Biology subjects

Taylor, K. R.

Publications and source records attributed to Taylor, K. R..

8 recordsLinked to original sources

bioRxiv2025

Dysregulated Microglial Synaptic Engulfment in Diffuse Midline Glioma

Diffuse midline glioma (DMG) is a near-universally lethal form of pediatric high-grade glioma, driven by neuronal activity-regulated paracrine signaling and synaptic integration of malignant cells into neural circuits. In turn, DMG increases neuronal excitability, augmenting neuron-to-glioma signaling. In the healthy brain, microglia, the resident immune cells of the central nervous system (CNS), regulate neuronal excitability and synaptic connectivity. However, the role of microglia in promoting tumor-associated hyperexcitable neural networks in glioma remains unknown. Here, we investigate the activity-regulated engulfment of neuronal synapses by microglia in both healthy and glioma-bearing mice, and further explore how glioma cells alter microglia-mediated circuit refinement, contributing to pathogenic neuronal hyperexcitability. Microglia-mediated circuit refinement in the glioma microenvironment was characterized through synaptic engulfment analysis of both excitatory and inhibitory synapses by microglia in healthy mice and patient-derived DMG xenograft models, paired with optogenetic stimulation in the neocortex. We found that glutamatergic neuronal activity in the healthy brain increased excitatory synaptic engulfment by microglia in a previously unappreciated negative feedback mechanism that may guard against hyperexcitability. In contrast, this activity-regulated increase in excitatory synaptic engulfment was abrogated in DMG-infiltrated brains. Instead, inhibitory synaptic engulfment was significantly increased in DMG in response to glutamatergic neuronal activity. Together, these dysregulated synaptic engulfment mechanisms may create imbalance in the excitatory to inhibitory (E:I) synapse ratio predicted to increase neuronal excitability. Complementary single-nuclei sequencing studies revealed concordant tumor-specific, activity-regulated changes in microglia-neuron signaling showing reduced expression of excitatory synaptic refinement gene programs in microglia, potentially mediating the aberrant synaptic engulfment observed in DMG. These findings reveal novel cancer-neuron-immune interactions in DMG and provide an opportunity to potentially modulate tumor-associated neuronal hyperexcitability by targeting aberrant microglial synaptic engulfment. HIGHLIGHTSO_LIExcitatory synaptic engulfment by microglia increases in a glutamatergic neuronal activity-dependent manner in the healthy brain. C_LIO_LIIn the glioma-infiltrated brain, this feedback regulatory mechanism is inverted, with loss of activity-regulated excitatory synaptic engulfment and aberrant increased inhibitory synaptic engulfment. C_LIO_LITranscriptomic changes in glioma-associated microglia contribute to differential excitatory and inhibitory synaptic engulfment, with reduced excitatory synaptic refinement gene programs in tumor-associated microglia. C_LIO_LIActivity-regulated soluble factors drive this imbalanced excitatory-inhibitory postsynaptic engulfment by glioma-associated microglia. C_LI

neuroscience↗

bioRxiv2025

AlphaGenome: advancing regulatory variant effect prediction with a unified DNA sequence model

Deep learning models that predict functional genomic measurements from DNA sequence are powerful tools for deciphering the genetic regulatory code. Existing methods trade off between input sequence length and prediction resolution, thereby limiting their modality scope and performance. We present AlphaGenome, which takes as input 1 megabase of DNA sequence and predicts thousands of functional genomic tracks up to single base pair resolution across diverse modalities - including gene expression, transcription initiation, chromatin accessibility, histone modifications, transcription factor binding, chro- matin contact maps, splice site usage, and splice junction coordinates and strength. Trained on human and mouse genomes, AlphaGenome matches or exceeds the strongest respective available external models on 24 out of 26 evaluations on variant effect prediction. AlphaGenomes ability to simultaneously score variant effects across all modalities accurately recapitulates the mechanisms of clinically-relevant variants near the TAL1 oncogene. To facilitate broader use, we provide tools for making genome track and variant effect predictions from sequence.

bioinformatics↗

bioRxiv2024

Cholinergic Neuronal Activity Promotes Diffuse Midline Glioma Growth through Muscarinic Signaling

Neuronal activity promotes the proliferation of healthy oligodendrocyte precursor cells (OPC) and their malignant counterparts, gliomas. Many gliomas arise from and closely resemble oligodendroglial lineage precursors, including diffuse midline glioma (DMG), a cancer affecting midline structures such as the thalamus, brainstem and spinal cord. In DMG, glutamatergic and GABAergic neuronal activity promotes progression through both paracrine signaling and through bona-fide neuron-to-glioma synapses. However, the putative roles of other neuronal subpopulations - especially neuromodulatory neurons located in the brainstem that project to long-range target sites in midline anatomical locations where DMGs arise - remain largely unexplored. Here, we demonstrate that the activity of cholinergic midbrain neurons modulates both healthy OPC and malignant DMG proliferation in a circuit-specific manner at sites of long-range cholinergic projections. Optogenetic stimulation of the cholinergic pedunculopontine nucleus (PPN) promotes glioma growth in pons, while stimulation of the laterodorsal tegmentum nucleus (LDT) facilitates proliferation in thalamus, consistent with the predominant projection patterns of each cholinergic midbrain nucleus. Reciprocal signaling was evident, as increased activity of cholinergic neurons in the PPN and LDT was observed in pontine DMG-bearing mice. In co-culture, hiPSC-derived cholinergic neurons form neuron-to-glioma networks with DMG cells and robustly promote proliferation. Single-cell RNA sequencing analyses revealed prominent expression of the muscarinic receptor genes CHRM1 and CHRM3 in primary patient DMG samples, particularly enriched in the OPC-like tumor subpopulation. Acetylcholine, the neurotransmitter cholinergic neurons release, exerts a direct effect on DMG tumor cells, promoting increased proliferation and invasion through muscarinic receptors. Pharmacological blockade of M1 and M3 acetylcholine receptors abolished the activity-regulated increase in DMG proliferation in cholinergic neuron-glioma co-culture and in vivo. Taken together, these findings demonstrate that midbrain cholinergic neuron long-range projections to midline structures promote activity-dependent DMG growth through M1 and M3 cholinergic receptors, mirroring a parallel proliferative effect on healthy OPCs. HIGHLIGHTSO_LIActivity of midbrain cholinergic neuron long-range projections increases proliferation of both healthy oligodendrocyte precursor cells (OPC) and malignant diffuse midline glioma (DMG) cells. C_LIO_LIOptogenetic stimulation of cholinergic midbrain nuclei promotes growth in thalamic and pontine glioma in a circuit-dependent manner. C_LIO_LIReciprocally, DMG cells increase cholinergic neuronal activity in cholinergic midbrain nuclei. C_LIO_LIThe muscarinic receptors CHRM1 and CHRM3 are identified as therapeutic targets in DMG. C_LI

neuroscience↗

bioRxiv2022

GABAergic neuron-to-glioma synapses in diffuse midline gliomas

Pediatric high-grade gliomas are the leading cause of brain cancer-related death in children. High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling1,2 and direct neuron-to-glioma synapses3-5. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric3 and adult high-grade gliomas4, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation3, we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam - a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety - increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and diffuse midline glioma cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.

neuroscience↗

bioRxiv2022

Myelin plasticity in ventral tegmental area is required for opioid reward

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward. One-Sentence SummaryActivity-dependent myelin plasticity in the ventral tegmental area modulates dopaminergic circuit function and opioid reward

neuroscience↗

bioRxiv2022

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

neuroscience↗

bioRxiv2021

Glioma synapses recruit mechanisms of adaptive plasticity

The nervous system plays an increasingly appreciated role in the regulation of cancer. In malignant gliomas, neuronal activity drives tumor progression not only through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF)1-3, but also through electrophysiologically functional neuron-to-glioma synapses4-6. Malignant synapses are mediated by calcium-permeable AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in both pediatric and adult high-grade gliomas4, 5, and consequent depolarization of the glioma cell membrane drives tumor proliferation4. The nervous system exhibits plasticity of both synaptic connectivity and synaptic strength, contributing to neural circuit form and functions. In health, one factor that promotes plasticity of synaptic connectivity7, 8 and strength9-13 is activity-regulated secretion of the neurotrophin BDNF. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF-TrkB (tropomyosin receptor kinase B) signaling. Signaling through the receptor TrkB14, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with the long-term potentiation (LTP)15-23 that is thought to contribute to memory and learning in the healthy brain22 24-27 28, 29. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells exerts growth inhibitory effects in vivo and in neuron:glioma co-cultures that cannot be explained by classical growth factor signaling alone. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.

neuroscience↗

bioRxiv2021

Effective gene expression prediction from sequence by integrating long-range interactions

The next phase of genome biology research requires understanding how DNA sequence encodes phenotypes, from the molecular to organismal levels. How noncoding DNA determines gene expression in different cell types is a major unsolved problem, and critical downstream applications in human genetics depend on improved solutions. Here, we report substantially improved gene expression prediction accuracy from DNA sequence through the use of a new deep learning architecture called Enformer that is able to integrate long-range interactions (up to 100 kb away) in the genome. This improvement yielded more accurate variant effect predictions on gene expression for both natural genetic variants and saturation mutagenesis measured by massively parallel reporter assays. Notably, Enformer outperformed the best team on the critical assessment of genome interpretation (CAGI5) challenge for noncoding variant interpretation with no additional training. Furthermore, Enformer learned to predict promoter-enhancer interactions directly from DNA sequence competitively with methods that take direct experimental data as input. We expect that these advances will enable more effective fine-mapping of growing human disease associations to cell-type-specific gene regulatory mechanisms and provide a framework to interpret cis-regulatory evolution. To foster these downstream applications, we have made the pre-trained Enformer model openly available, and provide pre-computed effect predictions for all common variants in the 1000 Genomes dataset. One-sentence summaryImproved noncoding variant effect prediction and candidate enhancer prioritization from a more accurate sequence to expression model driven by extended long-range interaction modelling.

genomics↗