Biology subjects

Brindley, E.

Publications and source records attributed to Brindley, E..

6 recordsLinked to original sources

bioRxiv2026

Large-scale reorganization of DNA methylation and upregulation of extracellular matrix genes in the dorsal dentate gyrus following cocaine taking

Cocaine self-administration induces neurobiological adaptations in brain circuits involved in encoding reward-associated context. The dorsal hippocampus, particularly the dorsal dentate gyrus, plays a critical role in the precise encoding of spatial and contextual information. We hypothesized that the dentate gyrus is uniquely positioned to undergo epigenomic and transcriptomic changes because of the convergence of the contextual features of reward and cocaine-enhanced dopamine and norepinephrine signals during volitional drug-taking. We report that cocaine self-administration produces significant DNA methylation changes at an unusually large number of [~]30,000 genomic regions (>10%, q<0.01) in dentate granule cells (DGCs) of male mice. Cocaine preferentially hypomethylated regions with heterogenous methylation, switching the methylation state in [~]16% of DGCs on average. The cocaine-sensitive/responsive epigenomic regions were overrepresented in enhancers and were associated with 9,833 genes, many of which were involved in diverse functions relevant to neuronal functioning. However, among the differentially methylated genes only two regulatory genes, c-fos and cartpt (known to be activated by cocaine), and a cluster of genes encoding components of the extracellular matrix (implicated in neuroplasticity) were differentially expressed (mostly upregulated) following cocaine self-administration, suggesting a gene regulatory network that is transcriptionally robust to perturbations but still specific for context-driven and reward associated neuroplasticity in DGCs. Overall, our data demonstrates that cocaine self-administration induces epigenomic and transcriptomic changes in the dorsal dentate gyrus that may contribute to dorsal hippocampal plasticity and contextual memory associated with cocaine self-administration.

neuroscience↗

bioRxiv2025

Prenatal adversity configures a subpopulation of ventral dentate granule cells for recruitment to drive innate anxiety

Adverse prenatal environment is a risk factor for the development of psychiatric disorders. Although studies have implicated epigenetic mechanisms, little is known about how epigenomic changes come about and lead to abnormal behaviors in affected individuals. We sought to identify epigenomic and transcriptomic signatures induced by a proinflammatory gestational environment in the ventral dentate gyrus (vDG), a hippocampal region linked to avoidance of threatening contexts, that persist and promote anxiety-like behavior in mice. Here we show that adversity shifted the methylation of enhancers and promoters with intermediate methylation and altered synapse-related gene expression, resulting in epigenetic and transcriptional heterogeneity in the vDG. Exposure to an anxiogenic environment recruited vDG neurons with the most transcriptional alterations. Differentially expressed synapse-relevant genes in ensemble neurons tended to be differentially methylated. Finally, this ensemble exhibited higher activity in threatening than safe environment suggesting a prenatal adversity-induced epigenetic and neurobiological sequence that leads to anxiety.

neuroscience↗

bioRxiv2024

Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation

Protein monoaminylation is a class of posttranslational modification (PTM) that contributes to transcription, physiology and behavior. While recent analyses have focused on histones as critical substrates of monoaminylation, the broader repertoire of monoaminylated proteins in brain remains unclear. Here, we report the development/implementation of a chemical probe for the bioorthogonal labeling, enrichment and proteomics-based detection of dopaminylated proteins in brain. We identified 1,557 dopaminylated proteins - many synaptic - including {gamma}CaMKII, which mediates Ca2+-dependent cellular signaling and hippocampal-dependent memory. We found that {gamma}CaMKII dopaminylation is largely synaptic and mediates synaptic-to-nuclear signaling, neuronal gene expression and intrinsic excitability, and contextual memory. These results indicate a critical role for synaptic dopaminylation in adaptive brain plasticity, and may suggest roles for these phenomena in pathologies associated with altered monoaminergic signaling.

neuroscience↗

bioRxiv2023

Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy

The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.

neuroscience↗

bioRxiv2022

Regions with intermediate DNA methylation are epigenomic hotspots governing behavioral adaptation to changing environments

Epigenetic and associated gene expression changes in the brain drive animals ability to adapt to changing environments. However, epigenetic attributes of environmental adaptation are unknown. Here we show that exercise, unpredictable stress, and environmental enrichment, conditions that elicit adaptive changes in synaptic plasticity and spatial learning, result in CpG methylation changes in regions that exist in both methylated and unmethylated states (i.e., epigenetically bistable) in hippocampal granule cells. Sustained exposures altered both the epiallelic proportions at these regions and neuronal and behavioral adaptation, indicating their adaptive nature. These malleable regions were enriched in exons and enhancer-associated chromatin marks. Their locations were mostly unique to specific environments but converged on similar synaptic genes. Lastly, manipulating DNA methylation altered epiallelic proportions at bistable regions in granule cells and phenocopied adaptive behavior. We propose that shifts in epiallelic proportions at evolutionarily conserved bistable regions, via gene expression changes, contribute to hippocampal plasticity and behavioral adaptation to changing environments.

neuroscience↗

bioRxiv2019

Epigenetically bistable regions across neuron-specific genes govern neuron eligibility to a coding ensemble in the hippocampus

Episodic memories are stored in distributed neurons but how eligibility of individual neurons to coding ensembles is determined remains elusive. We identified thousands of predominantly bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during the development of the mouse hippocampal dentate gyrus. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromised novel context-induced neuronal activation and spatial memory. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhanced intrinsic excitability and spatial memory but impaired spatial working memory, indicating that the developmentally established methylated-unmethylated epiallelic balance at bistable regions is essential for proper neuronal excitability and hippocampal cognitive functions. Single-nucleus profiling revealed the enrichment of specific epialleles from a subset of bistable regions, primarily exonic, in encoding neurons. We propose a model in which epigenetically bistable regions create neuron heterogeneity, and specific constellations of exonic epialleles dictate, via modulating neuronal excitability, eligibility to a coding ensemble.

neuroscience↗