Biology subjects

Banks, G.

Publications and source records attributed to Banks, G..

9 recordsLinked to original sources

bioRxiv2025

The neural basis of emotional generalization in empathy

The essence of empathy is generalization of emotion across persons. Here, we leverage recent theoretical advances in the neuroscience of generalization to help us understand empathy. We measured brain activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one identifying emotional responses in others. We quantified the representational geometry of local field potential (LFP) high-gamma activity in four regions: the medial temporal lobe, anterior cingulate cortex, orbitofrontal cortex, and insula. We found encoding of both self- and other-emotions in all four regions, but codes for emotion and person are disentangled (that is, factorized) in the insula, but not the other regions. This factorized representation allows for cross-person generalization of emotion in a way that tangled (non-factorized) representations do not. Together, these results support the hypothesis that the insula uniquely contributes to social mirroring processes by which we understand emotions across individuals.

neuroscience↗

bioRxiv2024

Long-read transcriptomic identification of synaptic adaptation to amyloid pathology in the App(NL-G-F) knock-in mouse model of the earliest phase of Alzheimer's disease

Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimers disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA-sequencing (RNA-seq) in the AppNL-G-F knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-{beta}. We show that long-read RNA-seq can recapitulate the expected induction of microglial expressed risk genes such as Trem2 in response to amyloid-{beta} at 9 months of age associated with ageing-dependent deficiencies in spatial short-term memory in the AppNL-G-F knock-in mice. Our results not only identified novel splicing events and transcript isoform abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in microglia, neurons and oligodendrocytes, and included genes such as Syngr1 that modulate synaptic physiology. We saw alternative splicing in genes such as Ctsa, Clta, Dennd2a, Irf9 and Smad4 in mice in response to amyloid, and the orthologues of these genes also showed transcript usage changes in human AD brains. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-{beta} during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for treatment of AD.

genetics↗

bioRxiv2024

Insula uses overlapping codes for emotion in self and others

In daily life, we must recognize others emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

neuroscience↗

bioRxiv2023

Loss of zinc finger homeobox-3 (ZFHX3) affects rhythmic gene transcription in mammalian central clock

The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn co-ordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing (ChIP-seq) to map the genomic localization of ZFHX3 binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites (TSS), co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF Bmal1. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12h light-12h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.

neuroscience↗

bioRxiv2023

A biophysically constrained brain connectivity model based on stimulation-evoked potentials.

BackgroundSingle-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies. New MethodUsing intracranial electrophysiology data recorded from a single patient undergoing sEEG evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D conductivity propagation from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features. ResultsThe proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlates with additional PEP features and displayed stable, weak correlations with tractography measures. Comparison with existing methodsExisting methods for estimating conductivity propagation are imaging-based and thus rely on anatomical inferences. ConclusionsThese results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors.

neuroscience↗

bioRxiv2022

Dynamic modulation of genomic enhancer elements in the suprachiasmatic nucleus mediates daily timekeeping in mammals

The mammalian suprachiasmatic nucleus (SCN), located in the ventral hypothalamus, is crucial for synchronising and resetting all cellular rhythms in accordance with critical environmental and visceral cues. Consequently, the systematic regulation of spatiotemporal gene transcription in the SCN is vital for daily timekeeping. Here, we sought to identify SCN enriched gene regulatory elements that enable temporal gene expression using histone-ChIP-seq. We found a vast majority of SCN enhancers not only exhibit robust 24-hour rhythmic modulation in H3K27ac occupancy, but also possess canonical E-box (CACGTG) motif, potentially influencing downstream cycling gene expression. In parallel, we conducted RNA-Seq at six distinct times to establish enhancer-gene relationships in the SCN. Surprisingly, around 35% of cycling H3K27ac abundance is seen adjacent to rhythmic gene transcripts, often preceding the rise in mRNA levels. We also noted that enhancers encompass non-coding actively transcribing enhancer RNAs (eRNAs), that in turn oscillate along with cyclic histone acetylation to direct gene transcription. Taken together, these findings shed light on genome-wide pre-transcriptional regulation operative in the central clock that enables its orchestration of daily timekeeping mechanisms in mammals.

genomics↗

bioRxiv2022

A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.

A protein altering variant in the gene encoding zinc finger homeobox-3 (ZFHX3) has recently been associated with lower BMI in a human genome-wide association study. We investigated metabolic parameters in mice harbouring a missense mutation in Zfhx3 (Zfhx3Sci/+) and looked for altered in situ expression of transcripts that are associated with energy balance in the hypothalamus to understand how ZFHX3 may influence growth and metabolic effects. One year old male and female Zfhx3Sci/+ mice weighed less, had shorter body length, reduced fat mass, smaller mesenteric fat depots, and lower circulating insulin, leptin, and insulin-like growth factor-1 (IGF1) concentrations than Zfhx3+/+ littermates. In a second cohort of 9 - 20-week-old males and females, Zfhx3Sci/+ mice ate less than wildtype controls, in proportion to body weight. In a third cohort of female-only Zfhx3Sci/+ and Zfhx3+/+ mice that underwent metabolic phenotyping from 6 - 14 weeks old, Zfhx3Sci/+ mice weighed less and had lower lean mass and energy expenditure, but fat mass didnt differ. We detected increased expression of somatostatin, and decreased expression of growth hormone-releasing hormone and growth hormone-receptor mRNAs in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y was decreased and ventricular ependymal expression of orphan G protein-coupled receptor Gpr50 was decreased. We demonstrate for the first time an energy balance effect of the Zfhx3Sci mutation, likely by altering expression of key ARC neuropeptides to alter growth, food intake and energy expenditure.

physiology↗

bioRxiv2021

DNA Methylation Networks Underlying Mammalian Traits

Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to construct phyloepigenetic trees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolution, aging and lifespan.

evolutionary biology↗

bioRxiv2018

Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

Summary statementIn this study, we show that the loss of the epilepsy-related gene Frrs1l in mice causes a dramatic reduction in AMPA receptor levels at the synapse. This change elicits severe motor and coordination disabilities, hyperactivity, cognitive defects, behavioural seizures and abnormal electroencephalographic (EEG) patterns.\n\nAbstractLoss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis and assembly, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l-/- mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l-/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l-/- mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in glycosylation deficits in GLUA2 and GLUA4 AMPA receptor proteins, leading to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.

neuroscience↗