Biology subjects

Connolly, M. G.

Publications and source records attributed to Connolly, M. G..

4 recordsLinked to original sources

bioRxiv2025

Exercise-induced plasma-derived extracellular vesicles increase adult hippocampal neurogenesis

Aerobic exercise enhances cognition in part by increasing adult hippocampal neurogenesis, angiogenesis, and astrogliogenesis. Since hippocampal atrophy is a hallmark of several neurological and psychiatric conditions--including depression, PTSD, Alzheimers disease, and aging--understanding the mechanisms by which exercise increases neurogenesis has broad therapeutic relevance. One potential mechanism involves extracellular vesicles (EVs), lipid bilayer-enclosed particles released by multiple tissues during exercise that transport bioactive molecular cargo to distant organs, including the brain. In this study, we tested whether plasma-derived EVs from exercising mice (ExerVs) are sufficient to promote hippocampal neurogenesis, astrogliogenesis, and vascular density in sedentary mice. EVs were isolated from the plasma of sedentary or exercising C57BL/6J mice and injected intraperitoneally into sedentary recipients twice weekly for four weeks. To evaluate reproducibility, the study was conducted across two independent cohorts using identical procedures. ExerV-treated mice showed a significant increase in BrdU-positive cells in the granule cell layer compared to both PBS- and SedV-treated controls in both cohorts. Approximately 90% of these cells co-expressed NeuN, indicating neuronal differentiation, while 6% co-expressed S100{beta}, indicating astrocyte generation. No changes were observed in vascular density across groups. These findings provide initial evidence that systemically delivered exercise-derived EVs can enhance hippocampal neurogenesis and astrogliogenesis in sedentary mice. This proof-of-concept work supports further investigation into ExerVs as a potential therapeutic strategy for conditions associated with hippocampal atrophy. HighlightsO_LIExerVs increase hippocampal neurogenesis and astrogliogenesis in sedentary mice C_LIO_LIExerVs do not affect hippocampal vascular area C_LIO_LICirculating ExerVs are sufficient to recapitulate key brain benefits of exercise C_LI

neuroscience↗

bioRxiv2025

NanoString Technologies Neuropathology Panel Produces Unreliable Measurements of Mouse Hippocampal Gene Expression

Technologies for measuring gene expression (i.e., the number of RNA transcripts) of large numbers of genes simultaneously in specific tissues have exploded in recent years. Current methods include high-throughput RNA sequencing (RNA-seq), transcript counting platforms like NanoStrings nCounter(R), and spatially resolved techniques based on fluorescent in situ hybridization (FISH). Several studies have evaluated the reliability of these different methods and performance in comparison to one another. Typically, technical reliability, as measured by Pearsons correlation of two measurements of the same sample, is usually well above 90%, and is statistically significant even for small sample sizes (e.g., 8 samples measured twice). We performed an experiment where we aimed to compare hippocampal gene expression between 3 groups (n=5 per group) of young adult male C57BL/6J mice. Before sampling, the groups were treated with either repeated injections of PBS (vehicle), extracellular vesicles taken from the blood plasma of sedentary mice (SedVs) or exercising mice (ExerVs). The hippocampus was dissected, and RNA purified using standard methods. The samples were analyzed using the NanoString Neuropathology panel, that measures 770 genes simultaneously. To estimate reliability, we measured 8 of the samples twice in two separate assays. Surprisingly, only 85 genes showed a significant Pearsons correlation (p<0.05), and none of these met false discovery significance (all q<0.05). To confirm that no errors were made transferring labels, the individual samples were permuted to see whether a different assignment could recover a greater number of positive correlations. Results showed that the original assignment was best suggesting no errors in sample assignments were made. We conclude that the Nanostring neuropathology panel produces unreliable data for mouse hippocampal gene expression.

neuroscience↗

bioRxiv2024

Single-nucleus RNA sequencing of striatal microglia reveals distinct transcriptomic signatures of acute stress and chronic exercise

Acute stress has enduring effects on the brain and motivated behavior across species. For example, acute stress produces persisting decreases in voluntary physical activity as well as molecular changes in the striatum, a brain region that regulates voluntary physical activity and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, are positioned at the interface between neural responses to stress and neural coordination of voluntary activity in that they respond to stress, sense molecular changes in the striatum, and modulate neuronal activity. However, the role of striatal microglia in stress-induced long-term suppression of voluntary activity is unknown. Here we employ single nucleus RNA-sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that striatal microglia display altered activation profiles six weeks after an acute stressor. Furthermore, we show that access to a running wheel is associated with an additional and distinct microglial activation profile characterized by upregulation of genes related to complement components and phagocytosis pathways. Lastly, we find that distinct gene sets show expression changes associated with general access to a running wheel versus variation in running levels. Taken together, our results deepen our understanding of the diverse molecular states that striatal microglia assume in response to stress and exercise and suggest that microglia exhibit a broader range of functional states than previously thought.

neuroscience↗

bioRxiv2023

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner

Epidemiological studies link neurodevelopmental disorders (NDDs) with exposure to maternal viral infection in utero. It is hypothesized that the mechanism governing this link involves the activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17. While IL-17 is implicated as a major driver of fetal brain abnormalities, this inflammation-induced TH17 pathway has not been thoroughly examined in models of live viral infection during pregnancy. Influenza A virus (IAV) infection is consistently linked to offspring NDDs and can result in host intestinal dysregulation. Therefore, it is possible that intestinal TH17 cells and subsequent production of IL-17 could drive fetal brain abnormalities during gestational IAV infection. To test this, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-dose IAV group, despite a lack of IL-17 signaling. Profiling fetal microglia and border-associated macrophages (BAMs) -potential cellular mediators of IAV-induced cortical abnormalities -revealed dose-dependent differences in the numbers of BAMs but not microglia. Overall, our data support the idea of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, confirming the use of live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

neuroscience↗