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ABOUT THIS COLLECTION

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. Use the “UMass Chan Affiliation” Filter by Category in the left sidebar to see the publications produced by a specific lab.

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Recently Published

  • A Novel Mouse Home Cage Lickometer System Reveals Sex- and Housing-Based Influences on Alcohol Drinking

    Petersen, Nicholas; Adank, Danielle N; Quan, Yizhen; Edwards, Caitlyn M; Hallal, Sabrina D; Taylor, Anne; Winder, Danny G; Doyle, Marie A (2024-10-09)
    Alcohol 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.
  • Role of Microglia in Central Nervous System Development and Plasticity

    Schafer, Dorothy P; Stevens, Beth; Bennett, Mariko L; Bennett, Frederick C (2024-09-30)
    The 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.
  • Operant ethanol self-administration behaviors do not predict sex differences in continuous access home cage drinking

    Yoon, Hye Jean; Doyle, Marie A; Altemus, Megan E; Bethi, Rishik; Lago, Sofia H; Winder, Danny G; Calipari, Erin S (2024-08-30)
    Understanding 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.
  • Bed nucleus of the stria terminalis network responses to unpredictable threat in early alcohol abstinence

    Zabik, Nicole L; Flook, Elizabeth A; Feola, Brandee; Benningfield, Margaret M; Silveri, Marisa M; Winder, Danny G; Blackford, Jennifer Urbano (2024-08-24)
    Background: Anxiety during early alcohol abstinence, likely resulting from neural changes caused by chronic alcohol use, contributes to high relapse rates. Studies in rodents show heightened activation during early abstinence in the bed nucleus of the stria terminalis (BNST)-a neural hub for anxiety-and its extended anxiety-related corticolimbic network. Despite the clinical importance of early abstinence, few studies investigate the underlying neural mechanisms. Methods: To address this gap, we investigated brain function in early alcohol abstinence (EA = 20, 9 women) relative to controls (HC = 20, 11 women) using an unpredictable threat task shown to engage the BNST and corticolimbic brain regions involved in anxiety and alcohol use disorder (AUD). Group, anxiety, and sex were predictors used to determine whole-brain activation and BNST functional connectivity. Results: We found widespread interactions of group × anxiety and group × anxiety × sex for both activation and BNST connectivity during unpredictable threat. In the EA group, higher anxiety was correlated with activation in the BNST, rostral anterior cingulate cortex (ACC), insula (men only), and dorsal ACC (men only). In the HC group, higher anxiety was negatively correlated with activation in the BNST, nucleus accumbens, thalamus, and insula (men only). For connectivity, anxiety was positively correlated in EA and negatively correlated in HC, between the BNST and the amygdala, ventromedial prefrontal cortex (PFC), and dorsomedial PFC; EA men showed stronger BNST-vmPFC connectivity than HC men. Conclusions: These novel findings provide preliminary evidence for alterations in the BNST and anxiety-related corticolimbic brain regions in early alcohol abstinence, adding to growing literature in humans supporting the BNST's role in anxiety and sex-dependent effects of chronic alcohol use.
  • BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

    Doyle, Marie A; Salimando, Gregory J; Altemus, Megan E; Badt, Justin K; Bedenbaugh, Michelle N; Vardy, Alexander S; Adank, Danielle N; Park, Anika S; Winder, Danny G (2024-08-23)
    Background: Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST) and Crh+ neurons in this region play a key role in chronic ethanol-induced increases in volitional intake, hypothesized to be driven by emergent negative affective behaviors. Excitatory N-methyl-d-aspartate receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. Specifically, GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. Methods: Male and female mice underwent a home cage chronic drinking forced abstinence model (CDFA) to assess the impact of 1 day or 2 weeks of ethanol abstinence on BNST synaptic transmission and BNST Grin gene expression. Constitutive and conditional BNST GluN2D knockout mice were used to assess the impact of GluN2D deletion on continuous access ethanol intake as well as negative affect behaviors, using the open field, elevated zero maze, and forced swim tasks. Results: We report here that excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Further, knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in the dBNST or dBNST Crh+ neurons. Finally, we find that deletion of GluN2D fails to alter negative affect in ethanol-naïve female mice. Conclusions: These data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking but not ethanol abstinence, highlighting sex differences and behavioral specificity. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.
  • Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration

    Hochbaum, Daniel R; Hulshof, Lauren; Urke, Amanda; Wang, Wengang; Dubinsky, Alexandra C; Farnsworth, Hannah C; Hakim, Richard; Lin, Sherry; Kleinberg, Giona; Robertson, Keiramarie; et al. (2024-08-19)
    Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.
  • West Nile Virus-Induced Expression of Senescent Gene Regulates Microglial Phenotype within Cerebral Cortex

    Arutyunov, Artem; Duran-Laforet, Violeta; Ai, Shenjian; Ferrari, Loris; Murphy, Robert; Schafer, Dorothy P; Klein, Robyn S (2024-07-08)
    Microglia, the resident macrophages of the central nervous system, exhibit altered gene expression in response to various neurological conditions. This study investigates the relationship between West Nile Virus infection and microglial senescence, focusing on the role of LGALS3BP, a protein implicated in both antiviral responses and aging. Using spatial transcriptomics, RNA sequencing and flow cytometry, we characterized changes in microglial gene signatures in adult and aged mice following recovery from WNV encephalitis. Additionally, we analyzed Lgals3bp expression and generated Lgals3bp-deficient mice to assess the impact on neuroinflammation and microglial phenotypes. Our results show that WNV-activated microglia share transcriptional signatures with aged microglia, including upregulation of genes involved in interferon response and inflammation. Lgals3bp was broadly expressed in the CNS and robustly upregulated during WNV infection and aging. Lgals3bp-deficient mice exhibited reduced neuroinflammation, increased homeostatic microglial numbers, and altered T cell populations without differences in virologic control or survival. These data indicate that LGALS3BP has a role in regulating neuroinflammation and microglial activation and suggest that targeting LGALS3BP might provide a potential route for mitigating neuroinflammation-related cognitive decline in aging and post-viral infections.
  • An orbitocortical-thalamic circuit suppresses binge alcohol-drinking [preprint]

    Gimenez-Gomez, Pablo; Le, Timmy; Zinter, Max; M'Angale, Peter; Duran-Laforet, Violeta; Freels, Timothy G; Pavchinskiy, Rebecca G; Molas, Susanna; Schafer, Dorothy P; Tapper, Andrew R; et al. (2024-07-05)
    Alcohol consumption remains a significant global health challenge, causing millions of direct and indirect deaths annually. Intriguingly, recent work has highlighted the prefrontal cortex, a major brain area that regulates inhibitory control of behaviors, whose activity becomes dysregulated upon alcohol abuse. However, whether an endogenous mechanism exists within this brain area that limits alcohol consumption is unknown. Here we identify a discrete GABAergic neuronal ensemble in the medial orbitofrontal cortex (mOFC) that is selectively recruited during binge alcohol-drinking and intoxication. Upon alcohol intoxication, this neuronal ensemble suppresses binge drinking behavior. Optogenetically silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. We find that this neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. We further show, using brain-wide analysis, that this neuronal ensemble projects widely, and that its projections specifically to the mediodorsal thalamus are responsible for regulating binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by halting alcohol intake. These results provide valuable insights into the complex nature of alcohol abuse and offers potential avenues for the development of mOFC neuronal ensemble-targeted interventions.
  • Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity

    Nabit, Bretton P; Taylor, Anne; Winder, Danny G (2024-06-25)
    Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively) as well as the cortical layers involved in corticothalamic signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (AAV-CRE mediated) and cell type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knockout (PV grm8 KO) mice exhibited 1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and 2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field testing. Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 KD) in repeated open field testing. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.Significance statement Group III mGlu receptors and the Thalamic Reticular Nucleus (TRN) are critical modulators of reciprocal cortico-thalamic neurotransmission and are implicated in anxiety and locomotor behaviors. The present study demonstrates a specific enrichment of grm8 mRNA within the TRN and thalamus-projecting cortical layers and characterizes the role of mGlu8 receptors in controlling spontaneous excitatory neurotransmission onto cells located within the dorsal thalamus and regulating sensorimotor behaviors from open field and PPI testing. These findings add to growing bodies of literature regarding both TRN and grm8 regulation of thalamocortical activity and related behaviors implicated in neurological and neuropsychiatric disorders.
  • A cocaine-activated ensemble exerts increased control over behavior while decreasing in size

    Thibeault, Kimberly C; Leonard, Michael Z; Kondev, Veronika; Emerson, Soren D; Bethi, Rishik; Lopez, Alberto J; Sens, Jonathon P; Nabit, Brett P; Elam, Hannah B; Winder, Danny G; et al. (2024-06-18)
    Background: Substance use disorder (SUD) is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens (NAc). Previous work has shown that cocaine exposure induces plasticity in broad, genetically-defined cell types in the NAc; however, in response to a stimulus, only a small percent of neurons are transcriptionally active - termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure. Method: Using Arc-CreERT2 transgenic mice, we expressed transgenes in Arc+ ensembles activated by cocaine exposure [either acute (1 x 10mg/kg IP), or repeated (10 x 10mg/kg IP)]. Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with SUD. Results: Repeated cocaine exposure reduced the size of the ensemble, while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement. Conclusions: We show that repeated, but not acute, cocaine exposure induces a physiologically distinct ensemble characterized by the expression of the immediate early gene Arc, that is uniquely capable of modulating reinforcement behavior.
  • A master regulator of opioid reward in the ventral prefrontal cortex

    Smith, Alexander C W; Ghoshal, Soham; Centanni, Samuel W; Heyer, Mary P; Corona, Alberto; Wills, Lauren; Andraka, Emma; Lei, Ye; O'Connor, Richard M; Caligiuri, Stephanie P B; et al. (2024-06-07)
    In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.
  • Fly into tranquility: GABA's role in Drosophila sleep

    Chaturvedi, Ratna; Emery, Patrick (2024-06-05)
    Sleep is conserved across the animal kingdom, and Drosophila melanogaster is a prime model to understand its intricate circadian and homeostatic control. GABA (gamma-aminobutyric acid), the brain's main inhibitory neurotransmitter, plays a central role in sleep. This review delves into GABA's complex mechanisms of actions within Drosophila's sleep-regulating neural networks. We discuss how GABA promotes sleep, both by inhibiting circadian arousal neurons and by being a key neurotransmitter in sleep homeostatic circuits. GABA's impact on sleep is modulated by glia through astrocytic GABA recapture and metabolism. Interestingly, GABA can be coexpressed with other neurotransmitters in sleep-regulating neurons, which likely contributes to context-based sleep plasticity.
  • Senescent-like microglia limit remyelination through the senescence associated secretory phenotype [preprint]

    Gross, Phillip S; Duran-Laforet, Violeta; Manavi, Zeeba; Zia, Sameera; Lee, Sung Hyun; Shults, Nataliia; Selva, Sean; Alvarez, Enrique; Plemel, Jason R; Schafer, Dorothy P; et al. (2024-05-26)
    The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence-associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.
  • A novel mouse home cage lickometer system reveals sex- and housing-based influences on alcohol drinking [preprint]

    Petersen, Nicholas; Adank, Danielle N; Quan, Yizhen; Edwards, Caitlyn M; Taylor, Anne; Winder, Danny G; Doyle, Marie A (2024-05-23)
    Alcohol 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-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.
  • BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice [preprint]

    Doyle, Marie A; Salimando, Gregory J; Altemus, Megan E; Badt, Justin K; Bedenbaugh, Michelle N; Vardy, Alexander S; Adank, Danielle N; Park, Anika S; Winder, Danny G (2024-04-21)
    Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and Crh + neurons in this region are thought to play a key role in chronic ethanol-induced increases in volitional ethanol intake. This role has been hypothesized to be driven by emergent BNST-dependent negative affective behaviors. Indeed, we report here that in female mice undergoing a home cage chronic drinking forced abstinence model (CDFA), excitatory transmission undergoes time-dependent upregulation in BNST Crh + cells. Excitatory NMDA receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. We find that knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in dBNST or specifically in dBNST Crh + neurons. Finally, to determine the impact of GluN2D expression on negative affective behaviors, open field, elevated zero maze, and forced swim tasks were used to measure anxiety- and depressive-like behaviors in constitutive and conditional BNST GluN2D knockout mice. Surprisingly, we find that deletion of GluN2D fails to alter negative affect in ethanol-naïve female mice. Together, these data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking behaviors but not abstinence from ethanol, highlighting potential sex differences and behavioral specificity in the context of AUD behaviors. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.
  • Microglia phagocytic mechanisms: Development informing disease

    Beiter, Rebecca M; Sheehan, Patrick W; Schafer, Dorothy P (2024-04-16)
    Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important for sculpting the cellular architecture. This includes the engulfment of dead/dying cells, pruning extranumerary synapses and axons, and phagocytosing fragments of myelin sheaths. Intriguingly, these developmental phagocytic mechanisms by which microglia sculpt the CNS are now appreciated as important for eliminating synapses, myelin, and proteins during neurodegeneration. Here, we discuss parallels between neurodevelopment and neurodegeneration, which highlights how development is informing disease. We further discuss recent advances and challenges towards therapeutically targeting these phagocytic pathways and how we can leverage development to overcome these challenges.
  • Eviatar Yemini

    Yemini, Eviatar (2024-04-08)
    Interview with Eviatar Yemini, who studies how neurobehavioral circuits grow and evolve to meet the needs at different stages of development at UMass Chan Medical School.
  • Dopamine control of social novelty preference is constrained by an interpeduncular-tegmentum circuit

    Molas, Susanna; Freels, Timothy G; Zhao-Shea, Rubing; Lee, Timothy; Gimenez-Gomez, Pablo; Barbini, Melanie; Martin, Gilles E; Tapper, Andrew R (2024-04-03)
    Animals are inherently motivated to explore social novelty cues over familiar ones, resulting in a novelty preference (NP), although the behavioral and circuit bases underlying NP are unclear. Combining calcium and neurotransmitter sensors with fiber photometry and optogenetics in mice, we find that mesolimbic dopamine (DA) neurotransmission is strongly and predominantly activated by social novelty controlling bout length of interaction during NP, a response significantly reduced by familiarity. In contrast, interpeduncular nucleus (IPN) GABAergic neurons that project to the lateral dorsal tegmentum (LDTg) were inhibited by social novelty but activated during terminations with familiar social stimuli. Inhibition of this pathway during NP increased interaction and bout length with familiar social stimuli, while activation reduced interaction and bout length with novel social stimuli via decreasing DA neurotransmission. These data indicate interest towards novel social stimuli is encoded by mesolimbic DA which is dynamically regulated by an IPN→LDTg circuit to control NP.
  • Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis

    Cordano, Christian; Werneburg, Sebastian; Abdelhak, Ahmed; Bennett, Daniel J; Beaudry-Richard, Alexandra; Duncan, Greg J; Oertel, Frederike C; Boscardin, W John; Yiu, Hao H; Jabassini, Nora; et al. (2024-04-03)
    While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.
  • Combinatorial expression of neurexin genes regulates glomerular targeting by olfactory sensory neurons [preprint]

    Park, Sung Jin; Wang, I-Hao; Lee, Namgyu; Jiang, Hao-Ching; Uemura, Takeshi; Futai, Kensuke; Kim, Dohoon; Macosko, Evan; Greer, Paul (2024-04-02)
    Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher cognitive functions. While trans -interactions between synaptic membrane proteins have emerged as crucial elements in orchestrating the assembly of these neural circuits, the synaptic surface proteins involved in neuronal wiring remain largely unknown. Here, using unbiased single-cell transcriptomic and mouse genetic approaches, we uncover that the neurexin family of genes enables olfactory sensory neuron (OSNs) axons to form appropriate synaptic connections with their mitral and tufted (M/T) cell synaptic partners, within the mammalian olfactory system. Neurexin isoforms are differentially expressed within distinct populations of OSNs, resulting in unique pattern of neurexin expression that is specific to each OSN type, and synergistically cooperate to regulate axonal innervation, guiding OSN axons to their designated glomeruli. This process is facilitated through the interactions of neurexins with their postsynaptic partners, including neuroligins, which have distinct expression patterns in M/T cells. Our findings suggest a novel mechanism underpinning the precise assembly of olfactory neural circuits, driven by the trans -interaction between neurexins and their ligands.

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