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Founded in 2001, the Department of Neurobiology at UMass Chan Medical School has evolved into a unique and integrated hub of investigators addressing fundamental problems in neurobiology, from single molecules to behavior, primarily using invertebrate model organisms. Combining cell biological, physiological and behavioral analyses with a critical interventionist angle afforded by cutting-edge genetic approaches, the Department aims to understand the complexity of brain development and function. This collection showcases journal articles and other publications authored by Neurobiology faculty and researchers. Browse by “UMass Chan Affiliation” to see the publications produced by a specific lab.
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Recent Publications
Publication Circadian rhythms and the light-dark cycle interact to regulate amyloid plaque accumulation and tau phosphorylation in 5xFAD mice [preprint](2025-04-04) King, Melvin W; Jacob, Sophie; Sharma, Ashish; Lawrence, Jennifer H; Weaver, David R; Musiek, Erik S; Neurobiology; Weaver LabBackground: Circadian disruption has long been appreciated as a downstream consequence of Alzheimer's Disease in humans. However, an upstream role for behavioral circadian disruption in regulating AD pathology remains an open question. Methods: To determine the role of the central circadian clock in the suprachiasmatic nucleus (SCN) in regulating amyloid pathology, we crossed the 5xFAD amyloid mouse model with mice harboring deletion of the critical clock gene Bmal1 in GABAergic neurons using VGAT-iCre, which is expressed in >95% of SCN cells. To examine the role the light-dark cycle in this process, we aged these mice in either regular 12:12 light-dark (LD) or constant darkness (DD) conditions. Transcriptional, behavioral, and physiological rhythms were examined in VGAT-iCre; 5xFAD; Bmal1 fl/fl (VGAT-BMAL1KO;5xFAD) mice under varying light conditions. Amyloid plaque deposition, peri-plaque tau phosphorylation, and other pathology was examined by immunohistochemistry, and transcriptomic changes were examined by high-throughput qPCR. Results: VGAT-BMAL1KO;5xFAD mice showed loss of SCN BMAL1 expression and severe disruption of behavioral rhythms in both LD and DD, with loss of day-night rhythms in consolidated sleep and blunting of rhythmic clock gene expression in the brain. Surprisingly, VGAT-BMAL1KO;5xFAD mice kept under LD showed reduced total plaque accumulation and peri-plaque tau phosphorylation, compared to Cre-negative controls. These changes were gated by the light-dark cycle, as they were absent in VGAT-BMAL1KO;5xFAD mice kept in DD conditions. Total plaque accumulation was also reduced in control 5xFAD mice kept in DD as compared to LD, suggesting a general effect of light-dark cycle on amyloid aggregation. Expression of murine presenilin 1 (Psen1) -- which catalyzes the processing of sAPPβ into Aβ -- as well as APP cleavage to C-terminal fragments, were suppressed in VGAT-BMAL1KO;5xFAD under LD conditions. Conclusions: These studies elucidated an interaction between the circadian clock in GABAergic neurons and the light-dark cycle in regulating amyloid pathology and suggest that decoupling the central clock form the light-dark cycle may reduce APP cleavage and plaque formation. These results call into question the proposed simple positive feedback loop between circadian rhythm disruption and Alzheimer's Disease pathology.Publication Adenosine A2A Receptors Link Astrocytic α1-Adrenergic Signaling to Wake-Promoting Dopamine Neurons(2024-10-16) Petersen, Nicholas; McCann, Katharine E; Stavarache, Mihaela A; Kim, Lisa Y; Weinshenker, David; Winder, Danny G; Neurobiology; Winder LabBackground: Sleep and arousal disorders are common, but the underlying physiology of wakefulness is not fully understood. The locus coeruleus promotes arousal via α1-adrenergic receptor (α1AR)-driven recruitment of wake-promoting dopamine neurons in the ventral periaqueductal gray (vPAGDA neurons). α1AR expression is enriched on vPAG astrocytes, and chemogenetic activation of astrocytic Gq signaling promotes wakefulness. Astrocytes can release extracellular gliotransmitters, such as ATP and adenosine, but the mechanism underlying how vPAG astrocytic α1ARs influence sleep/wake behavior and vPAGDA neuron physiology is unknown. Methods: In this study, we utilized genetic manipulations with ex vivo calcium imaging in vPAGDA neurons and astrocytes, patch-clamp electrophysiology, and behavioral experiments in mice to test our hypothesis that astrocytic α1ARs mediate noradrenergic modulation of wake-promoting vPAGDA neurons via adenosine signaling. Results: Activation of α1ARs with phenylephrine increased calcium transients in vPAGDA neurons and vPAG astrocytes and increased vPAGDA neuron excitability ex vivo. Chemogenetic Gq-DREADD (designer receptor exclusively activated by designer drugs) activation of vPAG astrocytes similarly increased vPAGDA neuron calcium activity and intrinsic excitability. Conversely, short hairpin RNA knockdown of vPAG astrocytic α1ARs reduced the excitatory effect of phenylephrine on vPAGDA neurons and blunted arousal during the wake phase. Pharmacological blockade of adenosine A2A receptors precluded the α1AR-induced increase in vPAGDA calcium activity and excitability in brain slices, as well as the wake-promoting effects of vPAG α1AR activation in vivo. Conclusions: We have identified a crucial role for vPAG astrocytic α1ARs in sustaining arousal through heightened excitability and activity of vPAGDA neurons mediated by local A2A receptors.Publication Senescent-like microglia limit remyelination through the senescence associated secretory phenotype(2025-03-07) Gross, Phillip S; Durán-Laforet, Violeta; Ho, Lana T; Melchor, George S; Zia, Sameera; Manavi, Zeeba; Barclay, William E; Lee, Sung Hyun; Shults, Nataliia; Selva, Sean; Alvarez, Enrique; Plemel, Jason R; Fu, Meng-Meng; Schafer, Dorothy P; Huang, Jeffrey K; Brudnick Neuropsychiatric Research Institute; Neurobiology; Schafer LabThe capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.Publication 4D marmoset brain map reveals MRI and molecular signatures for onset of multiple sclerosis-like lesions(2025-02-28) Lin, Jing-Ping; Brake, Alexis; Donadieu, Maxime; Lee, Amanda; Smith, Ginger; Hu, Kevin; Nair, Govind; Kawaguchi, Riki; Sati, Pascal; Geschwind, Daniel H; Jacobson, Steven; Schafer, Dorothy P; Reich, Daniel S; Brudnick Neuropsychiatric Research Institute; Neurobiology; Schafer LabInferring cellular and molecular dynamics of multiple sclerosis (MS) lesions from postmortem tissue collected decades after onset is challenging. Using magnetic resonance image (MRI)-guided spatiotemporal RNA profiling in marmoset experimental autoimmune encephalitis (EAE), we mapped lesion dynamics and modeled molecular perturbations relevant to MS. Five distinct lesion microenvironments emerged, involving neuroglial responses, tissue destruction and repair, and brain border regulation. Before demyelination, MRI identified a high ratio of proton density-weighted signal to relaxation time, capturing early hypercellularity, and elevated astrocytic and ependymal senescence signals marked perivascular and periventricular areas that later became demyelination hotspots. As lesions expanded, concentric glial barriers formed, initially dominated by proliferating and diversifying microglia and oligodendrocyte precursors, later replaced by monocytes and lymphocytes. We highlight SERPINE1 astrocytes as a signaling hub underlying lesion onset in both marmoset EAE and MS.Publication Capsid transfer of the retrotransposon Copia controls structural synaptic plasticity in Drosophila(2025-02-18) M'Angale, P Githure; Lemieux, Adrienne; Liu, Yumeng; Wang, Shuhao; Zinter, Max; Alegre, Gimena; Simkin, Alfred; Budnik, Vivian; Kelch, Brian A; Thomson, Travis; Biochemistry and Molecular Biotechnology; NeurobiologyTransposons are parasitic genome elements that can also serve as raw material for the evolution of new cellular functions. However, how retrotransposons are selected and domesticated by host organisms to modulate synaptic plasticity remains largely unknown. Here, we show that the Ty1 retrotransposon Copia forms virus-like capsids in vivo and transfers between cells. Copia is enriched at the Drosophila neuromuscular junction (NMJ) and transported across synapses, and disrupting its expression promotes both synapse development and structural synaptic plasticity. We show that proper synaptic plasticity is maintained in Drosophila by the balance of Copia and the Arc1 (activity-regulated cytoskeleton-associated protein) homolog. High-resolution cryogenic-electron microscopy imaging shows that the structure of the Copia capsid has a large capacity and pores like retroviruses but is distinct from domesticated capsids such as dArc1. Our results suggest a fully functional transposon mediates synaptic plasticity, possibly representing an early stage of domestication of a retrotransposon.Publication VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans(2025-02-17) Yin, Xiaomeng; Wang, Ruoxi; Thackeray, Andrea; Baehrecke, Eric H; Alkema, Mark J; Neurobiology; Molecular, Cell and Cancer Biology; Alkema LabMitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. VPS13D encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. VPS13D mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create VPS13D related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in VPS13D's orthologue vps-13D in C. elegans. Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a vps-13D deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPRmt). The cellular and behavioral changes caused by VPS13D mutations in C. elegans advance the development of animal models that are needed to study SCAR4 pathogenesis.Publication VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans [preprint](2025-01-25) Yin, Xiaomeng; Wang, Ruoxi; Thackeray, Andrea; Baehrecke, Eric H; Alkema, Mark J; Neurobiology; Molecular, Cell and Cancer Biology; Alkema LabMitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in 's orthologue in . Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPR ). The cellular and behavioral changes caused by mutations in advance the development of animal models that are needed to study SCAR4 pathogenesis.Publication The neurohormone tyramine stimulates the secretion of an insulin-like peptide from the Caenorhabditis elegans intestine to modulate the systemic stress response(2025-01-28) Veuthey, Tania; Florman, Jeremy T; Giunti, Sebastián; Romussi, Stefano; De Rosa, María José; Alkema, Mark J; Rayes, Diego; NeurobiologyThe DAF-2/insulin/insulin-like growth factor signaling (IIS) pathway plays an evolutionarily conserved role in regulating reproductive development, life span, and stress resistance. In Caenorhabditis elegans, DAF-2/IIS signaling is modulated by an extensive array of insulin-like peptides (ILPs) with diverse spatial and temporal expression patterns. However, the release dynamics and specific functions of these ILPs in adapting to different environmental conditions remain poorly understood. Here, we show that the ILP, insulin-3 (INS-3), plays a crucial role in modulating the response to various environmental stressors in C. elegans. ins-3 mutants display increased resistance to heat, oxidative stress, and starvation; however, this advantage is countered by slower reproductive development under favorable conditions. We find that ins-3 expression is downregulated in response to environmental stressors, whereas, the neurohormone tyramine, which is released during the acute flight response, increases ins-3 expression. We show that tyramine induces intestinal calcium (Ca2+) transients through the activation of the TYRA-3 receptor. Our data support a model in which tyramine negatively impacts environmental stress resistance by stimulating the release of INS-3 from the intestine via the activation of a TYRA-3-Gαq-IP3 pathway. The release of INS-3 systemically activates the DAF-2 pathway, resulting in the inhibition of cytoprotective mechanisms mediated by DAF-16/FOXO. These studies offer mechanistic insights into a brain-gut communication pathway that weighs adaptive strategies to respond to acute and long-term stressors.Publication Unifying community whole-brain imaging datasets enables robust neuron identification and reveals determinants of neuron position in C. elegans(2025-01-15) Sprague, Daniel Y; Rusch, Kevin; Dunn, Raymond L; Borchardt, Jackson M; Ban, Steven; Bubnis, Greg; Chiu, Grace C; Wen, Chentao; Suzuki, Ryoga; Chaudhary, Shivesh; Lee, Hyun Jee; Yu, Zikai; Dichter, Benjamin; Ly, Ryan; Onami, Shuichi; Lu, Hang; Kimura, Koutarou D; Yemini, Eviatar; Kato, Saul; NeurobiologyWe develop a data harmonization approach for C. elegans volumetric microscopy data, consisting of a standardized format, pre-processing techniques, and human-in-the-loop machine-learning-based analysis tools. Using this approach, we unify a diverse collection of 118 whole-brain neural activity imaging datasets from five labs, storing these and accompanying tools in an online repository WormID (wormid.org). With this repository, we train three existing automated cell-identification algorithms, CPD, StatAtlas, and CRF_ID, to enable accuracy that generalizes across labs, recovering all human-labeled neurons in some cases. We mine this repository to identify factors that influence the developmental positioning of neurons. This growing resource of data, code, apps, and tutorials enables users to (1) study neuroanatomical organization and neural activity across diverse experimental paradigms, (2) develop and benchmark algorithms for automated neuron detection, segmentation, cell identification, tracking, and activity extraction, and (3) share data with the community and comply with data-sharing policies.Publication Deep learning-based aberration compensation improves contrast and resolution in fluorescence microscopy(2025-01-02) Guo, Min; Wu, Yicong; Hobson, Chad M; Su, Yijun; Qian, Shuhao; Krueger, Eric; Christensen, Ryan; Kroeschell, Grant; Bui, Johnny; Chaw, Matthew; Zhang, Lixia; Liu, Jiamin; Hou, Xuekai; Han, Xiaofei; Lu, Zhiye; Ma, Xuefei; Zhovmer, Alexander; Combs, Christian; Moyle, Mark; Yemini, Eviatar; Liu, Huafeng; Liu, Zhiyi; Benedetto, Alexandre; La Riviere, Patrick; Colón-Ramos, Daniel; Shroff, Hari; Neurobiology; Yemini LabOptical aberrations hinder fluorescence microscopy of thick samples, reducing image signal, contrast, and resolution. Here we introduce a deep learning-based strategy for aberration compensation, improving image quality without slowing image acquisition, applying additional dose, or introducing more optics. Our method (i) introduces synthetic aberrations to images acquired on the shallow side of image stacks, making them resemble those acquired deeper into the volume and (ii) trains neural networks to reverse the effect of these aberrations. We use simulations and experiments to show that applying the trained 'de-aberration' networks outperforms alternative methods, providing restoration on par with adaptive optics techniques; and subsequently apply the networks to diverse datasets captured with confocal, light-sheet, multi-photon, and super-resolution microscopy. In all cases, the improved quality of the restored data facilitates qualitative image inspection and improves downstream image quantitation, including orientational analysis of blood vessels in mouse tissue and improved membrane and nuclear segmentation in C. elegans embryos.Publication Neuroinflammation in Alzheimer disease(2024-12-09) Heneka, Michael T.; van der Flier, Wiesje M.; Jessen, Frank; Hoozemanns, Jeroen; Thal, Dietmar Rudolf; Boche, Delphine; Brosseron, Frederic; Teunissen, Charlotte; Zetterberg, Henrik; Jacobs, Andreas H.; Edison, Paul; Ramirez, Alfredo; Cruchaga, Carlos; Lambert, Jean-Charles; Laza, Agustin Ruiz; Sanchez-Mut, Jose Vicente; Fischer, Andre; Castro-Gomez, Sergio; Stein, Thor D.; Kleineidam, Luca; Wagner, Michael; Neher, Jonas J.; Cunningham, Colm; Singhrao, Sim K.; Prinz, Marco; Glass, Christopher K.; Schlachetzki, Johannes C. M.; Butovsky, Oleg; Kleemann, Kilian; De Jaeger, Philip L.; Scheiblich, Hannah; Brown, Guy C.; Landreth, Gary; Moutinho, Miguel; Grutzendler, Jaime; Gomez-Nicola, Diego; McManus, Róisín M.; Andreasson, Katrin; Ising, Christina; Karabag, Deniz; Baker, Darren J.; Liddelow, Shane A.; Verkhratsky, Alexei; Tansey, Malu; Monsonego, Alon; Aigner, Ludwig; Guillaume, Dorothée; Nave, Klaus-Armin; Simons, Mikael; Constantin, Gabriela; Rosenzweig, Neta; Pascual, Alberto; Petzold, Gabor C.; Kipnis, Jonathan; Venegas, Carmen; Colonna, Marco; Walter, Jochen; Tenner, Andrea J.; O’Banion, M. Kerry; Steinert, Joern R.; Feinstein, Douglas L.; Sastre, Magdalena; Bhaskar, Kiran; Hong, Soyon; Schafer, Dorothy P.; Golde, Todd; Ransohoff, Richard M.; Morgan, David; Breitner, John; Mancuso, Renzo; Riechers, Sean-Patrick; Brudnick Neuropsychiatric Research Institute; Neurobiology; Schafer LabIncreasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.Publication Dopamine transporter endocytic trafficking: Neuronal mechanisms and potential impact on DA-dependent behaviors.(2024-12-10) Bolden, Nicholas C; Pavchinskiy, Rebecca G; Melikian, Haley E; Neurobiology; Morningside Graduate School of Biomedical Sciences; Brudnick Neuropsychiatric Research Institute; Melikian LabThe dopamine (DA) transporter (DAT) is a major determinant of DAergic neurotransmission, and is a primary target for addictive and therapeutic psychostimulants. Evidence accumulated over decades in cell lines and in vitro preparations revealed that DAT function is acutely regulated by membrane trafficking. Many of these findings have recently been validated in vivo and in situ, and several behavioral and physiological findings raise the possibility that regulated DAT trafficking may impact DA signaling and DA-dependent behaviors. Here we review key DAT trafficking findings across multiple systems, and discuss the cellular mechanisms that mediate DAT trafficking, as well as the endogenous receptors and signaling pathways that drive regulated DAT trafficking. We additionally discuss recent findings that DAT trafficking dysfunction correlates to perturbations in DA signaling and DA-dependent behaviors.Publication Cell non-autonomous signaling through the conserved C. elegans glycoprotein hormone receptor FSHR-1 regulates cholinergic neurotransmission(2024-11-19) Buckley, Morgan; Jacob, William P; Bortey, Letitia; McClain, Makenzi E; Ritter, Alyssa L; Godfrey, Amy; Munneke, Allyson S; Ramachandran, Shankar; Kenis, Signe; Kolnik, Julie C; Olofsson, Sarah; Nenadovich, Milica; Kutoloski, Tanner; Rademacher, Lillian; Alva, Alexandra; Heinecke, Olivia; Adkins, Ryan; Parkar, Shums; Bhagat, Reesha; Lunato, Jaelin; Beets, Isabel; Francis, Michael M; Kowalski, Jennifer R; Neurobiology; Francis LabModulation of neurotransmission is key for organismal responses to varying physiological contexts such as during infection, injury, or other stresses, as well as in learning and memory and for sensory adaptation. Roles for cell autonomous neuromodulatory mechanisms in these processes have been well described. The importance of cell non-autonomous pathways for inter-tissue signaling, such as gut-to-brain or glia-to-neuron, has emerged more recently, but the cellular mechanisms mediating such regulation remain comparatively unexplored. Glycoproteins and their G protein-coupled receptors (GPCRs) are well-established orchestrators of multi-tissue signaling events that govern diverse physiological processes through both cell-autonomous and cell non-autonomous regulation. Here, we show that follicle stimulating hormone receptor, FSHR-1, the sole Caenorhabditis elegans ortholog of mammalian glycoprotein hormone GPCRs, is important for cell non-autonomous modulation of synaptic transmission. Inhibition of fshr-1 expression reduces muscle contraction and leads to synaptic vesicle accumulation in cholinergic motor neurons. The neuromuscular and locomotor defects in fshr-1 loss-of-function mutants are associated with an underlying accumulation of synaptic vesicles, build-up of the synaptic vesicle priming factor UNC-10/RIM, and decreased synaptic vesicle release from cholinergic motor neurons. Restoration of FSHR-1 to the intestine is sufficient to restore neuromuscular activity and synaptic vesicle localization to fshr-1-deficient animals. Intestine-specific knockdown of FSHR-1 reduces neuromuscular function, indicating FSHR-1 is both necessary and sufficient in the intestine for its neuromuscular effects. Re-expression of FSHR-1 in other sites of endogenous expression, including glial cells and neurons, also restored some neuromuscular deficits, indicating potential cross-tissue regulation from these tissues as well. Genetic interaction studies provide evidence that downstream effectors gsa-1/GαS, acy-1/adenylyl cyclase and sphk-1/sphingosine kinase and glycoprotein hormone subunit orthologs, GPLA-1/GPA2 and GPLB-1/GPB5, are important for intestinal FSHR-1 modulation of the NMJ. Together, our results demonstrate that FSHR-1 modulation directs inter-tissue signaling systems, which promote synaptic vesicle release at neuromuscular synapses.Publication Comamonas aquatica inhibits TIR-1/SARM1 induced axon degeneration [preprint](2024-11-21) O'Connor, Lauren C; Kang, Woo Kyu; Vo, Paula; Spinelli, Jessica B; Alkema, Mark J; Byrne, Alexandra B; Neurobiology; NeuroNexus Institute; Program in Molecular Medicine; Alkema Lab; Byrne LabEmerging evidence suggests the microbiome critically influences the onset and progression of neurodegenerative diseases; however, the identity of neuroprotective bacteria and the molecular mechanisms that respond within the host remain largely unknown. We took advantage of well characterized nervous system and ability to eat uni-bacterial diets to determine how metabolites and neuroprotective molecules from single species of bacteria suppress degeneration of motor neurons. We found significantly protects against degeneration induced by overexpressing a key regulator of axon degeneration, TIR-1/SARM1. Genetic analyses and metabolomics reveal protects against neurodegeneration by providing sufficient Vitamin B12 to activate METR-1/MTR methionine synthase in the intestine, which then lowers toxic levels of homocysteine in TIR-1-expressing animals. Defining a molecular pathway between and neurodegeneration adds significantly to our understanding of gut-brain interactions and, given the prominent role of homocysteine in neurodegenerative disorders, reveals how such a bacterium could protect against disease.Publication Inhibiting AMPA receptor signaling in oligodendrocytes rescues synapse loss in a model of autoimmune demyelination(2024-10-22) Mey, Gabrielle M; Evonuk, Kirsten S; Shelestak, John; Irfan, Muhammad; Wolfe, Laura M; Laye, Sophia E; Schafer, Dorothy P; DeSilva, Tara M; Brudnick Neuropsychiatric Research Institute; Neurobiology; Schafer LabMultiple sclerosis (MS) is initially characterized by myelin and axonal damage in central nervous system white matter lesions, but their causal role in synapse loss remains undefined. Gray matter atrophy is also present early in MS, making it unclear if synaptic alterations are driven by white matter demyelinating lesions or primary gray matter damage. Furthermore, whether axonal pathology occurs secondary to or independent of demyelination to drive synaptic changes is not clear. Here, we address whether reducing demyelination by selectively manipulating glutamatergic signaling in mature oligodendrocytes (OLs) preserves synapses in experimental autoimmune encephalomyelitis (EAE), a preclinical model of demyelinating disease. We demonstrate that inducible reduction of the GluA4 AMPA-type glutamate receptor subunit selectively in mature (OLs) reduces demyelination and axonal injury, preserves synapses, and improves visual function during EAE. These data link demyelination to the pathophysiology of synaptic loss with therapeutic implications for both motor and cognitive disability in MS.Publication Crosstalk between the circatidal and circadian clocks mediates behavioral adaptation to tidal patterns(2024-10-22) Kwiatkowski, Erica R; Rosenthal, Joshua J C; Emery, Patrick; Neurobiology; Emery LabThe ability to anticipate tides is critical for a wide range of marine organisms, but this task is complicated by the diversity of tidal patterns on Earth. Previous findings suggest that organisms whose geographic range spans multiple types of tidal cycles can produce distinct patterns of rhythmic behavior that correspond to the tidal cycles they experience. How this behavioral plasticity is achieved, however, is unclear. Here, we show that Parhyale hawaiensis adapts its rhythmic behavior to various naturally occurring tidal regimens through the plastic contribution of its circatidal and circadian clocks. After entrainment to a tidal cycle that deviated only mildly from a regular 12.4 h tidal cycle, animals exhibited strong circatidal rhythms. By contrast, following entrainment to more irregularly spaced tides or to tides that occurred every 24.8 h, a significant fraction of animals instead synchronized to the light/dark (LD) cycle and exhibited circadian behavior, while others showed rhythmic behavior with both circatidal and circadian traits. We also show that the circatidal clock, while able to entrain to various naturally occurring tidal patterns, does not entrain to an unnatural one. We propose that Parhyale hawaiensis's ecological success around the world relies in part on the plastic interactions between the circatidal and circadian clocks, which shape its rhythmic behavior appropriately according to tidal patterns.Publication Nucleic acid sensing in the central nervous system: Implications for neural circuit development, function, and degeneration(2024-11-06) Stillman, Jacob M; Kiniwa, Tsuyoshi; Schafer, Dorothy P; Neurobiology; Brudnick Neuropsychiatric Research Institute; Morningside Graduate School of Biomedical Sciences; Schafer LabNucleic acids are a critical trigger for the innate immune response to infection, wherein pathogen-derived RNA and DNA are sensed by nucleic acid sensing receptors. This subsequently drives the production of type I interferon and other inflammatory cytokines to combat infection. While the system is designed such that these receptors should specifically recognize pathogen-derived nucleic acids, it is now clear that self-derived RNA and DNA can also stimulate these receptors to cause aberrant inflammation and autoimmune disease. Intriguingly, similar pathways are now emerging in the central nervous system in neurons and glial cells. As in the periphery, these signaling pathways are active in neurons and glia to present the spread of pathogens in the CNS. They further appear to be active even under steady conditions to regulate neuronal development and function, and they can become activated aberrantly during disease to propagate neuroinflammation and neurodegeneration. Here, we review the emerging new roles for nucleic acid sensing mechanisms in the CNS and raise open questions that we are poised to explore in the future.Publication Operant ethanol self-administration behaviors do not predict sex differences in continuous access home cage drinking(2024-08-30) Yoon, Hye Jean; Doyle, Marie A; Altemus, Megan E; Bethi, Rishik; Lago, Sofia H; Winder, Danny G; Calipari, Erin S; Neurobiology; Winder LabUnderstanding sex differences in disease prevalence is critical to public health, particularly in the context of alcohol use disorder (AUD). The goal of this study was to understand sex differences in ethanol drinking behavior and define the precise conditions under which sex differences emerge. Consistent with prior work, C57BL/6J females drank more than males under continuous access two-bottle choice conditions. However, using ethanol self-administration - where an operant response results in access to an ethanol sipper for a fixed time period - we found no sex differences in operant response rates or ethanol consumption (volume per body weight consumed, as well as lick behavior). This remained true across a wide range of parameters including acquisition, when the ethanol sipper access period was manipulated, and when the concentration of the ethanol available was scaled. The only sex differences observed were in total ethanol consumption, which was explained by differences in body weight between males and females, rather than by sex differences in motivation to drink. Using dimensionality reduction approaches, we found that drinking behavior in the operant context did not cluster by sex, but rather clustered by high and low drinking phenotypes. Interestingly, these high and low drinking phenotypes in the operant context showed no correlation with those same categorizations in the home cage context within the same animals. These data underscore the complexity of sex differences in ethanol consumption, highlighting the important role that drinking conditions/context plays in the expression of these differences.Publication Role of Microglia in Central Nervous System Development and Plasticity(2024-09-30) Schafer, Dorothy P; Stevens, Beth; Bennett, Mariko L; Bennett, Frederick C; Brudnick Neuropsychiatric Research Institute; Neurobiology; Schafer LabThe nervous system comprises a remarkably diverse and complex network of cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS, and highlight exciting new discoveries about their contributions to CNS development, maintenance, and plasticity.Publication A Novel Mouse Home Cage Lickometer System Reveals Sex- and Housing-Based Influences on Alcohol Drinking(2024-10-09) Petersen, Nicholas; Adank, Danielle N; Quan, Yizhen; Edwards, Caitlyn M; Hallal, Sabrina D; Taylor, Anne; Winder, Danny G; Doyle, Marie A; Neurobiology; Winder LabAlcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress or novelty-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these effects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology.