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The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT 2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT 2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT 2A receptors within adult glia reestablishes “critical period-like” experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT 2A receptors for experience-dependent synapse elimination.

Serotonin (5-hydroxytryptamine, 5-HT) has central roles enabling learning and memory, particularly via serotonin receptor 2A (5-HT 2A R) signaling. Drosophila Fragile X syndrome model ( dfmr1 null mutant) studies reveal impaired learning and memory, which may reflect serotonergic signaling deficits. Here, we use classical olfactory T-maze conditioning to assess behavior, combined with imaging to assess 5-HT and 5-HT 2A R levels within the underlying Mushroom Body (MB) brain circuitry. Null dfmr1 mutants exhibit learning and memory deficits that are corrected by elevating 5-HT signaling via 1) overexpression of the serotonin biosynthetic enzyme tryptophan hydroxylase (Trhn) or 2) knockdown of the serotonin reuptake transporter (SERT). Direct comparisons reveal both Trhn and SERT manipulations equally restore learning and memory in dfmr1 null mutants. 5-HT 2A R levels in the MB circuit are reduced relative to controls in dfmr1 mutants, and 5-HT 2A R RNAi phenocopies dfmr1 null behavioral deficits, suggesting these phenotypes are primarily caused by the loss of 5-HT 2A R signaling. Consistently, 5-HT 2A R overexpression in dfmr1 nulls restores normal learning and memory compared to controls. These findings suggest loss of 5-HT 2A R signaling causes learning and memory deficits in this Fragile X syndrome model, and that rectifying this signaling impairment can restore learning and memory, providing a framework for serotonergic intervention strategies.

Background Young adult cancer survivors experience early aging‐related morbidities and mortality. Biological aging biomarkers may identify at‐risk survivors and increase our understanding of mechanisms underlying this accelerated aging. Methods Using an observational study design, we cross‐sectionally measured DNA methylation‐based epigenetic age in young adult cancer survivors at a tertiary, academic state cancer hospital. Participants were a convenience sample of consecutively enrolled survivors of childhood, adolescent, and young adult cancers treated with either an anthracycline or alkylating agent, and who were at least 3 months post‐treatment. Similarly aged healthy comparators were consecutively enrolled. Cancer treatment and treatment intensity were compared to DNA methylation‐based epigenetic age and pace of aging. Results Sixty survivors (58 completing assessments, mean age 20.5 years, range 18–29) and 27 comparators (mean age 20 years, range 17–29) underwent DNA methylation measurement. Survivors were predominantly female (62%) and white (60%) and averaged nearly 6 years post‐treatment (range 0.2–25 years). Both epigenetic age (AgeAccelGrim: 1.5 vs. −2.4, p < 0.0001; AgeAccelPheno 2.3 vs. −3.8, p = 0.0013) and pace of aging (DunedinPACE 0.99 vs. 0.83, p < 0.0001) were greater in survivors versus comparators. In case–case adjusted analysis, compared to survivors with normal muscle mass, myopenic survivors had higher AgeAccelGrim (2.2 years, 95% CI 0.02–4.33, p = 0.02), AgeAccelPheno (6.2 years, 2.36–10.09, p < 0.001), and DunedinPACE (0.11, 0.05–0.17, p < 0.001). Conclusions Epigenetic age is older and pace of aging is faster in young adult cancer survivors compared to noncancer peers, which is evident in the early post‐therapy period. Survivors with physiological impairment demonstrate greater epigenetic age advancement. Measures of epigenetic age may identify young adult survivors at higher risk for poor functional and health outcomes. In this cohort study of 58 young adult cancer survivors and 27 comparably aged, noncancer comparators, epigenetic age was greater among survivors compared to controls. Among survivors, greater epigenetic age was associated with myopenia and frailty. Young adult cancer survivors have greater epigenetic age potentially providing a useful tool to assess risk for physiological impairment, disability, and poor health.

Abstract Race is a social construct, commonly used in epidemiologic research to adjust for confounding. However, adjustment of race may mask racial disparities, thereby perpetuating structural racism. We conducted a systematic review of articles published in Epidemiology and American Journal of Epidemiology between 2020 and 2021 to (1) understand how race, ethnicity, and similar social constructs were operationalized, used, and reported; and (2) characterize good and poor practices of utilization and reporting of race data on the basis of the extent to which they reveal or mask systemic racism. Original research articles were considered for full review and data extraction if race data were used in the study analysis. We extracted how race was categorized, used—as a descriptor, confounder, or for effect measure modification (EMM)—and reported if the authors discussed racial disparities and systemic bias–related mechanisms responsible for perpetuating the disparities. Of the 561 articles, 299 had race data available and 192 (34.2%) used race data in analyses. Among the 160 US-based studies, 81 different racial categorizations were used. Race was most often used as a confounder (52%), followed by effect measure modifier (33%), and descriptive variable (12%). Fewer than 1 in 4 articles (22.9%) exhibited good practices (EMM along with discussing disparities and mechanisms), 63.5% of the articles exhibited poor practices (confounding only or not discussing mechanisms), and 13.5% were considered neither poor nor good practices. We discuss implications and provide 13 recommendations for operationalization, utilization, and reporting of race in epidemiologic and public health research.

Synapse connectivity is optimized in response to environmental input in critical periods, characterized by experience-dependent, temporally-restricted, and transiently-reversible synapse pruning by glial phagocytes. This precise, targeted synaptic elimination process requires glial serotonergic intercellular signaling. We discover glia-to-glia communication between different glial classes is essential for experience-dependent synaptic pruning in a well-defined Drosophila juvenile brain olfactory critical period. We find ensheathing glia infiltrate specific target synaptic glomeruli in response to guiding odorant experience via 5-HT2A receptor (5-HT2AR) signaling. Using cell-targeted tryptophan hydroxylase (Trhn) RNAi to block serotonin production, we discover serotonin signaling from ensheathing glia is required for experience-dependent synapse pruning. Using cell-targeted 5-HT2AR RNAi, we find the serotonin receptor is required exclusively in astrocyte-like glia (ALG). Using cell-targeted 5-HT2AR rescue in 5-HT2AR null mutants, we discover the serotonin receptor mediates experience-dependent synapse pruning. Thus, glia-to-glia serotonin signaling between different glial classes mediated by 5-HT2A receptors is necessary and sufficient for synapse elimination. We discover that ALG-targeted conditional 5-HT2AR in mature adults induces experience-dependent synapse pruning indistinguishable from the critical period mechanism. Thus, astrocyte 5-HT2AR signaling is sufficient to 're-open' this characteristic critical period remodeling capability at maturity. We find astrocytic matrix metalloproteinase-1 (MMP-1) induced by critical period odorant experience is required for experience-dependent synapse pruning downstream of 5HT2AR activation. We discover that ALG-targeted MMP-1 induction restores synapse pruning in the absence of 5HT2AR signaling. Taken together, we conclude that glia-to-glia serotonergic 5HT2AR signaling drives MMP-1 for experience-dependent infiltration phagocytosis synapse pruning, and can rekindle this remodeling capacity at adult maturity.

Experience-dependent brain circuit optimization choreographed by environmental sensory input activity involves synapse formation, pruning, and remodeling to sculpt appropriate connectivity. The serotonin (5-HT) neuromodulator acts as a core regulator of this circuit plasticity. Classically, serotonergic control has been understood solely through neuronal mechanisms, however new evidence reveals glial 5-HT signaling roles. This review focuses on recent studies in Drosophila with reference to foundational mammalian work to discuss 5-HT functions in both neurons and glia, particularly experience-dependent extracellular matrix remodeling, glial infiltration, and synapse elimination in early-life critical periods. Disruption of serotonergic regulation is proposed to contribute to a spectrum of neurodevelopmental disorders, including Fragile X syndrome, in which failure to prune and persistence of immature connectivity cause severe life-long behavioral impairments. Recent discoveries further reveal targeted induction of glial serotonergic signaling can re-open “critical period-like” synapse pruning at maturity. Enabling large-scale connectivity changes has broad potential therapeutic applications for disease, injury, trauma, and cognitive dysfunction. A key advance is the emerging evidence that glia—not just neurons—are serotonergic mediators of synaptic remodeling: glial 5-HT biosynthesis, 5-HT 2A receptor activation, and matrix metalloprotease-mediated function together allow access for experience-driven synapse elimination. We propose glia-to-glia class serotonergic signaling—linking sensory experience to synapse pruning—may represent a conserved plasticity gating mechanism that determines whether circuitry is permissive or resistant to synaptic connectivity modification. Harnessing glial class-specific serotonergic control of experience-dependent brain circuit remodeling may enable new targeted therapies to correct brain function while avoiding the negative side effects of global serotonin elevation.

The neurofibromatoses (neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis) are rare disorders having clinical manifestations that vary greatly from patient to patient. The rarity and variability of these disorders has made it challenging for investigators to identify sufficient numbers of patients with particular clinical characteristics or specific germline mutations for participation in interventional studies. Similarly, because the natural history of all types of neurofibromatosis (NF) is variable and unique for each individual, it is difficult to identify meaningful clinical outcome measures for potential therapeutic interventions. In 2012, the Children's Tumor Foundation created a web-based patient-entered database, the NF Registry, to inform patients of research opportunities for which they fit general eligibility criteria and enable patients to contact investigators who are seeking to enroll patients in approved trials. Registrants were recruited through CTF-affiliated NF clinics and conferences, through its website, and by word-of-mouth and social media. Following online consent, demographic information and details regarding manifestations of NF were solicited on the Registry website. Statistical analyses were performed on data from a cohort of 4680 registrants (the number of registrants as of October 9, 2015) who met diagnostic criteria for one of the 3 NF conditions. The analyses support our hypothesis that patient-reported symptom incidences in the NF Registry are congruent with published clinician-sourced data. Between April 26, 2013 and July 8, 2016, the registry has been useful to investigators in recruitment, particularly for observational trials, especially those for development of patient-reported outcomes.

Experience-dependent glial synapse pruning plays a pivotal role in sculpting brain circuit connectivity during early-life critical periods of development. Recent advances suggest a layered cascade of intercellular communication between neurons and glial phagocytes orchestrates this precise, targeted synapse elimination. We focus here on studies from the powerful Drosophila forward genetic model, with reference to complementary findings from mouse work. We present both neuron-to-glia and glia-to-glia intercellular signaling pathways directing experience-dependent glial synapse pruning. We discuss a putative hierarchy of secreted long-distance cues and cell surface short-distance cues that act to sequentially orchestrate glia activation, infiltration, target recognition, engulfment, and then phagocytosis for synapse pruning. Ligand-receptor partners mediating these stages in different contexts are discussed from recent Drosophila and mouse studies. Signaling cues include phospholipids, small neurotransmitters, insulin-like peptides, and proteins. Conserved receptors for these ligands are discussed, together with mechanisms where the receptor identity remains unknown. Potential mechanisms are proposed for the tight temporal-restriction of heightened experience-dependent glial synapse elimination during early-life critical periods, as well as potential means to re-open such plasticity at maturity.

Background/Objectives: Increasing evidence supports the hypothesis that dietary intervention can improve pain among individuals with headaches, including migraine, a highly prevalent condition that can be disabling. Non-pharmacologic treatments for migraine are particularly attractive. In this secondary analysis of 182 participants enrolled in a randomized controlled trial of a dietary intervention designed to increase omega-3 (n-3) compared with a control diet, we examined the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both thought to decrease inflammatory processes. Methods: Path models with two time points (baseline and 16 weeks after randomization), were used to test the relationships between exposures of n-3 blood levels and self-reported dietary intake on outcomes of pain interference using the PROMIS pain interference scale and the Headache Impact Test (HIT-6). Model building was based on our published conceptual model. Results: Good fit was demonstrated for both models (EPA model: CFI = 0.984, RMSEA = 0.039, and SRMR = 0.045; DHA model: CFI = 0.981, RMSEA = 0.040, and SRMR = 0.040). Both EPA and DHA in the blood at 16 weeks were associated with lower levels of pain interference, but the effect for EPA was stronger (B = −0.56, p < 0.001 for EPA, and B = −0.43, p = 0.057 for DHA). Conclusions: Our findings are consistent with an indirect pathway linking diet to pain interference through blood levels of EPA and DHA in migraine.