Biology subjects

Seney, M. L.

Publications and source records attributed to Seney, M. L..

14 recordsLinked to original sources

bioRxiv2026

Sex differences in cell type-specific transcriptional programs and GPCR signaling in the human subgenual anterior cingulate cortex

Psychiatric conditions show marked sex differences in disease onset, symptom presentation, and response to treatments. Understanding how sex differences manifest across molecularly distinct neuronal populations in individuals without psychiatric conditions may help explain sex-dependent variation in neural circuit function and treatment response. Here, we examined molecularly distinct cell types within the subgenual anterior cingulate cortex (sgACC) of non-psychiatric subjects. Using RNA sequencing data previously generated from laser-capture microdissected neurons, we investigated sex differences in gene expression and co-expression networks in excitatory pyramidal neurons (layers 2/3 and 5/6) and somatostatin (SST)-, parvalbumin (PVALB)-, and vasoactive intestinal peptide (VIP)-expressing inhibitory interneurons (N=10 males, 9 females). We identified sex differences in transcriptomic profiles, biological pathways, and co-expression network connectivity. PVALB cells showed stronger overall female transcriptional enrichment, while SST cells exhibited male-enriched transcriptional signatures. Weighted gene co-expression network analysis identified PVALB and SST modules more connected in males and females, respectively, which included hub genes involved in immune, extracellular matrix, and bioenergetic processes. Since G protein-coupled receptors (GPCRs) are viable therapeutic targets, we examined sex differences in GPCR transcripts. Across all GPCR-cell-type combinations, CHRM2 in PVALB cells showed the second strongest sex difference (enriched in females). To test the functional relevance of this difference, we used patch-clamp electrophysiology in mouse prefrontal cortex. M2 receptor activation increased maximal firing rates in PVALB cells from female but not male mice. Collectively, our findings demonstrate cell type-specific sex differences in the sgACC corresponding to functional differences in neuromodulator signaling, with potential implications for treatment response.

neuroscience↗

bioRxiv2026

Astrocyte molecular rhythm disruption in nucleus accumbens promotes increased binge-like drinking in mice

Alcohol misuse is a leading cause of preventable death worldwide. Chronic alcohol is associated with disrupted circadian rhythms, yet molecular mechanisms linking circadian rhythm dysregulation and alcohol consumption are poorly understood. Current FDA-approved treatments for alcohol use disorder (AUD) do not target molecular rhythms or sleep-wake cycles. Mammalian circadian rhythms are regulated by transcription-translation feedback loops that regulate expression of 'clock genes' (e.g., Arntl encoding for BMAL1). Both human and rodent studies demonstrate associations between clock gene variants and changes in reward-seeking behavior. Evidence suggests astrocytes, non-neuronal brain cells with cell-autonomous rhythms, may regulate both circadian rhythms and reward. In the nucleus accumbens (NAc), a region responsible for modulating alcohol- and reward-related behavior, over 43% of the astrocyte transcriptome is expressed rhythmically. However, no studies to date have investigated roles of NAc astrocyte rhythmicity in regulating alcohol drinking. We used AAV8-Gfap-Cre to functionally ablate molecular rhythms in NAc astrocytes of BMAL1 floxed mice. Two-bottle choice (2BC), drinking-in-the-light (DIL), and drinking-in-the-dark (DID) assessed alcohol drinking. Behavioral assays included locomotor response to novelty, sucrose preference, and social interaction. Disrupting molecular clock function in NAc astrocytes increased binge-like drinking during both DIL and DID paradigms (d = 1.44), but not with any other drinking paradigm or behavior. This study carves out a unique role for astrocytes in controlling the temporal organization of reward circuitry and susceptibility to binge-drinking. Future studies will investigate clock-controlled astrocyte mechanisms, such as glutamate uptake and ATP release, that may underlie binge-like drinking behavior.

neuroscience↗

bioRxiv2026

Gene-specific exponent-corrected normalization for library size in bulk RNA-seq

Correcting for library size is an essential step in bulk RNA-seq analyses, as differences in sequencing depth across samples can obscure biological signal with technical noise. While numerous normalization methods and model-based strategies have been proposed, we demonstrate here that library size-normalized counts and differential expression results obtained from such widely adopted approaches often remain strongly correlated with library size in large-scale RNA-seq experiments. Through a systematic analysis of over 100 publicly available GEO and TCGA RNA-seq datasets with raw count data, we show that library size association is observed for a substantial proportion of genes even after state-of-the-art library size correction approaches recommended by leading normalization tools. To address this issue, we propose gecco, a gene-specific exponent-corrected normalization method for RNA-seq counts that incorporates library size directly into the statistical framework via a gene-specific correction term, rather than applying a uniform adjustment factor across all genes. This formulation generalizes existing normalization approaches and yields normalized counts that are free of residual library size effects. Using both simulation studies and real large-scale RNA-seq datasets, we show that our method mitigates library size bias while preserving biological signal across a range of parameter settings. We further demonstrate that our approach leads to higher detection accuracy and more biologically meaningful pathway enrichment results in downstream differential expression and rhythmicity analyses without compromising false discovery rate control. Our method is implemented in R and is fully compatible with the widely used differential expression analysis methods DESeq2 and edgeR.

bioinformatics↗

bioRxiv2026

Unraveling Tissue-Specific Molecular Signatures and Convergent Pathway Enrichments in Suicidal Behavior

Suicide is a leading cause of death worldwide, yet the biological mechanisms underlying suicide remain poorly understood. A clearer understanding at the molecular level is essential for developing objective biomarkers and targeted interventions. In this study, we used transcriptomic profiling to investigate gene expression patterns associated with suicidal thoughts and behaviors across peripheral blood (n=264) and postmortem brain tissue from two prefrontal regions (dorsolateral prefrontal cortex, DLPFC; subgenual anterior cingulate cortex, sgACC) of individuals with and without psychiatric illness (n=249). Peripheral analyses revealed broad transcriptional changes associated with suicidal thoughts and behaviors, marked by dysregulated immune-related and inflammatory processes. Longitudinal modeling further revealed gene co-expression modules that predicted future suicide attempts over a 12-month follow-up, highlighting processes related to apoptosis, mitochondrial function, and immune regulation. By contrast, transcriptomic analyses of postmortem tissue derived from the DLPFC and sgACC revealed largely suppressed neuroimmune activity. Gene co-expression analyses in the brain identified suicide-associated modules enriched for synaptic plasticity, oxidative stress, and neuroimmune function, some of which displayed regional specificity. Cross-tissue comparison showed minimal gene-level overlap between brain and blood, although shared pathway-level themes emerged in immune, sensory, and cellular stress processes. Taken together, these findings suggest that suicide is associated with distinct but functionally convergent transcriptional alterations across brain and blood. By integrating tissue-specific and systems-level molecular signatures, this work provides insight into the biological architecture of suicide and lays the groundwork for developing novel biomarkers and therapeutic targets to improve prevention and treatment outcomes.

neuroscience↗

bioRxiv2026

Bayesian rhythmic model for jointly detecting circadian biomarkers and predicting molecular circadian time in human post-mortem brain transcriptome

Transcriptomic circadian analysis of human post-mortem brain provides a unique opportunity to characterize in vivo molecular circadian rhythms across brain regions implicated in aging and psychiatric disorders. A primary goal in such analyses is the detection of circadian biomarkers. However, this task is complicated by the frequent mismatch between a subjects recorded circadian clock time and their true molecular circadian time -- arising from observational or recording errors, as well as intrinsic biological variability. Existing methods typically address either biomarker detection or circadian time prediction in isolation. Because errors in one task can degrade performance in the other, the lack of a unified approach remains a key limitation. We propose BayCT -- a Bayesian model for simultaneous circadian marker detection and molecular circadian time estimation. The model extends naturally to repeated measurements from multiple brain regions or organs. For circular data, we employ a von Mises prior distribution, with slice sampling and reversible-jump Markov chain Monte Carlo (MCMC) for Bayesian inference. Through extensive simulations and applications to transcriptomic data from three human brain regions and from 12 mouse organs, BayCT demonstrates superior performance in both biomarker detection and circadian time estimation. Furthermore, we highlight the advantages of integrating data across brain regions, achieving substantial improvements in both tasks.

bioinformatics↗

bioRxiv2024

Comparative transcriptomic rhythms in the mouse and human prefrontal cortex

Alterations in multiple subregions of the human prefrontal cortex (PFC) have been heavily implicated in psychiatric diseases. Moreover, emerging evidence suggests that circadian rhythms in gene expression are present across the brain, including in the PFC, and that these rhythms are altered in disease. However, investigation into the potential circadian mechanisms underlying these diseases in animal models must contend with the fact that the human PFC is highly evolved and specialized relative to that of rodents. Here, we use RNA sequencing to lay the groundwork for translational studies of molecular rhythms through a sex-specific, cross species comparison of transcriptomic rhythms between the mouse medial PFC (mPFC) and two subregions of the human PFC, the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). We find that while circadian rhythm signaling is conserved across species and subregions, there is a phase shift in the expression of core clock genes between the mouse mPFC and human PFC subregions that differs by sex. Furthermore, we find that the identity of rhythmic transcripts is largely unique between the mouse mPFC and human PFC subregions, with the most overlap (20%, 236 transcripts) between the mouse mPFC and the human ACC in females. Nevertheless, we find that basic biological processes are enriched for rhythmic transcripts across species, with key differences between regions and sexes. Together, this work highlights both the evolutionary conservation of transcriptomic rhythms and the advancement of the human PFC, underscoring the importance of considering cross-species differences when using animal models.

neuroscience↗

bioRxiv2024

Peripubertal antagonism of corticotropin-releasing factor receptor 1 results in sustained, sex-specific changes in behavioral plasticity and the transcriptomic profile of the amygdala

Peripuberty is a significant period of neurodevelopment with long-lasting effects on the brain and behavior. Blocking type 1 corticotropin-releasing factor receptors (CRFR1) in neonatal and peripubertal rats attenuates detrimental effects of early-life stress on neural plasticity, behavior, and stress hormone action, long after exposure to the drug has ended. CRFR1 antagonism can also impact neural and behavioral development in the absence of stressful stimuli, suggesting sustained alterations under baseline conditions. To investigate this further, we administered the CRFR1 antagonist (CRFR1a) R121919 to young adolescent male and female rats across 4 days. Following each treatment, rats were tested for locomotion, social behavior, mechanical allodynia, or prepulse inhibition (PPI). Acute CRFR1 blockade immediately reduced PPI in peripubertal males, but not females. In adulthood, each assay was repeated without CRFR1a exposure to test for persistent effects of the adolescent treatment. Males continued to experience deficits in PPI while females displayed altered locomotion, PPI, and social behavior. The amygdala was collected to measure long-term effects on gene expression. In the adult amygdala, peripubertal CRFR1a induced alterations in pathways related to neural plasticity and stress in males. In females, pathways related to central nervous system myelination, cell junction organization, and glutamatergic regulation of synaptic transmission were affected. Understanding how acute exposure to neuropharmacological agents can have sustained impacts on brain and behavior, in the absence of further exposures, has important clinical implications for developing adolescents.

neuroscience↗

bioRxiv2023

Parvalbumin interneuron mGlu5 receptors govern sex differences in prefrontal cortex physiology and binge drinking

Despite established sex differences in the prevalence and presentation of psychiatric disorders, little is known about the cellular and synaptic mechanisms that guide these differences under basal conditions. Proper function of the prefrontal cortex (PFC) is essential for the top-down regulation of motivated behaviors. Activity of the PFC is tightly controlled by parvalbumin-expressing interneurons (PV-INs), a key subpopulation of fast-spiking GABAergic cells that regulate cortical excitability through direct innervations onto the perisomatic regions of nearby pyramidal cells. Recent rodent studies have identified notable sex differences in PV-IN activity and adaptations to experiences such as binge drinking. Here, we investigated the cellular and molecular mechanisms that underlie sex-specific regulation of PFC PV-IN function. Using whole-cell patch clamp electrophysiology and selective pharmacology, we report that PV-INs from female mice are more excitable than those from males. Moreover, we find that mGlu1 and mGlu5 metabotropic glutamate receptors regulate cell excitability, excitatory drive, and endocannabinoid signaling at PFC PV-INs in a sex-dependent manner. Genetic deletion of mGlu5 receptors from PV-expressing cells abrogates all sex differences observed in PV-IN membrane and synaptic physiology. Lastly, we report that female, but not male, PV-mGlu5-/- mice exhibit decreased voluntary drinking on an intermittent access schedule, which could be related to changes in ethanols stimulant properties. Importantly, these studies identify mGlu1 and mGlu5 receptors as candidate signaling molecules involved in sex differences in PV-IN activity and behaviors relevant for alcohol use.

neuroscience↗

bioRxiv2023

Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration

Parkinsons disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1{beta} as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

neuroscience↗

bioRxiv2023

Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11{beta}-hydroxylase inhibitor used to treat hypercortisolism in pregnant and neonatal populations. Maternal, placental, and fetal CNS levels of corticosterone and placental 11{beta}HSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11{beta}HSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in the ventral hippocampus of adult males, but not females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

neuroscience↗

bioRxiv2023

Single nucleus transcriptomics of human and monkey striatum implicates DNA damage, neuroinflammation, and neurodegeneration signaling in opioid use disorder

The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are involved in altered reward processing, formation of habits, and development of negative affect states associated with OUD. Using single nuclei RNA-sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g., dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2-hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We also identified sex-dependent differences in the expression of stress-induced transcripts among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.

neuroscience↗

bioRxiv2023

Uncovering circadian rhythm disruptions of synaptic proteome signaling in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)--key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24- hour cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes related to vesicle-mediated transport and membrane trafficking in the NAc and platelet derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.

neuroscience↗

bioRxiv2022

The ultradian transcriptome of the human prefrontal cortex and abnormalities in schizophrenia

Twelve-hour (12 h) ultradian rhythms are a well-known phenomenon in coastal marine organisms. While 12 h cycles are observed in human behavior and physiology, no study has measured 12 h rhythms in the human brain. Here we identify 12 h rhythms in transcripts which either peak at sleep/wake transitions (~9 AM/PM) or static times (~3 PM/AM) in the dorsolateral prefrontal cortex, a region involved in cognition. Subjects with schizophrenia lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance. Moreover, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peak instead at static times in schizophrenia, suggesting suboptimal timing of these essential processes that may contribute to cognitive deficits commonly found in schizophrenia.

neuroscience↗

bioRxiv2022

Experimental Design and Power Calculation in Omics Circadian Rhythmicity Detection

Circadian clocks are 24-hour endogenous oscillators in physiological and behavioral processes. Though recent transcriptomic studies have been successful in revealing the circadian rhythmicity in gene expression, the power calculation for omics circadian analysis have not been fully explored. In this paper, we develop a statistical method, namely CircaPower, to perform power calculation for circadian pattern detection. Our theoretical framework is determined by three key factors in circadian gene detection: sample size, intrinsic effect size and sampling design. Via simulations, we systematically investigate the impact of these key factors on circadian power calculation. We not only demonstrate that CircaPower is fast and accurate, but also show its underlying cosinor model is robust against variety of violations of model assumptions. In real applications, we demonstrate the performance of CircaPower using mouse pan-tissue data and human post-mortem brain data, and illustrate how to perform circadian power calculation using mouse skeleton muscle RNA-Seq pilot as case study. Our method CircaPower has been implemented in an R package, which is made publicly available on GitHub (https://github.com/circaPower/circaPower).

genomics↗