriate approaches to increase the efficacy of therapeutic interventions in the treatment and prevention of chronic early-onset obesity.

This study aimed to determine whether epigenetic malprogramming induced by high-fat diet (HFD) has an obesogenic effect on nonmated and mated female rats and their offspring. Further, it aimed to reprogram offspring's epigenetic malprogramming and phenotype by providing normal diet after weaning. Body weight (BW) was measured, and plasma and hypothalamic arcuate nuclei were collected for analysis of hormones, mRNA, and DNA CpG methylation of the promoter of Pomc, a key factor in control of food intake. In nonmated females, HFD decreased Pomc/leptin ratio by ∼38%. This finding was associated with Pomc promoter hypermethylation. While heavier during pregnancy, during lactation HFD dams showed sharper BW decrease (2.5-fold) and loss of Pomc promoter hypermethylation. Moreover, their weight loss was correlated with demethylation (r=-0.707) and with gadd45b mRNA expression levels (r=0.905). Even though offspring of HFD dams ate standard chow from weaning, they displayed increased BW, Pomc promoter hypermethylation, and vulnerability to HFD challenge (3-fold kilocalorie intake increase). These findings demonstrate a long-term effect of maternal HFD on CpG methylation of the Pomc promoter in the offspring, which was not reprogrammed by standard chow from weaning. Further, the results suggest a possible mechanism of demethylation of the Pomc promoter following pregnancy and lactation.

Highlights d Trisomy 21 disrupts nuclear architecture and transcriptome of neural progenitors d Trisomy 21 harboring neural progenitors display signatures of cellular senescence d Senolytic drugs ameliorate trisomy-21-associated molecular and cellular dysfunctions

No abstract

A maternal high-fat diet (HFD) alters the offspring's feeding regulation, leading to obesity. This phenomenon is partially mediated by aberrant expression of the hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC). Nevertheless, although some individual offspring suffer from morbid obesity, others escape the malprogramming. It is suggested that this difference is due to epigenetic programming. In this study, we report that in lean offspring of non-HFD–fed dams, essential promoter regions for Pomc expression were enriched with 5-hydroxymethylcytosine (5hmC) together with a reduction in the level of 5-methylcytosine (5mC). Moreover, 5hmC was negatively correlated whereas 5mC was positively correlated with body weight in offspring from both HFD- and control-fed dams. We further found that Pomc expression in obese offspring is determined by a two-step epigenetic inhibitory mechanism in which CpG methylation is linked with histone posttranslational modifications. An increase in CpG methylation at the Poxmc promoter enables binding of methyl-binding domain 1 (MBD1) to 5mC, but not to its derivative 5hmC. MBD1 then interacts with SET domain bifurcated 1 methyltransferase to promote bimethylation on the histone 3 lysine 9 residue, reducing Pomc mRNA expression. These results suggest an epigenetic regulatory mechanism that affects obesity-prone or resilient traits.

Given that food is a natural reinforcement, deficits in the reward system can lead to disordered eating behavior, inducing or worsening an already existing pre-obese phenotype. In order to evaluate developmental, food-reward-related measures we used the OLETF rat, an animal model of early-onset overeating-induced obesity, and a natural CCK-1 receptor knockout. Dopamine-like-receptor type 1 (D1R) and D2R levels were examined in a reward-related brain area (Nac shell) and sucrose preference was assessed at selected time points from weaning to adulthood (postnatal day [PND]90). In addition, a group of OLETF was pair fed (PF) to the amount of food consumed by same age LETO controls (from weaning to PND90) to examine the contribution of overweight to the alteration in DR expression. In addition, we examined food “craving”-like behavior by analyzing microstructural patterns of licking a palatable liquid diet. OLETF rats expressed significantly lower D2R levels than LETO controls only on PND90. In PF OLETF, weight and D2R levels were normalized. In addition, OLETF presented exaggerated preference for the high sucrose concentration. After 30-day abstinence, OLETF rats presented significant increased initial rate of licking, suggesting food “craving”. Thus, adult OLETF rats demonstrated altered D2R signaling similar to drug-induced sensitization, suggesting a link with their avidity for sucrose and their abnormal craving response. However, the current findings of a late deficit appearance and the novel PF results suggest that deficits in the motivation/regulatory systems of the OLETF rat are a developing process (at least from weaning and on) depending on the overeating and obese phenotype of the rats and not only on the CCK mutation.