Biology subjects

Rocks, D.

Publications and source records attributed to Rocks, D..

7 recordsLinked to original sources

bioRxiv2026

Stress-induced motivational impairment is marked by diminished frontocortical cellular communication and neuropeptide signaling

BackgroundRepeated stress is a risk factor for developing motivational deficits which are common across a variety of disease states including depression and are particularly resistant to treatment with conventional pharmacotherapies. Amotivation is multifaceted and can be caused by impairments in value learning, reward anticipation, and cost-benefit decision-making. Importantly, not all individuals who experience chronic stress develop motivational symptoms, suggesting there may be neurobiological signatures of resilience. MethodsWe developed a novel head-restrained effortful reinforcement task in which anticipatory and consummatory behavior can be tracked. Chronic non-discriminatory social defeat stress combined with behavioral analysis and spatially resolved RNA sequencing were used to determine the transcriptional signatures of stress in the anterior cingulate cortex of mice with varying levels of motivational impairment as well as unstressed controls. ResultsWhile stress led to a general impairment in effortful reward seeking, animals differed in the extent of behavioral deficit, with increased susceptibility marked by a unique set of differentially expressed genes within the anterior cingulate cortex (ACC). By leveraging the spatial component of our data, we were further able to identify altered interactions from inhibitory neurons and astrocytes to excitatory pyramidal cells, which correlated with intact or impaired motivated responding following stress exposure. ConclusionsChronic psychosocial stress results in divergent effects on motivated behavior and distinct ACC transcriptional signatures that are concentrated in excitatory pyramidal neurons. Cell interaction analysis implicates enhanced inhibitory neuropeptide signaling and reduced astrocytic contact signaling as upstream markers of motivational resilience and point toward ACC hyperexcitability as a targetable feature of stress susceptibility.

neuroscience↗

bioRxiv2026

Single-cell map of the female brain across reproductive transitions

Ovarian hormone shifts enable reproduction and are associated with substantial brain plasticity and disease risks. While imaging studies provide (micro)structural insights into brain changes across the ovarian cycle and pregnancy, the high resolution, single-cell map of the brain across reproductive transitions is missing. Here, we performed multiome (gene expression and chromatin accessibility) analysis of the mouse ventral hippocampus (vHIP) across sex, estrous cycle, and peripartum period at single cell resolution. We identify dynamic changes in vHIP cellular composition across the estrous cycle and pregnancy, including in the neural stem cells of the dentate gyrus (DG), enabling hormone-driven neurogenesis. Major gene expression changes are neuronal function-relevant, cell type-specific, and found in excitatory neurons of CA1, CA3, and DG subfields, across sex and reproductive transitions. In contrast, chromatin accessibility changes are more extensive and found across cell types, likely driven by estrogen level shifts in both within-female and between-sex comparisons. We show that chromatin remodeling during the estrous cycle primes the genome for gene expression changes during pregnancy and is also enriched for brain disease-relevant genes. Finally, we reveal a thyroid hormone transporter (Transthyretin, Ttr) gene as the major candidate gene that drives structural and behavioral changes across the estrous cycle and pregnancy. Our study provides an extensive cellular and molecular view of how reproductive transitions shape the brain and opens the possibility to target downstream targets of estrogen, including thyroid hormone signaling, as a treatment option for hormone-sensitive periods in women.

neuroscience↗

bioRxiv2023

Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Sex differences are found in brain structure and function across species, and across brain disorders in humans1-3. The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan4. Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk5-7. However, due to limited molecular studies in female rodents8, very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that overexpressing Egr1, a candidate oestrous cycle-dependent transcription factor9, induces sex-specific changes in ventral hippocampal neuronal chromatin, gene expression, and synaptic plasticity, along with hippocampus-dependent behaviours. Importantly, Egr1 overexpression mimics the high-oestrogenic phase of the oestrous cycle, and affects behaviours in ovarian hormone-depleted females but not in males. We demonstrate that Egr1 opens neuronal chromatin directly across the sexes, although with limited genomic overlap. Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation1 in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.

neuroscience↗

bioRxiv2023

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here we reveal molecular substrates in the key reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine in mice. We find shared involvement of X chromosome and estrogen signaling gene regulation in enhanced conditioning responses seen after early-life stress and during the low-estrogenic state in females. During the low-estrogenic state, females respond to acute cocaine exposure by increasing the accessibility of neuronal chromatin enriched for the binding sites of {Delta}FosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential closing of neuronal chromatin, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, exposure to early-life stress, and absence of the second X chromosome all nullify the protective effect of high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to understand sex-specific neuronal mechanisms underlying cocaine use disorder.

neuroscience↗

bioRxiv2021

Sex-specific multi-level 3D genome dynamics in the mouse brain

The female mammalian brain exhibits sex-hormone-driven plasticity during the reproductive period. Evidence implicates chromatin dynamics in gene regulation underlying this plasticity. However, whether ovarian hormones impact higher-order chromatin organization in post-mitotic neurons in vivo is unknown. Here, we mapped 3D genome of ventral hippocampal neurons across the estrous cycle and by sex in mice. In females, we found cycle-driven dynamism in 3D chromatin organization, including in estrogen-response-elements-enriched X-chromosome compartments, autosomal CTCF loops, and enhancer-promoter interactions. With rising estrogen levels, the female 3D genome becomes more similar to the male genome. Cyclical enhancer-promoter interactions are partially associated with gene expression and enriched for brain disorder-relevant genes. Our study reveals unique 3D genome dynamics in the female brain relevant to female-specific gene regulation, neuroplasticity, and disease risk.

neuroscience↗

bioRxiv2020

Cell Type-Specific Chromatin Accessibility Analysis in the Mouse and Human Brain

The Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) is becoming increasingly popular in the neuroscience field where chromatin regulation is thought to be involved in neurodevelopment, activity-dependent gene regulation, hormonal and environmental responses, and the pathophysiology of neuropsychiatric disorders. The advantages of using this assay include a small amount of material needed, relatively simple and fast protocol, and the ability to capture a range of gene regulatory elements with a single assay. However, with increasing interest in chromatin research, it is an imperative to have feasible, reliable assays that are compatible with a range of neuroscience study designs in both animals and humans. Here we tested three different protocols for neuronal chromatin accessibility analysis, including a varying brain tissue freezing method followed by fluorescent-activated nuclei sorting (FANS) and the ATAC-seq analysis. Our study shows that the cryopreservation method impacts the number of open chromatin regions that can be identified from frozen brain tissue using the cell-type specific ATAC-seq assay. However, we show that all three protocols generate consistent and robust data and enable the identification of functional regulatory elements, promoters and enhancers, in neuronal cells. Our study also implies that the broad biological interpretation of chromatin accessibility data is not significantly affected by the freezing condition. In comparison to the mouse brain analysis, we reveal the additional challenges of doing chromatin analysis on post mortem human brain tissue. However, we also show that these studies are revealing important cell type-specific information about gene regulation in the human brain. Overall, the ATAC-seq coupled with FANS is a powerful method to capture cell-type specific chromatin accessibility information in the mouse and human brain. Our study provides alternative brain preservation methods that generate high quality ATAC-seq data while fitting in different study designs, and further encourages the use of this method to uncover the role of epigenetic (dys)regulation in healthy and malfunctioning brain.

neuroscience↗

bioRxiv2019

Sex and Estrous Cycle Effects on Anxiety- and Depression-related Phenotypes in Two-hit Developmental Stress Model

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c, that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders.

neuroscience↗