Biology subjects

Gould, E.

Publications and source records attributed to Gould, E..

8 recordsLinked to original sources

bioRxiv2026

Inhibition of VP2-mediated entry: a potential antiviral strategy to treat or prevent calicivirus disease

The Caliciviridae include many notable human and animal pathogens, including norovirus and sapovirus, which cause outbreaks of acute gastroenteritis. We previously demonstrated that, following receptor engagement, feline calicivirus (FCV) assembles a portal structure at a unique capsid three-fold axis. This comprises twelve copies of the minor capsid protein VP2 and is essential for genome delivery. We designed a short peptide based on our structure data that occludes the VP2 binding sites on the capsid surface, to prevent assembly of the VP2 portal and thereby halt the viral entry mechanism. Incubation with low micromolar concentrations of the peptide considerably reduced the infectivity of two laboratory strains and four clinical isolates of FCV associated with respiratory or virulent-systemic disease. Cryo-electron microscopy structures of FCV virions complexed with the peptide confirmed that the peptide occupies the VP2 binding site on the major capsid protein VP1, preventing portal assembly and subsequent genome delivery. Our data show that targeting VP2 is a viable antiviral approach to preventing calicivirus infection, with potential for the treatment or prevention of norovirus disease.

microbiology↗

bioRxiv2026

Developmental scarcity induces sex differences in social recognition and CA2 perineuronal nets

Early-life adversity has a lasting negative impact on social behavior in both humans and rodents. Sex differences exist in functional outcomes of postnatal stress, but underlying mechanisms remain incompletely explored. Using the limited bedding and nesting paradigm, a mouse model of developmental scarcity, we found sex differences in social behavior with adult males showing impaired social recognition and adult females showing intact social recognition with enhanced social novelty preference. Perineuronal nets, specialized extracellular matrix structures, are known to inhibit developmental plasticity and are concentrated in the CA2 region of the hippocampus in adulthood. We found higher intensity of CA2 perineuronal nets in adult males, but not adult females, after early life adversity. Focal degradation of the extracellular matrix in the CA2 region restored social recognition function in adult males previously subjected to early stress, suggesting that the effects of developmental adversity may be overcome by targeted intervention in adulthood.

neuroscience↗

bioRxiv2025

Developmental CA2 perineuronal net reduction restores social memory in Shank3B KO mice

Individuals with Autism Spectrum Disorder (ASD) and related neurodevelopmental conditions, like Phelan-McDermid syndrome (PMDS), exhibit social recognition deficits. Previous reports using Shank3B knockout (KO) mice, a genetic model with relevance to ASD and PMDS, revealed deficits in social memory in adulthood, but the postnatal onset and mechanisms underlying this dysfunction remain unknown. In the hippocampus, area CA2 contributes to the emergence of social memory during development and remains important for this ability through the lifespan. Perineuronal nets (PNNs), extracellular matrix structures, support social memory in CA2 and help orchestrate critical periods of plasticity in other brain regions. We found that Shank3B KO pups exhibit specific deficits in short-term social recognition and social novelty preference, which become evident at the end of the second postnatal week and persist into adulthood along with CA2 network aberrations. Excessive PNNs in area CA2 were detected in KO pups at the postnatal time when social recognition function typically emerges in healthy pups. This time was also characterized by greater sequestration of the guidance cue semaphorin-3A (sema3A) and overgrowth of afferents from the supramammillary nucleus (SuM) in KOs, suggesting that inordinate PNNs during a sensitive period may disorganize developing CA2 circuitry. Reduction of CA2 PNN levels prior to the onset of social dysfunction recovered social recognition function during development, as well as reduced sema3A and SuM inputs to the CA2. The restoration of behavioral function persisted into adulthood along with partial normalization of CA2 network activity. Together, these findings reveal how excess PNN formation in the developing hippocampus may give rise to impaired social memory by disrupting afferent input, effects that are reversible by early life intervention.

neuroscience↗

bioRxiv2024

Scn2a deletion disrupts oligodendroglia function: Implication for myelination, neural circuitry, and auditory hypersensitivity in ASD

Autism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, the Scn2a gene emerges as a pivotal player, crucially involved in both glial and neuronal functionality. This study elucidates the underexplored roles of Scn2a in oligodendrocytes, and its subsequent impact on myelination and auditory neural processes. The results reveal a nuanced interplay between oligodendrocytes and axons, where Scn2a deletion causes alterations in the intricate process of myelination. This disruption, in turn, instigates changes in axonal properties and neuronal activities at the single cell level. Furthermore, oligodendrocyte-specific Scn2a deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity--a common sensory abnormality observed in ASD. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes, highlighting the cellular consequences engendered by Scn2a deletion. In summary, the findings provide unprecedented insights into the pathway from Scn2a deletion in oligodendrocytes to sensory abnormalities in ASD, underscoring the integral role of Scn2a-mediated myelination in auditory responses. This research thereby provides novel insights into the intricate tapestry of genetic and cellular interactions inherent in ASD.

neuroscience↗

bioRxiv2023

Retrieval of developmental social memories requires activation of the adult-born granule cell-CA2 circuit in mice

Adult-born granule cells (abGCs) project to the CA2 region of the hippocampus, but it remains unknown how this circuit affects behavioral function. Here we show that abGC input to the CA2 of adult mice is involved in the retrieval of remote developmental memories of the mother. Ablation of abGCs impaired the ability to discriminate between a caregiving mother and a novel mother, and this ability returned after new neurons were regenerated. Chemogenetic inhibition of projections from abGCs to the CA2 also temporarily prevented the retrieval of remote mother memories. These findings were observed when abGCs were inhibited at 4-6 weeks old, but not when they were inhibited at 10-12 weeks old. We also found that abGCs are necessary for differentiating features of CA2 network activity, including theta-gamma coupling and sharp wave-ripples, in response to novel versus familiar social stimuli. Taken together, these findings suggest that abGCs are necessary for neuronal oscillations associated with discriminating between social stimuli, thus enabling retrieval of remote developmental memories of the mother by their adult offspring.

neuroscience↗

bioRxiv2022

Activation of the CA2-vCA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice

Social memory dysfunction is a feature of several neuropsychiatric and neurodevelopmental disorders. Mutation or deletion of the SHANK3 gene, which codes for a synaptic scaffolding protein, has been linked to autism spectrum disorder (ASD) and Phelan-McDermid syndrome, conditions associated with impairments in social memory. Shank3B knockout (KO) mice exhibit several behavioral abnormalities that may be analogous to symptoms of ASD, including social discrimination deficits. The CA2 region of the hippocampus integrates numerous afferents and sends a major output to the ventral CA1 (vCA1), circuitry that plays an important role in social memory. Despite finding few differences in excitatory afferents to the CA2 in Shank3B KO mice, chemogenetic activation of CA2 excitatory neurons restored social recognition function to wildtype (WT) levels. Specific activation of the CA2-vCA1 circuitry had a similar effect. Neuronal oscillations in the theta, gamma and, sharp wave ripple ranges have been linked to social memory, but we observed no differences in these measures between WT and Shank3B KO mice in the vCA1 in response to social stimuli. However, activation of CA2 excitatory neurons enhanced vCA1 theta power in Shank3B KO mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can be sufficient to invoke latent function, particularly with respect to social memory dysfunction. The extent to which vCA1 network oscillations in the theta range are responsible for rescued behavioral function remains unknown.

neuroscience↗

bioRxiv2022

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling

Early-life adversity (ELA) predisposes individuals to develop neuropsychiatric conditions, which are more prevalent in women than men. Efforts to model this sex difference in rodents have produced mixed results, with some studies paradoxically showing stronger phenotypes in males than females. Since changes in reproductive hormone levels can increase the likelihood of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when the ratio of progesterone to estrogen is relatively high, ELA mice exhibit increased avoidance behavior, altered activity levels in specific contexts, and increased theta oscillation power in the ventral hippocampus. Ovariectomy, which eliminates circulating estrogen but not progesterone, unexpectedly preserved some of the effects present in diestrus ELA mice. Progesterone receptor antagonism in diestrus normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of the progesterone metabolite allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice

neuroscience↗

bioRxiv2021

Loss of the Long Non-coding RNA OIP5-AS1 Exacerbates Heart Failure in a Sex-Specific Manner

BackgroundLong ncRNAs (lncRNAs) are known to influence numerous biological processes including cellular differentiation and tissue development. They are also implicated in the maintenance, health and physiological function of many tissues including the heart. Indeed, manipulating the expression of specific lncRNAs has been shown to improve pathological cardiac phenotypes such as heart failure. One lncRNA studied in various settings is OIP5-AS1 (also known as 1700020I14Rik and Cyrano), however its role in cardiac pathologies remains mostly uncharacterised. MethodsWe used data generated from FACS sorted murine cardiomyocytes, human iPSC derived cardiomyocytes, as well as heart tissue from various animal models to investigate OIP5-AS1 expression in health and disease. Using CRISPR we engineered a global OIP5-AS1 knock out (KO) mouse model and performed cardiac pressure overload experiments to study heart failure in these animals. RNA-sequencing of left ventricles provided mechanistic insight between WT and KO mice. ResultsWe demonstrate that OIP5-AS1 expression is regulated during cardiac development and cardiac specific pathologies in both rodent and human models. Moreover, we demonstrate that global female OIP5-AS1 KO mice develop exacerbated heart failure, but male mice do not. Transcriptomics and gene set enrichment analysis suggests that OIP5-AS1 may regulate pathways that impact mitochondrial function. ConclusionsOIP5-AS1 is regulated in cardiac tissue and its deletion leads to worsening heart function under pressure overload in female mice. This may be due to impairments in mitochondrial function, highlighting OIP5-AS1 as a gene of interest in sex-specific differences in heart failure.

physiology↗