Biology subjects

Dennis, E.

Publications and source records attributed to Dennis, E..

8 recordsLinked to original sources

bioRxiv2026

An integrated multi-omic atlas of the choroid plexus highlights conserved molecular programs of epithelial function

The choroid plexus (ChP) is a specialized epithelial tissue responsible for production of cerebrospinal fluid (CSF), maintenance of the blood-CSF barrier and regulation of CSF-borne signaling factors. However, despite the ChP's central role in CSF homeostasis, conserved molecular programs of ChP epithelial function across species and conditions remain incompletely defined. In this study, we integrated eight mouse and human single-cell/nucleus RNA-seq datasets to build a multi-species ChP atlas capturing major epithelial, stromal, vascular, and immune populations. Cross-dataset differential expression identified a conserved epithelial gene program encompassing ion transport, barrier function, ciliogenesis, and secretory signaling, while prioritizing understudied genes including CLIC6 and VAT1L. Co-expression network analysis resolved conserved epithelial meta-programs, and transcription factor regulatory inference identified OTX2, MSX1, and GLIS3 among conserved regulators of epithelial gene expression. We also generated a novel Visium HD spatial transcriptomic atlas of mouse fourth-ventricle ChP to orthogonally validate epithelial modules. Lastly, cross-tissue analyses revealed substantial transcriptional overlap between ChP and retinal pigment epithelium, including shared epithelial genes and OTX2-associated regulatory relationships. Together, these findings define conserved molecular programs of ChP epithelial specialization, nominate candidate regulators for functional investigation, and provide an integrated cross-species and spatial resource for studying ChP physiology.

neuroscience↗

bioRxiv2026

Single-Cell Analysis of Non-Functioning Gonadotroph Tumors Identifies Lineage Infidelity and Tumor Growth Programs

Non-functioning gonadotroph (NFG) tumors are the most common type of non-functioning pituitary adenomas and can cause significant symptoms due to mass effect. However, the molecular programs underlying NFG tumor growth and their relationship to the normal anterior pituitary gland (APG) are poorly understood. To gain a deeper understanding of NFG tumor biology in the context of the normal APG, we performed single-cell/nucleus RNA-sequencing on 21 NFG tumors and 8 APG samples in human, generating the largest transcriptomic dataset of its kind. Single-cell/nucleus sequencing yielded 77,342, cells from APG samples and 152,649 cells from NFG tumor samples. Differential expression analysis within the APG identified novel marker genes of each neuroendocrine cell type and defined distinct transcriptional signatures of anterior and posterior pituitary stem cell populations. Comparison with tumor transcriptomes revealed that NFG tumor cells most closely resemble gonadotrophs, while also showing significant enrichment of thyrotroph and somatotroph markers. Notably, there was no significant overlap with stem cell markers, suggesting that NFG tumors most likely originate from differentiated gonadotrophs but can take on transcriptional characteristics of other neuroendocrine cell types. Pseudobulk profiling of NFG tumor cells demonstrated that tumor volume is significantly positively correlated with 83 genes including known oncogenes CAD, BRF2, and SOX12, along with 16 zinc finger transcription factors. Lastly, analysis of the tumor microenvironment revealed proportional increases in myeloid, endothelial, and mural cell populations in tumor samples compared to APG samples and highlighted cross talk between tumor and endothelial, mesenchymal, and immune populations via VEGF, PDGF, and MIF signaling pathways respectively. This study identifies novel transcriptomic signatures determining cell type identity in both APG neuroendocrine and NFG tumor cells. Our findings elucidate molecular programs driving NFG lineage infidelity and tumor growth, highlighting candidate predictors of patient outcomes and potential targets for therapeutic intervention.

cancer biology↗

bioRxiv2026

Scaling of Neuronal Growth and Excitability Through Separable mTORC1 and mTORC2 Pathways

As neurons grow, they must regulate intrinsic excitability to maintain an appropriate level of spiking based on synaptic inputs. Using gene knockouts, phosphoproteomics, and electrophysiology we show PTEN regulates neuronal growth and intrinsic excitability through separable downstream mechanisms. Pten loss induces cellular hypertrophy, increased excitatory synaptic input, reduced fast afterhyperpolarization, and burst firing. Deleting the mTORC1 scaffold, Raptor, rescues overgrowth and synaptic input but fails to normalize firing, while deleting Akt or the mTORC2 scaffold, Rictor, restores firing without rescuing growth. This dissociation identifies an AKT-mTORC2 mechanism that regulates voltage-gated calcium and BK potassium channels to set spike repolarization and burst firing. In vivo, Pten knockout produces altered network synchrony, lethal seizures, and impaired object and location behavior; Raptor co-deletion display non-lethal hyperexcitability with improved object-location coupling. The biological and pathophysiological significance of these mechanisms is demonstrated by overlap of the PTEN-regulated phosphoproteome with ASD and epilepsy.

neuroscience↗

bioRxiv2025

Frontoamygdala hyperconnectivity predicts autonomic dysregulation and persisting symptoms in sports-related concussion

OBJECTIVEWe investigated longitudinal trajectories of resting-state fMRI (rsfMRI), autonomic function, and symptoms after sport-related concussion (SRC). BACKGROUNDLimbic circuitry may be particularly vulnerable to traumatic brain injury (TBI), which could explain the affective and autonomic dysfunction some patients develop. Relatively few studies have performed longitudinal rsfMRI analyses in concussion and fewer have combined imaging with autonomic and symptom data. We leveraged published limbic rsfMRI networks centered on the amygdala that include central autonomic structures in frontal and temporal lobes and their visceromotor targets. We hypothesized that frontoamygdala connectivity would differentiate athletes with SRC from matched, in-sport controls (ISC), predict autonomic function, and predict symptom recovery. DESIGN/METHODSUsing independent-samples t-tests, we compared rsfMRI connectivity strength in amygdala networks in college athletes with SRC (SRC: n=31, female=14) at three time points after concussion (T1[≤]4 days, T2=10-14 days, T3=60-90 days) and healthy, matched controls without a concussion in the same sport (ISC: n=36, female=17). RESULTSSRC athletes showed significantly greater frontoamygdala connectivity compared to ISCs at the acute and subacute post-injury time points (T1 p=0.003, T2 p=0.014) that normalized to control-level connectivity by the chronic time point (T3 p=0.182). When testing whether autonomic function interacts with network connectivity trajectory, we found that opposing trajectories of frontoamygdala connectivity between SRC athletes with higher versus lower acute heart rate variability (HRV), as measured by pNN50 (percentage of intervals between successive normal sinus beats greater than 50ms). SRC athletes with higher HRV acutely post-injury had significantly greater acute frontoamygdala connectivity compared to ISCs at T1; connectivity in these high-HRV SRC athletes normalized to control level over time (T1 p=0.001, T2 p=0.055, T3 p=0.576). SRC athletes with lower HRV acutely post-injury had control-level frontoamygdala connectivity at T1; connectivity in these low-HRV SRC athletes significantly exceeded control-level connectivity at T3 (T1 p=0.429, T2 p=0.050, T3 p=0.002). Furthermore, those SRC athletes with the greatest frontoamygdala connectivity at T3, had the most persistent symptoms on the graded symptom checklist at T3 (r=0.635, p=0.001). Differences in diffusion-tensor-imaging-based measures of structural connectivity in the uncinate fasciculus, the fiber bundle most critical to our frontoamygdala network, could not account for these relationships. CONCLUSIONSThese results suggest that increased connectivity in amygdala circuitry acutely after a concussion and its normalization over time may be protective or compensatory; acute measures of amygdala network connectivity and measures of HRV may be valuable biomarkers for predicting symptom persistence.

neuroscience↗

bioRxiv2021

The Presence of the Temporal Horn Exacerbates the Vulnerability of Hippocampus during Head Impacts

Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest that the presence of the temporal horn exacerbate the vulnerability of the hippocampus, highlighting the mechanobiological dependency of the hippocampus on the temporal horn.

bioengineering↗

bioRxiv2021

Structural Covariance Networks in Post-Traumatic Stress Disorder: A Multisite ENIGMA-PGC Study

IntroductionCortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCN) constructed from CT and SA may represent developmental associations, or unique interactions between brain regions, possibly influenced by a common causal antecedent. The ENIGMA-PGC PTSD Working Group aggregated PTSD and control subjects data from 29 cohorts in five countries (n=3439). MethodsUsing Destrieux Atlas, we built SCNs and compared centrality measures between PTSD subjects and controls. Centrality is a graph theory measure derived using SCN. ResultsNotable nodes with higher CT-based centrality in PTSD compared to controls were left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. We found sex-based centrality differences in bilateral frontal lobe regions, left anterior cingulate, left superior occipital cortex and right ventromedial prefrontal cortex (vmPFC). Comorbid PTSD and MDD showed higher CT-based centrality in the right anterior cingulate gyrus, right parahippocampal gyrus and lower SA-based centrality in left insular gyrus. ConclusionUnlike previous studies with smaller sample sizes ([≤]318), our study found differences in centrality measures using a sample size of 3439 subjects. This is the first cross-sectional study to examine SCN interactions with age, sex, and comorbid MDD. Although limited to group level inferences, centrality measures offer insights into a nodes relationship to the entire functional connectome unlike approaches like seed-based connectivity or independent component analysis. Nodes having higher centrality have greater structural or functional connections, lending them invaluable for translational treatments like neuromodulation.

neuroscience↗

bioRxiv2019

Dietary sugar inhibits satiation by decreasing the central processing of sweet taste

From humans to flies, exposure to diets rich in sugar and fat lowers taste sensation, changes food choices, and promotes feeding. However, how these peripheral alterations influence eating is unknown. Here we used the genetically tractable organism D. melanogaster to define the neural mechanisms through which this occurs. We characterized a population of protocerebral anterior medial dopaminergic neurons (PAM DANs) that innervates the {beta}2 compartment of the mushroom body and responds to sweet taste. In animals fed a high sugar diet, the response of PAM-{beta}2 to sweet stimuli was reduced and delayed, and sensitive to the strength of the signal transmission out of the sensory neurons. We found that PAM-{beta}2 DANs activity controls feeding rate and satiation: closed-loop optogenetic activation of {beta}2 DANs restored normal eating in animals fed high sucrose. These data argue that diet-dependent alterations in taste weaken satiation by impairing the central processing of sensory signals.

neuroscience↗

bioRxiv2019

Altered White Matter Microstructural Organization in Post-Traumatic Stress Disorder across 3,049 Adults: Results from the PGC-ENIGMA PTSD Consortium

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,049 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,446 individuals with PTSD and 1,603 controls (2152 males/897 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohens d=-0.12, p=0.0021). The tapetum connects the left and right hippocampus, structures for which structure and function have been consistently implicated in PTSD. Results remained significant/similar after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

neuroscience↗