ABOUT THIS COLLECTION

This collection showcases journal articles, preprints, book chapters, and other publications and presentations produced by faculty, postdocs, and researchers at UMass Chan Medical School.

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Recently Published

  • Francis Fontan (1929-2018): Pioneer pediatric cardiac surgeon

    Huynh, Elisah; Chernick, Rebecca E.; Desai, Manisha S. (2022-09-07)
    Up until the mid-1900s, tricuspid atresia - a birth defect of the tricuspid valve, was once categorized as a "death sentence." The challenge of achieving positive health outcomes for affected patients was compounded by a hesitancy to operate on children. The main concern was safely administering anesthesia to young patients who were going through a strenuous operation that was often poorly tolerated. Despite these assumed limitations, Francis Fontan, a pediatric cardiothoracic surgeon at the Hospital of Tondu in Bordeaux, was able to redirect blood flow from the superior and inferior vena cava to the pulmonary arteries in 1971, which elucidated the process of advancing clinical practice in medicine. With the support of mentors and a firm belief in this new technique, Fontan pioneered his eponymous procedure and ultimately paved the way for modern cardiovascular surgical techniques that helped to prolong the life of those with single functioning ventricles. The aim of this study is to examine the genesis and the evolution of the Fontan procedure to elucidate the process of advancing clinical practice in medicine by utilizing personal interviews, Fontan's works, associated primary and secondary sources in the context of 20th century cardiothoracic surgery and innovations.
  • Shear stress activates nociceptors to drive Drosophila mechanical nociception

    Gong, Jiaxin; Chen, Jiazhang; Gu, Pengyu; Shang, Ye; Ruppell, Kendra Takle; Yang, Ying; Wang, Fei; Wen, Qi; Xiang, Yang (2022-09-02)
    Mechanical nociception is essential for animal survival. However, the forces involved in nociceptor activation and the underlying mechanotransduction mechanisms remain elusive. Here, we address these problems by investigating nocifensive behavior in Drosophila larvae. We show that strong poking stimulates nociceptors with a mixture of forces including shear stress and stretch. Unexpectedly, nociceptors are selectively activated by shear stress, but not stretch. Both the shear stress responses of nociceptors and nocifensive behavior require transient receptor potential A1 (TrpA1), which is specifically expressed in nociceptors. We further demonstrate that expression of mammalian or Drosophila TrpA1 in heterologous cells confers responses to shear stress but not stretch. Finally, shear stress activates TrpA1 in a membrane-delimited manner, through modulation of membrane fluidity. Together, our study reveals TrpA1 as an evolutionarily conserved mechanosensitive channel specifically activated by shear stress and suggests a critical role of shear stress in activating nociceptors to drive mechanical nociception.
  • Paving the way for universal medical student training in serious illness communication: the Massachusetts Medical Schools' Collaborative

    Reidy, Jennifer A; Clark, Melissa A; Berman, Harris A; Chan, Stephanie H; Gawande, Atul A; Streid, Jocelyn; Vesel, Tamara; Young, Megan E; Zehm, April; Schaefer, Kristen G (2022-09-01)
    Background: Patients with serious illness look to their clinicians for discussion and guidance on high-stakes treatment decisions, which are complex, emotional and value-laden. However, required training in serious illness communication is rare in U.S. medical schools, with efforts at curricular reform stymied by competing institutional demands, lack of resources and accreditation requirements. We describe an approach to building and scaling medical student training in serious illness communication through the creation of a statewide collaborative of medical schools. Methods: The Massachusetts Medical Schools' Collaborative is a first-of-its-kind group that promotes longitudinal, developmentally-based curricula in serious illness communication for all students. Convened externally by the Massachusetts Coalition for Serious Illness Care, the collaborative includes faculty, staff, and students from four medical schools. Results: The collaborative started with listening to member's perspectives and collectively developed core competencies in serious illness communication for implementation at each school. We share early lessons on the opportunities, challenges and sustainability of our statewide collective action to influence curricular reform, which can be replicated in other topic areas. Conclusions: Our next steps include curriculum mapping, student focus groups and faculty development to guide successful and enduring implementation of the competencies to impact undergraduate medical education in Massachusetts and beyond.
  • Getting Started with the Scholarly Journal Publication Process

    Sefton, Laura A. (2022-08-25)
    Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA). Shares resources related to getting started in the publication process.
  • Validation of DREADD agonists and administration route in a murine model of sleep enhancement

    Ferrari, Loris L; Ogbeide-Latario, Oghomwen E; Gompf, Heinrich S; Anaclet, Christelle (2022-07-30)
    Chemogenetics is a powerful tool to study the role of specific neuronal populations in physiology and diseases. Of particular interest, in mice, acute and specific activation of parafacial zone (PZ) GABAergic neurons expressing the Designer Receptors Activated by Designer Drugs (DREADD) hM3Dq (PZGABA-hM3Dq) enhances slow-wave-sleep (SWS), and this effect lasts for up to 6 h, allowing prolonged and detailed study of SWS. However, the most widely used DREADDs ligand, clozapine N-oxide (CNO), is metabolized into clozapine which has the potential of inducing non-specific effects. In addition, CNO is usually injected intraperitoneally (IP) in mice, limiting the number and frequency of repeated administration.
  • Prevalence of Bipolar Disorder in Perinatal Women: A Systematic Review and Meta-Analysis

    Masters, Grace A; Hugunin, Julie; Xu, Lulu; Ulbricht, Christine M; Moore Simas, Tiffany A; Ko, Jean Y; Byatt, Nancy (2022-07-13)
    Objective: To estimate overall prevalence of bipolar disorder (BD) and the prevalence and timing of bipolar-spectrum mood episodes in perinatal women. Data Sources: Databases (PubMed, Scopus, PsycINFO, CINAHL, Cochrane, ClincalTrials.gov) were searched from inception to March 2020. Study Selection: Included studies were original research in English that had (1) populations of perinatal participants (pregnant or within 12 months postpartum), aged ≥ 18 years, and (2) a screening/diagnostic tool for BD. Search terms described the population (eg, perinatal), illness (eg, bipolar disorder), and detection (eg, screen, identify). Data Extraction: Study design data, rates, and timing of positive screens/diagnoses and mood episodes were extracted by 3 independent reviewers. Pooled prevalences were estimated using random-effects meta-analyses. Results: Twenty-two articles were included in qualitative review and 12 in the meta-analysis. In women with no known psychiatric illness preceding the perinatal period, pooled prevalence of BD was 2.6% (95% CI, 1.2%-4.5%) and prevalence of bipolar-spectrum mood episodes (including depressed, hypomanic/manic, mixed) during pregnancy and the postpartum period was 20.1% (95% CI, 16.0%-24.5%). In women with a prior BD diagnosis, 54.9% (95% CI, 39.2%-70.2%) were found to have at least one bipolar-spectrum mood episode occurrence in the perinatal period. Conclusions: Our review suggests that the perinatal period is associated with high rates of bipolar-spectrum mood episodes and that pregnant and postpartum women represent a special risk population. This review may help to inform clinical care recommendations, thus helping to identify those who may have.
  • Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8

    Feinberg, Philip A; Becker, Shannon C; Chung, Leeyup; Ferrari, Loris; Stellwagen, David; Anaclet, Christelle; Durán-Laforet, Violeta; Faust, Travis E; Sumbria, Rachita K; Schafer, Dorothy P. (2022-07-05)
    Interferon regulatory factor 8 (IRF8) is a transcription factor necessary for the maturation of microglia, as well as other peripheral immune cells. It also regulates the transition of microglia and other immune cells to a pro-inflammatory phenotype. Irf8 is also a known risk gene for multiple sclerosis and lupus, and it has recently been shown to be downregulated in schizophrenia. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. Here, we show by RNAseq from Irf8 -/- male and female mouse brains that several genes involved in regulation of neural activity are dysregulated. We then show that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to lethal seizures in male and female Irf8 -/- mice. Finally, we identify that TNF-α is elevated specifically in microglia in the CNS, and genetic or acute pharmacological blockade of TNF-α in the Irf8 -/- CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-α on neural circuits. Our data further suggest that neuronal function is impacted by loss of IRF8, a factor involved in neuropsychiatric and neurodegenerative diseases.SIGNIFICANCE STATEMENT Here, we identify a previously unknown and key role for interferon regulator factor 8 (IRF8) in regulating neural excitability and seizures. We further determine that these effects on neural circuits are through elevated TNF-α in the CNS. As IRF8 has most widely been studied in the context of regulating the development and inflammatory signaling in microglia and other immune cells, we have uncovered a novel function. Further, IRF8 is a risk gene for multiple sclerosis and lupus, IRF8 is dysregulated in schizophrenia, and elevated TNF-α has been identified in a multitude of neurologic conditions. Thus, elucidating these IRF8 and TNF-α-dependent effects on brain circuit function has profound implications for understanding underlying, therapeutically relevant mechanisms of disease.
  • The role of specialized cell cycles during erythroid lineage development: insights from single-cell RNA sequencing

    Socolovsky, Merav (2022-06-27)
    Early erythroid progenitors known as CFU-e undergo multiple self-renewal cell cycles. The CFU-e developmental stage ends with the onset of erythroid terminal differentiation (ETD). The transition from CFU-e to ETD is a critical cell fate decision that determines erythropoietic rate. Here we review recent insights into the regulation of this transition, garnered from flow cytometric and single-cell RNA sequencing studies. We find that the CFU-e/ETD transition is a rapid S phase-dependent transcriptional switch. It takes place during an S phase that is much shorter than in preceding or subsequent cycles, as a result of globally faster replication forks. Furthermore, it is preceded by cycles in which G1 becomes gradually shorter. These dramatic cell cycle and S phase remodeling events are directly linked to regulation of the CFU-e/ETD switch. Moreover, regulators of erythropoietic rate exert their effects by modulating cell cycle duration and S phase speed. Glucocorticoids increase erythropoietic rate by inducing the CDK inhibitor p57KIP2, which slows replication forks, inhibiting the CFU-e/ETD switch. Conversely, erythropoietin promotes induction of ETD by shortening the cycle. S phase shortening was reported during cell fate decisions in non-erythroid lineages, suggesting a fundamentally new developmental role for cell cycle speed.
  • Age-associated changes to neuronal dynamics involve a disruption of excitatory/inhibitory balance in C. elegans

    Wirak, Gregory S; Florman, Jeremy; Alkema, Mark J.; Connor, Christopher W; Gabel, Christopher V (2022-06-15)
    In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. Caenorhabditis elegans offers a powerful model for aging research, with a simple, well-studied nervous system to further our understanding of the cellular modifications and functional alterations accompanying senescence. We perform multi-neuronal functional imaging across the aged C. elegans nervous system, measuring an age-associated breakdown in system-wide functional organization. At single-cell resolution, we detect shifts in activity dynamics toward higher frequencies. In addition, we measure a specific loss of inhibitory signaling that occurs early in the aging process and alters the systems' critical excitatory/inhibitory balance. These effects are recapitulated with mutation of the calcium channel subunit UNC-2/CaV2α. We find that manipulation of inhibitory GABA signaling can partially ameliorate or accelerate the effects of aging. The effects of aging are also partially mitigated by disruption of the insulin signaling pathway, known to increase longevity, or by a reduction of caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age that leads to breakdown in global neuronal dynamics and functional decline.
  • PERIOD Phosphoclusters Control Temperature Compensation of the Circadian Clock

    Joshi, Radhika; Cai, Yao D; Xia, Yongliang; Chiu, Joanna C; Emery, Patrick (2022-06-02)
    Ambient temperature varies constantly. However, the period of circadian pacemakers is remarkably stable over a wide-range of ecologically- and physiologically-relevant temperatures, even though the kinetics of most biochemical reactions accelerates as temperature rises. This thermal buffering phenomenon, called temperature compensation, is a critical feature of circadian rhythms, but how it is achieved remains elusive. Here, we uncovered the important role played by the Drosophila PERIOD (PER) phosphodegron in temperature compensation. This phosphorylation hotspot is crucial for PER proteasomal degradation and is the functional homolog of mammalian PER2 S478 phosphodegron, which also impacts temperature compensation. Using CRISPR-Cas9, we introduced a series of mutations that altered three Serines of the PER phosphodegron. While all three Serine to Alanine substitutions lengthened period at all temperatures tested, temperature compensation was differentially affected. S44A and S45A substitutions caused undercompensation, while S47A resulted in overcompensation. These results thus reveal unexpected functional heterogeneity of phosphodegron residues in thermal compensation. Furthermore, mutations impairing phosphorylation of the per s phosphocluster showed undercompensation, consistent with its inhibitory role on S47 phosphorylation. We observed that S47A substitution caused increased accumulation of hyper-phosphorylated PER at warmer temperatures. This finding was corroborated by cell culture assays in which S47A slowed down phosphorylation-dependent PER degradation at high temperatures, causing PER degradation to be excessively temperature-compensated. Thus, our results point to a novel role of the PER phosphodegron in temperature compensation through temperature-dependent modulation of the abundance of hyper-phosphorylated PER. Our work reveals interesting mechanistic convergences and differences between mammalian and Drosophila temperature compensation of the circadian clock.
  • CPEB1 regulates the inflammatory immune response, phagocytosis, and alternative polyadenylation in microglia

    Ivshina, Maria P; van 't Spijker, Heleen M; Jung, Suna; Ponny, Sithara Raju; Schafer, Dorothy P.; Richter, Joel D (2022-05-30)
    Microglia are myeloid cells of the central nervous system that perform tasks essential for brain development, neural circuit homeostasis, and neural disease. Microglia react to inflammatory stimuli by upregulating inflammatory signaling through several different immune cell receptors such as the Toll-like receptor 4 (TLR4), which signals to several downstream effectors including transforming growth factor beta-activated kinase 1 (TAK1). Here, we show that TAK1 levels are regulated by CPEB1, a sequence-specific RNA binding protein that controls translation as well as RNA splicing and alternative poly(A) site selection in microglia. Lipopolysaccharide (LPS) binds the TLR4 receptor, which in CPEB1-deficient mice leads to elevated expression of ionized calcium binding adaptor molecule 1 (Iba1), a microglial protein that increases with inflammation, and increased levels of the cytokine IL6. This LPS-induced IL6 response is blocked by inhibitors of JNK, p38, ERK, NFκB, and TAK1. In contrast, phagocytosis, which is elevated in CPEB1-deficient microglia, is unaffected by LPS treatment or ERK inhibition, but is blocked by TAK1 inhibition. These data indicate that CPEB1 regulates microglial inflammatory responses and phagocytosis. RNA-seq indicates that these changes in inflammation and phagocytosis are accompanied by changes in RNA levels, splicing, and alternative poly(A) site selection. Thus, CPEB1 regulation of RNA expression plays a role in microglial function.
  • LGBTQ+ Health Research Guides: A Cross-institutional Pilot Study of Usage Patterns

    Stevens, Gregg A.; Fajardo, Francisco J.; Morris, Martin; Berry, Jessica; Parker, Robin M. N.; McLean, Katie D. (2022-05-06)
    Objectives: Multiple authors have recommended that health sciences libraries use research guides to promote LGBTQ+ health information, connect with their users and the community, and improve health equity. However, little is known about LGBTQ+ health guide usage patterns and whether such guides really meet the information needs of their users. Based on usage patterns from LGBTQ+ health research guides, we assessed the types of LGBTQ+ health information of greatest interest to health sciences library users and how, if appropriate, these guides might be revised to be more relevant to user needs. Methods: The data for LGBTQ+ health research guides of five health sciences libraries (three in the United States and two in Canada) were studied. Usage data were retrieved for a three year period (July 2018-June 2021). Two separate factors were chosen for analysis: monthly guide usage over time and the individual types of resources used. Monthly usage was studied by generating line graphs in Excel with trendlines to calculate overall guide usage trends. To determine the most sought-after types of resources by users, clicks for individual resources were categorized by type and focus using open coding in Google Sheets. Results: Overall guide usage was mixed, with some libraries’ guides trending upward over time and others downward. Analysis of the resource links showed that links to local and community health resources were among the most heavily clicked (64.11% of clicks), as were resources designed to help patients find healthcare providers and services (53.23%). Links to library-owned resources, such as books, journals, and databases, were generally clicked less (2.44%), as were links aimed at healthcare professionals (11.36%). Conclusions: The usage statistics for the guides were relatively low. However, the size of the LGBTQ+ community is relatively low compared to the general population and therefore LGBTQ+ health can be considered a category of minority health. We argue that the importance of providing quality LGBTQ+ health information outweighs any concerns of large-scale usage, and that providing such guides promotes health equity. The higher usage numbers for local resources supports the idea that guides are most useful when they link users to services and providers in their own communities. This suggests a best practice for librarians to focus on local resources and collaborations, and on consumer health resources, when creating and editing these guides.
  • Female Relatives as Lay Doulas and Birth Outcomes: A Systematic Review

    Nguyen, Hau Huu; Heelan-Fancher, Lisa (2022-04-01)
    Continuous labor support provided by professional doulas is associated with improved birth outcomes for pregnant women and their infants. However, there is limited data on the impact of using female relatives as lay doulas. This systematic review included nine published studies that examined the association between use of female relatives as lay doulas with childbirth outcomes. In some study populations, there was a decrease in the number of cesarean births and length of labor, and in all studies, there was improved maternal birth satisfaction. However, the woman's chosen female relative often did not receive education regarding labor support skills before providing continuous support. Educational programs designed to teach labor support skills to female relatives are needed.
  • Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS

    Eitan, Chen; Werneburg, Sebastian; Schafer, Dorothy P.; Brown, Robert H. Jr.; Hornstein, Eran (2022-03-31)
    The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of > 25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-kappaB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.
  • Medicinal Plant Extracts and Natural Compounds for the Treatment of Cutaneous Lupus Erythematosus: A Systematic Review

    Lubov, Janet E.; Jamison, Aisha S.; Baltich Nelson, Becky; Amudzi, Alice A.; Haas, Kelly N. (2022-03-31)
    Cutaneous lupus erythematosus (CLE) is a group of autoimmune connective tissue disorders that significantly impact quality of life. Current treatment approaches typically use antimalarial medications, though patients may become recalcitrant. Other treatment options include general immunosuppressants, highlighting the need for more and more targeted treatment options. The purpose of this systematic review was to identify potential compounds that could be repurposed for CLE from natural products since many rheumatologic drugs are derived from natural products, including antimalarials. This study was registered with PROSPERO, the international prospective register of systematic reviews (registration number CRD42021251048). We comprehensively searched Ovid Medline, Cochrane Library, and Scopus databases from inception to April 27th, 2021. These terms included cutaneous lupus erythematosus; general plant, fungus, bacteria terminology; selected plants and plant-derived products; selected antimalarials; and JAK inhibitors. Our search yielded 13,970 studies, of which 1,362 were duplicates. We screened 12,608 abstracts, found 12,043 to be irrelevant, and assessed 565 full-text studies for eligibility. Of these, 506 were excluded, and 59 studies were included in the data extraction. The ROBINS-I risk of bias assessment tool was used to assess studies that met our inclusion criteria. According to our findings, several natural compounds do reduce inflammation in lupus and other autoimmune skin diseases in studies using in vitro methods, mouse models, and clinical observational studies, along with a few randomized clinical trials. Our study has cataloged evidence in support of potential natural compounds and plant extracts that could serve as novel sources of active ingredients for the treatment of CLE. It is imperative that further studies in mice and humans are conducted to validate these findings.
  • Spatial transcriptomic reconstruction of the mouse olfactory glomerular map suggests principles of odor processing

    Wang, I-Hao; Andrews, Gregory; Donnard, Elisa; Duran-Laforet, Violeta; Faust, Travis E.; Garber, Manuel; Baer, Christina E.; Schafer, Dorothy P.; Weng, Zhiping; Greer, Paul L. (2022-03-21)
    The olfactory system's ability to detect and discriminate between the vast array of chemicals present in the environment is critical for an animal's survival. In mammals, the first step of this odor processing is executed by olfactory sensory neurons, which project their axons to a stereotyped location in the olfactory bulb (OB) to form glomeruli. The stereotyped positioning of glomeruli in the OB suggests an importance for this organization in odor perception. However, because the location of only a limited subset of glomeruli has been determined, it has been challenging to determine the relationship between glomerular location and odor discrimination. Using a combination of single-cell RNA sequencing, spatial transcriptomics and machine learning, we have generated a map of most glomerular positions in the mouse OB. These observations significantly extend earlier studies and suggest an overall organizational principle in the OB that may be used by the brain to assist in odor decoding.
  • Astrocytic GABA transporter controls sleep by modulating GABAergic signaling in Drosophila circadian neurons

    Chaturvedi, Ratna; Stork, Tobias; Yuan, Chunyan; Freeman, Marc R.; Emery, Patrick (2022-03-17)
    A precise balance between sleep and wakefulness is essential to sustain a good quality of life and optimal brain function. GABA is known to play a key and conserved role in sleep control, and GABAergic tone should, therefore, be tightly controlled in sleep circuits. Here, we examined the role of the astrocytic GABA transporter (GAT) in sleep regulation using Drosophila melanogaster. We found that a hypomorphic gat mutation (gat(33-1)) increased sleep amount, decreased sleep latency, and increased sleep consolidation at night. Interestingly, sleep defects were suppressed when gat(33-1) was combined with a mutation disrupting wide-awake (wake), a gene that regulates the cell-surface levels of the GABAA receptor resistance to dieldrin (RDL) in the wake-promoting large ventral lateral neurons (l-LNvs). Moreover, RNAi knockdown of rdl and its modulators dnlg4 and wake in these circadian neurons also suppressed gat(33-1) sleep phenotypes. Brain immunohistochemistry showed that GAT-expressing astrocytes were located near RDL-positive l-LNv cell bodies and dendritic processes. We concluded that astrocytic GAT decreases GABAergic tone and RDL activation in arousal-promoting LNvs, thus determining proper sleep amount and quality in Drosophila.
  • Nociception and hypersensitivity involve distinct neurons and molecular transducers in Drosophila

    Gu, Pengyu; Wang, Fei; Shang, Ye; Liu, Jingjing; Gong, Jiaxin; Xie, Wei; Han, Junhai; Xiang, Yang (2022-03-16)
    Significance: Functional plasticity of the nociceptive circuit is a remarkable feature and is of clinical relevance. As an example, nociceptors lower their threshold upon tissue injury, a process known as allodynia that would facilitate healing by guarding the injured areas. However, long-lasting hypersensitivity could lead to chronic pain, a debilitating disease not effectively treated. Therefore, it is crucial to dissect the mechanisms underlying basal nociception and nociceptive hypersensitivity. In both vertebrate and invertebrate species, conserved transient receptor potential (Trp) channels are the primary transducers of noxious stimuli. Here, we provide a precedent that in Drosophila larvae, heat sensing in the nociception and hypersensitivity states is mediated by distinct heat-sensitive neurons and TrpA1 alternative isoforms.
  • Prospective associations between acid suppressive therapy and food allergy in early childhood

    Seay, Hannah L; Martin, Victoria M; Virkud, Yamini V; Marget, Michael; Shreffler, Wayne G; Yuan, Qian (2022-03-13)
    We sought to prospectively evaluate the association between AST in infancy and development of IgE-FA in our healthy infant cohort.
  • Co-transmission of neuropeptides and monoamines choreograph the C. elegans escape response

    Florman, Jeremy T.; Alkema, Mark J. (2022-03-03)
    Co-localization and co-transmission of neurotransmitters and neuropeptides is a core property of neural signaling across species. While co-transmission can increase the flexibility of cellular communication, understanding the functional impact on neural dynamics and behavior remains a major challenge. Here we examine the role of neuropeptide/monoamine co-transmission in the orchestration of the C. elegans escape response. The tyraminergic RIM neurons, which coordinate distinct motor programs of the escape response, also co-express the neuropeptide encoding gene flp-18. We find that in response to a mechanical stimulus, flp-18 mutants have defects in locomotory arousal and head bending that facilitate the omega turn. We show that the induction of the escape response leads to the release of FLP-18 neuropeptides. FLP-18 modulates the escape response through the activation of the G-protein coupled receptor NPR-5. FLP-18 increases intracellular calcium levels in neck and body wall muscles to promote body bending. Our results show that FLP-18 and tyramine act in different tissues in both a complementary and antagonistic manner to control distinct motor programs during different phases of the C. elegans flight response. Our study reveals basic principles by which co-transmission of monoamines and neuropeptides orchestrate in arousal and behavior in response to stress.

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