Biology subjects

Richardson, R.

Publications and source records attributed to Richardson, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Parallel visual processing in the suprachiasmatic region of a diurnal mammal.

Light shapes mammalian physiology and behaviour through hypothalamic pathways, yet how these pathways process visual information in day-active species remains poorly understood. Based largely on work in nocturnal rodents, the suprachiasmatic nucleus (SCN) is classically viewed as a retinal target that encodes ambient illumination for circadian entrainment. We combine anatomical tracing, light-evoked c-Fos mapping and high-density silicon-probe electrophysiology to define visual processing in the suprachiasmatic region of the diurnal murid Rhabdomys pumilio. We find that retinal input and light-evoked activity extend beyond the SCN into rostral and lateral peri-SCN hypothalamus. Within the SCN, neurons encode irradiance with graded changes in maintained firing broadly similar to those observed in parallel recordings of nocturnal Mus domesticus. Across the wider suprachiasmatic region, Rhabdomys neurons show selectivity for more dynamic visual stimuli, including luminance transitions, contrast and temporal structure. Unsupervised clustering identifies five functionally distinct hypothalamic visual response classes with different anatomical distributions. These findings reveal an expanded hypothalamic visual network in a diurnal mammal, placing SCN irradiance coding within a broader system for processing dynamic visual features.

neuroscience↗

bioRxiv2026

Increased CSF volume, altered brain development and emotional reactivity after postnatal Zika virus infection in infant rhesus macaques

Although congenital Zika virus (ZIKV) syndrome is well-characterized, the neurodevelopmental consequences of postnatal infection are less understood. Here we used a rhesus macaque model to investigate the developmental consequences of ZIKV infection during infancy on the brain and behavior, building on our prior research. Male and female infant rhesus macaques infected with ZIKV at 1 month of age were compared to sex-, age-, and rearing-matched uninfected controls and infants treated with the TLR3 agonist PolyIC as a control for activation of the innate immune system. Longitudinal behavioral assessments revealed alterations in emotional regulation following ZIKV exposure, including poor state control scores obtained from the Infant Neurobehavioral Assessment Scale early after ZIKV infection and longer-term displays of increased hostility during an acute stressor. While attachment bonds to caregivers were preserved, ZIKV-infected infants showed sex-specific alterations in behavioral regulation during caregiver separation compared to controls. At 3 months of age, MRI scans revealed larger total cerebrospinal fluid (CSF) volume and reduced volumes in visual processing regions in ZIKV-infected infants compared to controls. Postnatal ZIKV exposure also resulted in sex-specific brain structural alterations with males exhibiting amygdala hypertrophy, whereas ZIKV-infected females had volumetric reductions in temporal-limbic and temporal-auditory cortices. These findings demonstrate that postnatal ZIKV infection disrupts the development of sensory, social and emotion-regulatory systems and CSF function, highlighting the critical need for long-term monitoring of exposed children. One-Sentence SummaryPostnatal Zika virus infection disrupts emotional regulation and alters brain development in infant rhesus macaques, revealing a critical window of neurodevelopmental vulnerability that extends beyond the fetal period.

neuroscience↗

bioRxiv2026

Cardiac-immune microniches programme macrophage states in the regenerating heart

Adult zebrafish regenerate their hearts after injury, a process that requires macrophages, yet how local tissue microenvironments instruct macrophage states and function remains unclear. Here we combine single cell RNA sequencing with Visium and high-resolution MERFISH spatial transcriptomics to map the cardio-immune landscape of homeostatic and regenerating zebrafish hearts. We identify a mpeg1.1+ compartment comprising macrophages, dendritic, B and NK-like cells, and show that injury establishes a macrophage-centred immune environment with transcriptional programmes spanning resident surveillance, damage sensing, inflammation, antigen presentation, resolution and metabolic support. Communication-aware spatial modelling reveals that these states are not randomly distributed but organised into discrete structural-immune microniches across the injury region, each defined by stereotyped cellular compositions and ligand-receptor circuits. Within a fibroblast-macrophage microniche, we uncover an il34-csf1ra-egr1 axis in which col12a1a+ il34+ fibroblasts promote an egr1 pro-regenerative macrophage state that couples fibrosis, vascular integrity and epicardial signalling. We show that disruption of this axis by csf1ra loss of function reduces macrophage-, endothelial- and epicardial-rich microniches, amplifying fibroblast-driven domains that shift macrophages towards stress and long-sustained inflammatory programmes, thereby biasing early injury response towards a pro-fibrotic state. Our work establishes spatially defined cardio-immune microniches as key organisers of macrophage function and regenerative outcome, providing a mechanistic framework and actionable targets for reprogramming cardiac repair.

developmental biology↗

bioRxiv2026

Mechanisms of disrupted neurodevelopment after Zika virus infection in infancy

Congenital and early-life Zika virus (ZIKV) infection can result in neurologic deficits. Precise mechanisms of injury, especially in the more subtle presentation of postnatal infection, are not fully elucidated. Here, we defined the effects of ZIKV on the developing brain using single cell transcriptomics, histopathology and design-based stereology, diffusion MRI, and neurobehavioral assessments in infant rhesus macaques. ZIKV upregulated interferon-stimulated genes in activated microglia and cell death pathways in neurons and downregulated metabolism and differentiation genes in mature oligodendrocytes. Abnormal micro-organization of the corpus collosum and limbic white matter tracts was seen on diffusion weighted imaging. A curated gene set associated with autism spectrum disorder risk was negatively enriched in inhibitory and excitatory neurons from ZIKV-infected infants, with increased emotional reactivity already evident two weeks following infection. From single cells to organism-level behaviors, these results define the pathways and processes disrupted by early-life ZIKV infection.

neuroscience↗

bioRxiv2025

Clinical Candida Lactobacillus Isolate Pairs Reveal Distinct Host-Pathogen Interactions in a Vaginal Epithelial Model

Vulvovaginal candidiasis (VVC) is a highly prevalent condition affecting up to 75% of women, yet the mechanisms underpinning the transition from asymptomatic colonisation by Candida albicans to symptomatic infection remain incompletely understood. VVC is hormonally driven and rare in young girls and postmenopausal women. A central challenge lies in dissecting the complex interplay between microbial communities, hormonal factors, and host epithelial responses. While C. albicans is part of the normal vaginal microbiota at low abundance, its morphogenic switch to the hyphal form is closely linked with pathogenicity. Concomitantly, the dominance of specific Lactobacillus species is known to modulate vaginal health, but their precise role in shaping host-pathogen interactions during VVC is unresolved. We hypothesised that clinical isolate pairs of C. albicans and Lactobacillus spp. may differ in their ability to drive host epithelial damage, and that hormonal signals such as estrogen may exacerbate these interactions. To test this, we developed an in vitro VVC model using human vaginal epithelial cell (VEC) monolayers co-cultured with clinical isolate pairs. Using LDH release as a marker of cytotoxicity, extracellular pH monitoring, and immunoassays of mitogen-activated protein kinase (MAPK) phosphorylation, we interrogated host responses across microbial conditions in the presence or absence of estrogen. Our findings demonstrate that two clinical isolate pairs exhibit divergent behaviours. Pair C (C. albicans 203 and L. gasseri 167) suppressed epithelial cytotoxicity and maintained acidic pH, while Pair D (C. albicans 205 and L. jensenii 172) enhanced host damage and did not acidify the environment. Morphological differences in C. albicans isolates correlated with MAPK activation profiles, supporting a phenotype-specific host response. These results reveal that strain-level interactions within the vaginal microbiota significantly modulate host-pathogen dynamics.

microbiology↗

bioRxiv2025

Sensitive and easily democratized environmental DNA methods for low-risk surveillance of at-risk bumble bees

Terrestrial environmental DNA (eDNA) techniques have been proposed as a means of sensitive, non-lethal pollinator monitoring. To date, however, no studies have provided evidence that eDNA methods can achieve detection densities on par with traditional pollinator surveys. Using a large-scale dataset of eDNA and corresponding net surveys, we show that eDNA methods enable sensitive, species-level characterization of whole bumble bee communities, including rare and critically endangered species such as the rusty pathed bumble bee (RPBB; Bombus affinis). All species present in netting surveys were detected within eDNA surveys, apart from two rare species in the socially parasitic subgenus Psithyrus (cuckoo bumble bees). Further, for rare non-parasitic species, eDNA methods exhibited similar sensitivity relative to traditional netting. Relative to flower eDNA samples, sequenced field negative controls resulted in significantly lower rates of Bombus detection, and these detections were likely attributable to high rates of background eDNA on environmental surfaces. Lastly, we found that eDNA-based frequency of detection across replicate surveys was strongly associated with net-based measures of abundance across site visits. We conclude that the method is cost-effective and highly scalable for semi-quantitative characterization of at-risk bumble bee communities, providing a new approach for improving our understanding of species habitat associations.

ecology↗

bioRxiv2025

Absence of a prolonged macrophage and B cell response inhibits heart regeneration in the Mexican cavefish

A balanced immune response after cardiac injury is crucial to successful heart regeneration, but knowledge of what distinguishes a regenerative from a scarring response is still limited. The Mexican cavefish provides a unique comparative model to study heart regeneration and scarring within a single species. Surface-dwelling fish are capable of heart regeneration whereas their cave-dwelling Pachon counterparts lack this ability, similar to the human heart. Using single-cell transcriptomics and immune perturbations, we find significant differences in the immune response between the two populations. Unlike the transient response in the scarring Pachon, the regenerative surface fish heart generates an unexpected functionally active prolonged innate and adaptive immune response at the late stages of regeneration. Inhibiting the overall prolonged immune response impairs regeneration and cardiomyocyte proliferation. Further characterisation of specific cell types shows that late-present macrophages are phagocytic, and their depletion disrupts regeneration but not cardiomyocyte proliferation while inhibiting B cells impairs regeneration by reducing cardiomyocyte proliferation. This B cell response is conserved in zebrafish. Our findings reveal critical immune mechanisms distinguishing regenerative and non-regenerative responses, offering insights for potential therapeutic strategies to enhance heart repair.

developmental biology↗

bioRxiv2025

Scalable environmental DNA methods reveal associations between landscape-scale forest habitat and insect richness

O_LIWhile aquatic environmental DNA (eDNA) methods have reached relative maturity, terrestrial eDNA methods are nascent and have yet to reach widespread use. Field-ready applications require eDNA survey methods where samples are easy to collect by inexperienced practitioners, easy to transport between the field and lab, and easy to process thereafter. Here, we demonstrate methods that satisfy these requirements and show strong potential for characterizing diverse terrestrial eDNA samples collected from flower and leaf surfaces. C_LIO_LIWe used novel methods to collect and process 236 flower eDNA samples and 21 leaf surface eDNA samples, obtaining 2,228 Arthropoda eDNA detections spanning 175 families using amplicon sequencing of two genetic markers. C_LIO_LIDetected taxa were diverse and included numerous groups of conservation concern, such as bees (Hymenoptera; Anthophila, 32 genera spanning 5 families) and Lepidoptera (209 genera from 21 families). Data reveal strong associations between insect community richness and remotely sensed measures of forest habitat, providing a quantitative perspective of relevance to insect conservation. C_LIO_LIIt is increasingly clear that a variety of organisms readily disperse eDNA throughout the environment, supporting the notion that eDNA will be a powerful tool for characterizing species distributions and monitoring at-risk species. However, we conclude that researchers seeking to characterize fine-scale habitat associations or plant-pollinator interactions using eDNA will need to carefully design studies with appropriate field controls, such as the leaf surface eDNA samples collected here. C_LI

ecology↗

bioRxiv2025

Candida albicans genome adaptation in azole resistant isolates from autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) patients

Chronic mucocutaneous candidosis due to Candida albicans is frequent in patients with autoimmune polyendocrinopathy candidosis ectodermal dystrophy (APECED). These patients require lifelong antifungal treatment with azoles which might result in the emergence of azole-resistant C. albicans isolates. However, the molecular mechanisms that allow C. albicans to cause disease and adapt to antifungal treatment in these patients in vastly unknown. Here we comparatively analysed the genome sequences and antifungal susceptibility profile of 14 C. albicans isolates from the oral cavities of five APECED patients. 14/13 C. albicans isolates showed reduced-susceptibly or resistance to fluconazole. Phylogenetic analyses demonstrated that all APECED isolates from individual patients arose from patient-specific lineages. Single nucleotide variants in genes related to homologous DNA repair mechanisms such as meiosis were associated with APECED (p <0.0001). Altogether our data demonstrates that antifungal adaptation of C. albicans in APECED patients might be associated with polymorphisms in proteins responsible for maintaining DNA repair mechanisms. ImportanceChronic mucocutaneous canididosis (CMC) caused by Candida albicans is common in patients with primary immunodeficiencies such as autoimmune polyendocrinopathy candidosis ectodermal dystrophy (APECED). These patients receive to long-term antifungal therapy thus promoting the emergence of antifungal resistance. Our knowledge about the mechanisms facilitating CMC in patients with APECED is very limited. Here we demonstrated that most C. albicans isolates from patients with CMC are resistant to azoles and that polymorphisms in genes responsible for maintaining DNA repair mechanisms might facilitate infection.

genomics↗

bioRxiv2024

A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism

Cellular signaling by membrane G protein-coupled receptors (GPCRs) is orchestrated by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome as it evolves over time and space in response to an agonist can offer a unique window on pleiotropic signaling decoding and functional selectivity at a cellular level. In this study, we employed proximity-based APEX2 proteomics to interrogate the interaction network of the GPCR for luteinizing hormone (LHR) on a minute-to-minute timescale. We developed an analytical approach integrating quantitative multiplexed proteomics and temporal reference profiles, providing a platform to identify the proteomic environment of APEX2-tagged LHR at the nanometer scale. LHR activity is exquisitely regulated at a spatial level, leading to identification of novel putative interactors including the Ras-related GTPase RAP2B that modulate both receptor signaling and post-endocytic trafficking, and providing a resource for spatiotemporal nanodomain mapping of LHR interactors across subcellular compartments. SignificanceG-protein coupled receptors (GPCRs) are the largest family of membrane proteins in the human body. GPCRs have established themselves as key drug targets, playing central roles in health and disease. The activity of this superfamily of receptors is highly dynamic, integrating diverse signaling pathways over time and across multiple subcellular compartments. Quantitative proximity proteomics using engineered ascorbate peroxidase (APEX2) has emerged as a powerful tool to map GPCR-protein interaction landscapes in both time and space. However, resolving these networks at a sub-minute timescale remains challenging, particularly for poorly characterized GPCRs with limited pharmacological tools or complex trafficking patterns. In this study, we applied APEX2 proximity proteomics to resolve at nanoscale the agonist (LH)-induced interactome of the luteinizing hormone receptor (LHR), a key GPCR in human reproduction. LHR undergoes rapid endocytosis upon LH stimulation, trafficking to a poorly understood compartment termed the very early endosome (VEE), where it engages in G protein signaling and post-endocytic sorting. Harnessing the temporal profile of GIPC1 protein, a key known interactor of LHR in the VEE pathway, we developed an analytical pipeline to identify novel endocytic interactors of LHR. Using our platform, we identified RAP2B and RAB38 as potential modulators of LHR signaling and trafficking. Overall, we present an APEX2 pipeline optimized for interrogating complex datasets, particularly for GPCRs, and potentially other membrane receptors, with limited known interactome data and minimal pharmacological tools. Our findings highlight both the complexity of GPCR interaction networks and an effective strategy to deconvolute them, providing a comprehensive resource to advance understanding of this large family of receptors. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/599010v2_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@13badf7org.highwire.dtl.DTLVardef@11a5182org.highwire.dtl.DTLVardef@dd5453org.highwire.dtl.DTLVardef@cb2c27_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Defining mononuclear phagocyte distribution and behaviour in the zebrafish heart

Mononuclear phagocytes (MNPs) are recognised as highly plastic, multifunctional cells that influence multiple physiological and pathophysiological states. In the heart, they support homeostatic functions, contribute to disease progression and play multiple roles in reparative and regenerative processes following tissue damage. Understanding the heterogeneous populations of cells that contribute to these diverse functions is crucial to facilitating beneficial, and limiting adverse, cardiac outcomes. However, characterisation of precise populations of cardiac immune cells remains incomplete in vertebrate models capable of endogenous regeneration, such as adult zebrafish. Here, we use a combination of transgenic lines to identify distinct MNPs in the zebrafish heart. We show that larval macrophage populations have different origins and a sub-population of csf1ra expressing cells are maintained on the surface of the adult heart. MNPs are differently distributed in the myocardium, exhibit different behaviours and are distinguished via expression level of csf1ra and mpeg1.1. Following injury, tissue resident macrophages rapidly proliferate potentially contributing to reduced scarring. The adult zebrafish heart contains multiple populations of MNPs that can be defined by existing tools. This new understanding of innate immune cell populations in the heart of adult zebrafish sheds light on the composition of a pro-regenerative cardiac microenvironment.

immunology↗

bioRxiv2023

Thermosensitivity of translation underlies the mammalian nocturnal-diurnal switch

Early mammals were nocturnal until the Cretaceous-Paleogene extinction enabled diurnal niche expansion. Diurnality evolved multiple times independently, but the mechanisms driving this shift remain unclear. We identify a conserved cell-intrinsic signal inversion that facilitates the transition from nocturnality to diurnality. Diurnal and nocturnal mammalian cells respond oppositely to temperature and osmotic cycles, mirroring species activity patterns. Cells exhibit differential global responses to temperature changes, including the phosphoproteome and protein synthesis. mTOR signaling is identified as a central mediator of this inversion, with diurnal mammals converging on modifications to mTOR and WNK pathways during evolution. Reducing mTOR activity induces nocturnal-to-diurnal shifting at cellular, tissue, and organismal levels. Therefore, the mTOR pathway is a cellular nexus that integrates energetic state and environmental signals to determine activity niche.

cell biology↗

bioRxiv2023

Evolution of neuronal cell classes and types in the vertebrate retina

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs (Baden et al., 2020). One might expect that retinal cell types evolved to accommodate these varied needs, but this has not been systematically studied. Here, we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a teleost fish, a bird, a reptile and a lamprey. Molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells [RGCs] and Muller glia) is striking, with transcriptomic differences across species correlated with evolutionary distance. Major subclasses are also conserved, whereas variation among types within classes or subclasses is more pronounced. However, an integrative analysis revealed that numerous types are shared across species based on conserved gene expression programs that likely trace back to the common ancestor of jawed vertebrates. The degree of variation among types increases from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified mammalian orthologs of midget RGCs, which comprise >80% of RGCs in the human retina, subserve high-acuity vision, and were believed to be primate-specific (Berson, 2008); in contrast, the mouse orthologs comprise <2% of mouse RGCs. Projections both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

neuroscience↗

bioRxiv2021

Mapping trait versus species turnover reveals spatiotemporal variation in functional redundancy in a plant-pollinator network

Functional overlap between species (redundancy) shapes competitive and mutualistic interactions, determining community responses to perturbations. Most studies view functional redundancy as static, even though individuals within species vary in traits over seasonal or spatial gradients. Consequently, we lack knowledge on trait turnover within species, how functional redundancy spatiotemporally varies, and when and where interaction networks are vulnerable to functional loss. Studying an Arctic bumblebee community, we investigated how body-size turnover over elevation and season shapes their host-plant interactions, and test how sensitive networks are to sequentially losing body-size groups. With trait turnover being larger than species, we found: i) late-season networks were less specialised when nodes comprised functionally similar bumblebees; ii) removal of bumblebee-body-size groups over species accelerated coextinction of host plants, with the magnitude varying in space and time. We demonstrate functional redundancy can vary spatiotemporally, and functional loss impacts interaction partners more than expected from species loss alone.

ecology↗

bioRxiv2020

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Oral rapamycin administration rapamycin is plagued by poor bioavailability and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycins hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects. While oral rapamycin inhibits naive T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+ CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to rapamycins cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.

bioengineering↗

bioRxiv2019

MetaCurator: A hidden Markov model-based toolkit for extracting and curating sequences from taxonomically-informative genetic markers

The community-level analysis of samples containing diverse genetic material, via metabarcoding and metagenomic approaches, is increasingly popular. While the production of sequence data for such studies has become straightforward, questions remain about how best to analyze and taxonomically characterize sequence data. For many sequence classification approaches, an important component of the workflow involves the curation of reference sequences. Ideally, this involves trimming away extraneous sequence at the 3 prime and 5 prime ends of the target marker of interest, as well as the removal of reference sequence duplicates. Here, we present MetaCurator, a software package written in Python, designed for automated reference sequence curation and highly generalizable across markers and study systems. MetaCurator is organized in a modular fashion, so users can implement tools individually in addition to utilizing the automated and flexible MetaCurator parental code. Aside from modules used to organize and format taxonomic lineage data, MetaCurator contains two signature tools. IterRazor utilizes profile hidden Markov models and an iterative search framework to exhaustively identify and extract the precise amplicon marker of interest from available reference sequence data. DerepByTaxonomy then facilitates sequence dereplication using a taxonomically aware approach, removing duplicates only when they belong to the same taxon. This is important for cases of incomplete lineage sorting between species and for highly conserved markers, such as plant rbcL and trnL, which often display no sequence divergence across taxa, even at the genus level.\n\nAvailability and implementationMetaCurator is supported on OSX and Linux (RedHat/CentOS) and is freely available under a GPL v3.0 license at https://github.com/RTRichar/MetaCurator.\n\nContactrtr87@yorku.ca\n\nSupplemental informationCode associated with this work is available at https://github.com/RTRichar/MetabarcodeDBsV2 and additional analysis is presented in supplementary files.

bioinformatics↗

bioRxiv2019

Chemogenetic inhibition of the amygdala modulates emotional behavior expression in infant rhesus monkeys

Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eyetracking task, compared to vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent lesions of the amygdala in infant monkeys, such that early amygdala lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results support the notion that early permanent damage leads to brain reorganization manifesting in a broader impact on behavior. The current study provides a proof-of-principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior. Statement of SignificanceMany neurodevelopmental disorders exhibit abnormal structural or functional amygdala development and alterations in socioemotional behavior. To date, developmental neuroscience studies have relied on permanent lesions techniques to investigate how atypical amygdala development impacts socioemotional behaviors, which may not adequately recapitulate the role of amygdala dysfunction in the manifestation of aberrant behavior. The present study sought to demonstrate that the DREADDs (designer receptors exclusively activated by designer drugs) chemogenetic tool could transiently inhibit amygdala activity in infant monkeys resulting in alterations in socioemotional behavior. This proof-of-principle study supports the use of chemogenetics for developmental neuroscience research, providing an opportunity to broaden our understanding of how changes in neuronal activity across early postnatal development influences behavior and clinical symptoms.

neuroscience↗

bioRxiv2018

Genetic and physical interactions between the organellar mechanosensitive ion channel homologs MSL1, MSL2, and MSL3 reveal a role for inter-organellar communication in plant development

Plant development requires communication on many levels, including between cells and between organelles within a cell. For example, mitochondria and plastids have been proposed to be sensors of environmental stress and to coordinate their responses. Here we present evidence for communication between mitochondria and chloroplasts during leaf and root development, based on genetic and physical interactions between three Mechanosensitive channels of Small conductance-Like (MSL) proteins from Arabidopsis thaliana. MSL proteins are Arabidopsis homologs of the bacterial Mechanosensitive channel of Small conductance (MscS), which relieves cellular osmotic pressure to protect against lysis during hypoosmotic shock. MSL1 localizes to the inner mitochondrial membrane, while MSL2 and MSL3 localize to the inner plastid membrane and are required to maintain plastid osmotic homeostasis during normal growth and development. In this study, we characterized the phenotypic effect of a genetic lesion in MSL1, both in wild type and in msl2 msl3 mutant backgrounds. msl1 single mutants appear wild type for all phenotypes examined. The characteristic leaf rumpling in msl2 msl3 double mutants was exacerbated in the msl1 msl2 msl3 triple mutant. However, the introduction of the msl1 lesion into the msl2 msl3 mutant background suppressed other msl2 msl3 mutant phenotypes, including ectopic callus formation, accumulation of superoxide and hydrogen peroxide in the shoot apical meristem, decreased root length, and reduced number of lateral roots. All these phenotypes could be recovered by molecular complementation with a transgene containing a wild type version of MSL1. In yeast-based interaction studies, MSL1 interacted with itself, but not with MSL2 or MSL3. These results establish that the abnormalities observed in msl2 msl3 double mutants is partially dependent on the presence of functional MSL1 and suggest a possible role for communication between plastid and mitochondria in seedling development.

plant biology↗