Biology subjects

Brown, S. A.

Publications and source records attributed to Brown, S. A..

9 recordsLinked to original sources

bioRxiv2026

Neurodevelopment of Corticostriatal Circuits and Risk for Alcohol Use During the Transition from Adolescence to Adulthood

Adolescence and early adulthood are marked by rapid neurobehavioral development in reward and decision-making processes, coinciding with the initiation and escalation of alcohol use. While adolescent and young adulthood alcohol initiation is not atypical, adult trajectories diverge: some individuals reduce or discontinue use, whereas others escalate to more frequent or problematic patterns leading to substance use disorders. Corticostriatal circuits, including the ventral striatum (nucleus accumbens; NAcc) and dorsal striatum (caudate and putamen), support reward processing, goal-directed behavior, and habit formation, and are thought to contribute to distinct stages of alcohol use. Yet, how the normative maturation of these circuits relates to alcohol initiation and the transition to habitual consumption remains unclear. We used data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence and Adulthood (NCANDA-A) cohort (822 participants, baseline ages 12 - 22 years old, 1 - 9 visits per participant, 4,356 total visits), a large multisite longitudinal neuroimaging sample spanning adolescence to young adulthood. We observed that rsfMRI functional connectivity (FC) patterns varied systematically across striatal subdivisions: NAcc FC followed an inverted U-shaped trajectory, peaking during adolescence; while caudate and putamen FC showed monotonic decreases with age. Adolescent peak NAcc connectivity was associated with alcohol use initiation, while a lack of normative decrease in putamen connectivity was linked to more frequent alcohol use in adulthood. Together, results suggest that the maturation of reward processing circuitry may support alcohol initiation, while a lack of habit system specialization may contribute to continued alcohol use, with potential implications for the timing of interventions aimed at limiting at-risk drinking.

neuroscience↗

bioRxiv2026

Molecular methods reveal responses of bacterial communities, including indicator species, to ballast water management

Ballast water (BW) is an important vector for the global translocation of bacterial taxa, including pathogens. Legal frameworks establishing limits on the discharge of live organisms into recipient environments have been designed to reduce risks of microbial invasions, and understanding the impacts of BW management on bacterial communities is critical for assessing the effectiveness of these practices. Here we evaluate changes in bacterial communities associated with both BW treatment (BWT) and a combined management approach of BWT plus BW exchange (BWT+E). Samples were collected on two experimental voyages designed specifically to compare BW-associated biota before and after management. Microbial community structure and inferred function were assessed based on high throughput sequencing of 16S rRNA amplicons, and bacterial indicator taxa E. coli and enterococci were analyzed using targeted qPCR. As expected, both BWT alone and BWT+E dramatically changed bacterial communities, with the latter resulting in the largest overall decreases in bacterial diversity. Increases in Gammaproteobacteria, especially in the genus Pseudomonas, were particularly notable, with concomitant decreases in Alphaproteobacteria and Bacteroidia. Shifts in predicted bacterial function associated with BWT were similar for both voyages, despite significant differences in community structure, and may represent selection for r-strategists capable of active regrowth after BWT. qPCR estimates of indicator taxa were similar to those obtained through standard culture methods but may offer increased sensitivity for detecting changes associated with management. Our results indicate that BW management is effective at reducing bacterial communities but suggest that further research is needed to understand risks associated with taxa that may survive BWT.

ecology↗

bioRxiv2025

Neuromedin U Receptor 2 orchestrates sleep continuity and circadian entrainment

Neuromedin S signaling has recently been identified as a modulator of both sleep and circadian rhythms in the central nervous systems of mammals. Nevertheless, the involvement of its preferred receptor, NMUR2, in sleep and circadian regulation remains elusive. Here, employing its only selective antagonist R-PSOP, we demonstrate that NMUR2 function in the mouse brain is essential for physiological sleep architecture under baseline conditions, as well as for responses to homeostatic and circadian challenges. Using a combination of pharmacological, neuronal tagging, brain clearing and chemogenetic tools, we identified and functionally validated a group of PVH neurons as one of the targets mediating the effect of R-PSOP on sleep. These findings establish NMUR2 as a potential therapeutic target for the integral treatment of sleep and circadian neurological disorders. HIGHLIGHTSSelective NMUR2 antagonism via R-PSOP disrupts vigilance state continuity in a dose- and circadian phase-dependent manner R-PSOP administration delays circadian phase entrainment and hinders sleep homeostasis recovery PVH neurons are activated by R-PSOP and boost wake-to-NREM sleep transitions in the active period

neuroscience↗

bioRxiv2023

A Framework to Determine Active Connectivity within the Mouse Brain

Tremendous effort has focused on determining the physical connectivity within the mouse brain. However, the strength of connections within the brain constantly changes throughout the 24-hour day. Here, we combine experimental and computational methods to determine an "active connectivity" of the physical connections between the most active neurons. Brain cells of freely behaving mice are genetically marked with the activity- dependent TRAP2 system, imaged, digitized, and their connectivity is inferred from the latest brain atlases. We apply our methods to determine the most active networks in the early light and early dark hours of the day, two periods with distinct differences in sleep, wake, and feeding behavior. Increased signaling is seen through the visceral and agranular insular (AI) regions in the early day as peripheral stimuli are integrated. On the other hand, there is an increase in the activity of the retrosplenial cortex (RSP) and the anterior cingulate cortex (ACC) during the early night, when more sustained attention is required. Our framework carves a window to the three-dimensional networks of active connections in the mouse brain that underlie spontaneous behaviors or responses to environmental changes, thus providing the basis for direct computer simulations and analysis of such networks in the future.

neuroscience↗

bioRxiv2023

AAV-mediated gene therapy for Sialidosis

Sialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids. The disease belongs to the group of orphan disorders with no therapy currently available. Here, we have tested the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis in a mouse model of the disease. One-month-old Neu1-/- mice were co-injected with two scAAV2/8 vectors, expressing NEU1 and its chaperone PPCA, and sacrificed at 3 months post-injection. Treated mice were phenotypically indistinguishable from their WT controls. Histopathologically, they showed diminished or absent vacuolization in cells of visceral organs, including the kidney, as well as the choroid plexus and other areas of the brain. This was accompanied by restoration of NEU1 activity in most tissues, reversal of sialyl-oligosacchariduria, and normalization of lysosomal exocytosis in the CSF and serum of treated mice. AAV injection prevented the occurrence of generalized fibrosis, which is a prominent contributor of disease pathogenesis in Neu1-/- mice and likely in patients. Overall, this therapeutic strategy holds promise for the treatment of sialidosis and may be applicable to adult forms of human idiopathic fibrosis with low NEU1 expression.

genetics↗

bioRxiv2023

microRNA-218-5p Coordinates Scaling of Excitatory and Inhibitory Synapses during Homeostatic Synaptic Plasticity

Homeostatic synaptic plasticity (HSP) is a fundamental neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating both of these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of miRNA-binding sites in differentially expressed genes changing upon PTX-induced HSD, we bioinformatically predicted and experimentally validated increased miR-218-5p activity upon PTX-treatment in the process compartment. By monitoring synapse structure in vitro with confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: it prevents the downscaling of excitatory synapses and dendritic spines, while at the same time blocking inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a crucial target of miR-218-5p in the context of homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic (EEG) recordings, we further revealed that local inhibition of miR-218-5p in the somatosensory cortex reduced local slow-wave activity (SWA) during non-rapid-eye-movement (NREM) sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with potential implications for both physiological and pathological conditions. Significance StatementHomeostatic synaptic plasticity mechanisms evolved to keep neuronal firing rates within a physiological range in response to alterations in neural network activity. It has been proposed that similar mechanisms take place during sleep in a process that promotes memory consolidation and synaptic renormalization. In this study, posttranscriptional regulation of synaptic proteins by miR-218-5p has been identified to coordinate both excitatory and inhibitory synaptic scaling during activity-dependent homeostatic synaptic plasticity. Intriguingly, local inhibition of miR-218-5p in the cortex of mice resulted in reduced slow-wave activity, an EEG-signature of synchronous firing during non-rapid eye movement sleep and a hallmark correlate of sleep pressure. Overall, these findings propose a convergent, posttranscriptional mechanism to coordinate both excitatory and inhibitory synaptic strength in response to alterations in neuronal activity with potential implications for sleep.

neuroscience↗

bioRxiv2022

A novel Smg6 mouse model reveals regulation of circadian period and daily CRY2 accumulation through the nonsense-mediated mRNA decay pathway

Nonsense-mediated mRNA decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in controlling regular mRNA stability have emerged, possible functions in mammalian physiology in vivo have remained unclear. Here, we report a novel conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We analyzed how NMD downregulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. We uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks, and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. In the entrained livers of Smg6 mutant animals we reveal transcriptome-wide alterations in daily mRNA accumulation patterns, altogether expanding the known scope of NMD regulation in mammalian gene expression and physiology.

genetics↗

bioRxiv2021

Alcohol Use Disrupts Age-Appropriate Cortical Thinning in Adolescence: A Data Driven Approach

ObjectiveCortical thickness changes dramatically during development and is influenced by adolescent drinking. However, previous findings have been inconsistent and limited by region-of-interest approaches that are underpowered because they do not conform to the underlying heterogeneity from the effects of alcohol. MethodsAdolescents (n=657; 12-22 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) who endorsed little to no alcohol use at baseline were assessed with structural MRI and followed longitudinally at four yearly intervals. Seven unique spatially covarying patterns of cortical thickness were obtained from the baseline scans by applying a novel data-driven method called non-negative matrix factorization (NMF). The cortical thickness maps of all participants longitudinal scans were projected onto vertex-level cortical patterns to obtain participant-specific coefficients for each pattern. Linear mixed-effects models were fit to each pattern to investigate longitudinal effects of alcohol consumption on cortical thickness. ResultsIn most NMF-derived cortical thickness patterns, the longitudinal rate of decline in no/low drinkers was similar for all age cohorts, among moderate drinkers the decline was faster in the younger cohort and slower in the older cohort, among heavy drinkers the decline was fastest in the younger cohort and slowest in the older cohort (FDR corrected p-values < 0.01). ConclusionsThe NMF method can delineate spatially coordinated patterns of cortical thickness at the vertex level that are unconstrained by anatomical features. Age-appropriate cortical thinning is more rapid in younger adolescent drinkers and slower in older adolescent drinkers.

neuroscience↗

bioRxiv2020

Roughness and dynamics of proliferating cell fronts as a probe of cell-cell interactions

Juxtacellular interactions play an essential but still not fully understood role in both normal tissue development and tumour invasion. Using proliferating cell fronts as a model system, we explore the effects of cell-cell interactions on the geometry and dynamics of these one-dimensional biological interfaces. We observe two distinct scaling regimes of the steady state roughness of in-vitro propagating Rat1 fibroblast cell fronts, suggesting different hierarchies of interactions at sub-cell lengthscales and at a lengthscale of 2-10 cells. Pharmacological modulation significantly affects the proliferation speed of the cell fronts, and those modulators that promote cell mobility or division also lead to the most rapid evolution of cell front roughness. By comparing our experimental observations to numerical simulations of elastic cell fronts with purely short-range interactions, we demonstrate that the interactions at few-cell lengthscales play a key role. Our methodology provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping. Proliferating cell fronts underpin wound healing, tumour invasion, and morphogenesis, and are governed by a complex and still not fully understood interplay of multiple mechanical and chemical factors. From a physics perspective, these cell fronts can be described as elastic interfaces in disordered media. Thus, analysing their geometric properties and dynamics can reveal the characteristic lengthscales of the dominant interactions, and point towards the underlying biological pathways. Here, we show that the roughness of proliferating fronts of Rat1 fibroblasts is governed by two different hierarchies of interactions, with distinct behaviour at sub-cell and few-cell lengthscales. Using in-vitro scratch assays, we find moreover that pharmacological modulators significantly affect the proliferation speed of the cell fronts as well as the evolution of their roughness, increased when cell-cell communication via gap junctions is perturbed, and decreased when cell division is repressed. We determine that our experimental observations cannot be reproduced by numerical simulations of elastic cell fronts with purely short-range interactions, demonstrating the key role of juxtacellular interactions at few-cell lengthscales. Our approach provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping.

biophysics↗