Biology subjects

Bannerman, D.

Publications and source records attributed to Bannerman, D..

10 recordsLinked to original sources

bioRxiv2026

A hippocampal neuroimaging signature of neurovascular insulin signalling links metabolism to mood

Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance. However, the biological pathways connecting metabolic state to affective symptoms are unresolved. A growing body of evidence indicates that insulin, beyond its role in systemic glucose homeostasis, supports brain metabolism, synaptic function and cognition, yet its contribution to mood regulation remains unclear. Here, we identify a human hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans. Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.

neuroscience↗

bioRxiv2025

Epicardial extracellular vesicles modulate gene expression following ischemia-reperfusion injury in heart-on-a-chip

The epicardium is an essential regulator of cardiac development, homeostasis, and injury, yet the composition and impacts of epicardial cell-secreted extracellular vesicles (EVs) remain incompletely understood. Here, we harness an epicardial Biowire platform integrating human stem cell derived epicardial cells with functional myocardium and apply transcriptomics to reveal enriched EV transport in tissues containing epicardial cells. Profiling epicardial-EVs identified key miRNAs and their conservation through stimulated epithelial-to-mesenchymal transition. Supplementation of epicardial-EVs to tissues undergoing ischemia-reperfusion injury influenced gene expression associated with reduction of extracellular matrix remodeling, fibroblast activation, and suppression of cell-ECM interactions. Correlation of EV-miRNAs with mRNA targets highlighted the role of miR-30d-5p, miR-9-5p, miR-16-5p, and the let-7 family in moderating deleterious fibrotic activation and matrix remodelling during myocardial injury in vitro. TeaserCells from the hearts outer surface secrete tiny packages of biomolecules that influence how the heart responds to injury

bioengineering↗

bioRxiv2024

Pathological tau alters head direction signaling and induces spatial disorientation

Spatial disorientation, an early symptom of dementia, is emerging as an early and reliable cognitive biomarker predicting future memory problems associated with Alzheimers disease, but the underlying neural mechanisms have yet to be fully defined. The anterodorsal thalamic nucleus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimers disease and ageing. The ADn contains a high density of head direction (HD) cells, which contribute to spatial navigation and orientation. Hence, their disruption may contribute to spatial disorientation. To test this, we virally expressed human mutant tau (htau) in the ADn of adult mice. HD-tau mice were defined by phosphorylated and oligomeric forms of htau in ADn somata and in axon terminals in postsynaptic target regions. Compared to controls, HD-tau mice exhibited increased looping behavior during spatial learning, and made a greater number of head turns during memory recall, indicative of spatial disorientation. Using in vivo extracellular recordings, we identified htau-expressing ADn cells and found a lower proportion of HD cells in the ADn from HD-tau mice, along with reduced directionality and altered burst firing. These findings provide evidence that expression of pathological human tau can alter HD signaling, leading to impairments in spatial orientation.

neuroscience↗

bioRxiv2024

An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.

Cortical layer 6 (L6) neurons uniquely respond to orexin - a neuropeptide influencing arousal and emotion. We show that Drd1a-Cre+ neurons in the prefrontal cortex are selectively sensitive to orexin and regulate prefrontal network activation in vitro and in vivo. Chronically silencing these neurons impairs orexin-induced prefrontal activation and reduces anxiety-like behaviour, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.

neuroscience↗

bioRxiv2024

Biomimetic fractal topography enhances podocyte maturation in vitro

Cells and tissues in their native environment are organized into intricate fractal structures, which are rarely recapitulated in their culture in vitro. The extent to which fractal patterns that resemble complex topography in vivo influence cell maturation, and the cellular responses to such shape stimulation remain inadequately elucidated. Yet, the application of fractal cues (topographical stimulation via self-similar patterns) as an external input may offer a much-needed solution to the challenge of improving the differentiated cell phenotype in vitro. Here, we established fractality in podocytes, branching highly differentiated kidney cells, and glomerulus structure. Biomimetic fractal patterns derived from glomerular histology were used to generate topographical (2.5-D) substrates for cell culture. Podocytes grown on fractal topography were found to express higher levels of functional markers and exhibit enhanced cell polarity. To track morphological complexities of differentiated podocytes, we employed a fluorescent labelling assay where labelled individual cells are tracked within otherwise optically silent confluent cell monolayer to reveal cell-cell interdigitation. RNAseq analysis suggests enhanced ECM deposition and remodeling in podocytes grown on fractal topography compared to flat surface or non-fractal microcurvature, mediated by YAP signaling. The incorporation of fractal topography into standard tissue culture well plates as demonstrated here may serve as a user-friendly bioengineered platform for high-fidelity cell culture.

bioengineering↗

bioRxiv2023

Phenotypic screen-based discovery of a small molecule that can increase adult neurogenesis and improve memory

Stem cells and neurogenesis persist in the postnatal and adult brain. Adult brain stem cells can be neuroprotective in disease and augment hippocampal-dependent cognitive function and thus are an important therapeutic target. Although many molecules have been discovered that regulate neurogenesis, few studies have attempted to amplify the process pharmacologically as a therapeutic goal. To address this gap, we used murine neurosphere cultures from the two major stem cell niches: the subventricular zone (SVZ) and the subgranular zone (SGZ). We screened compounds sharing pharmacophores with known inducers of neurogenesis and found several dozen proneurogenic compounds in an in vitro phenotypic screen. One, OXS-N1 was stable, and had acceptable absorption, distribution, metabolism, and excretion profiles in animal studies. OXS-N1 could increase neurogenesis in the SVZ and SGZ in WT mice after both intraperitoneal and oral administration. The number of newborn neurons (BrdU+/NeuN+) was increased; however, the number of activated stem cells (BrdU+/GFAP+) was not, suggesting an effect on neurogenesis independent of stem cell activation. This was supported by OXS-N1 increasing neurosphere differentiation but not proliferation. OXS-N1 also increased neurogenesis and improved performance in a Y maze cognitive task in PDGF-APPSw,Ind mice, a model of Alzheimers disease. RNAseq of SVZ and SGZ neurospheres in turn showed that genes associated with synaptic function were significantly increased by OXS-N1. Our study demonstrates the utility of phenotypic screening for the identification of molecules that increase neurogenesis and might be of therapeutic relevance.

neuroscience↗

bioRxiv2021

Consequences of human Tau aggregation in the hippocampal formation of ageing mice in vivo

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely-moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.

neuroscience↗

bioRxiv2021

Intraneuronal chloride levels encode tiredness in cortex

Continuous periods of wakefulness are associated with reduced performance levels due to the build-up of sleep pressure in active regions of the brain. These effects manifest as use-dependent changes in cortical network activity and the mechanisms underlying these changes represent targets for overcoming the cognitive effects of tiredness. Here we reveal a central role for intraneuronal chloride levels, which increase in a use-dependent manner during waking, and reduce the strength of local synaptic inhibition in mouse cortex. Activity-dependent increases in chloride account for spatial and temporal features of sleep pressure, they underlie cortical network oscillations in the sleep-deprived state, and targeting chloride regulation in cortex can rescue performance levels when tired. These findings provide a missing link between sleep-wake history, synaptic transmission and cortical dynamics. One-Sentence SummaryThe effects of sleep pressure on cortical function are caused by use-dependent changes in chloride-mediated synaptic inhibition.

neuroscience↗

bioRxiv2021

Psilocin acutely disrupts sleep and affects local but not global sleep homeostasis in laboratory mice

Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the regulation of neuronal firing and activity homeostasis. It remains unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic in vivo electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 hours after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow wave activity. However, psilocin decreased the recovery rate of sleep slow wave activity following sleep deprivation in the local field potentials of electrodes targeting medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.

neuroscience↗

bioRxiv2017

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Acute episodes of delirium also contribute significantly to rates of long-term cognitive decline, implying that de novo pathology occurs during these acute episodes. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms has not been investigated. Here we show that systemic inflammation, induced by bacterial LPS, produces both working memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100g/kg) did not affect working memory but robustly impaired contextual fear conditioning (CFC). However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1{beta} replicated, these working memory deficits. Although LPS-induced deficits still occured in IL-1RI-/- mice, systemic TNF- was sufficient to induce similar deficits, indicating redundancy among these cytokines. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits despite failing to block brain IL-1{beta} synthesis. Direct application of IL-1{beta} to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/- dependent-fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1{beta} but dysfunction leading to neuronal death is mediated by hippocampal IL-1{beta}. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury that may lead to long-term cognitive impairment but that these events are mechanistically dissociable. This would have significant implications for management of cognitive dysfunction and decline during acute illness.

neuroscience↗