Biology subjects

Holmes, T. C.

Publications and source records attributed to Holmes, T. C..

7 recordsLinked to original sources

bioRxiv2025

UC Irvine Brain Initiative Cell Atlas Network (BICAN) Brain Procurement Program for the Center for Multiomic Human Brain Cell Atlas Project

High-quality neurotypical postmortem human brain tissue is essential but difficult to obtain for constructing comprehensive human brain cell atlases. Here we describe the establishment of UC Irvines Brain Procurement Program, a coordinated initiative to collect and process neurotypical donor brains for multiomic mapping studies within the NIH BRAIN Initiative Cell Atlas Network (BICAN) consortium. Through partnerships with the Orange County Coroners Office, the UC Irvine Willed Body Program, UCI Medical Center, and the Childrens Hospital of Orange County, we have developed standardized workflows encompassing donor identification, postmortem brain recovery and processing, region-of-interest dissection, neurotypical donor selection, and data management. Our experience demonstrates the feasibility of a community-based, multi-institutional procurement framework while highlighting challenges in recruiting neurotypical donors and ensuring demographic representation reflective of Southern California. We further identify opportunities to strengthen outreach and donation pathways. This program provides a scalable model for advancing population-reflective, high-quality human brain cell atlas efforts. HighlightsO_LIEstablish a multi-site pipeline for procuring high-quality neurotypical human brains. C_LIO_LIDemonstrate feasibility of donor collection across childhood to adulthood. C_LIO_LIIdentify barriers and propose strategies to improve broad donor recruitment. C_LI

neuroscience↗

bioRxiv2025

Multiscale Spatial Transcriptomic Atlas of Human Basal Ganglia Cell-Type and Cellular Community Organization

We generated a multi-region, subcellular-resolution spatial transcriptomic atlas of the human basal ganglia by integrating MERFISH+ and Stereo-seq across four neurotypical donors. These datasets profiled [~]7 million cells spanning the caudate, putamen, nucleus accumbens, and globus pallidus, resolving 60 transcriptionally distinct cell types. We show region-selective, molecular and spatial diversification of medium-spiny-neuron cell types and multiple non-neuronal populations with distinct molecular identities and spatial localizations. Subcellular RNA localization captures somatic size and projection-inferred signatures that reflect direct and indirect pathway topology. Cellular community analyses reveal the enrichment of sub-clusters of astrocytes and oligodendrocytes at striosome-matrix borders, while primate-expanded interneurons are confined to matrix territories. Cross-species mapping uncovers orthologous striosome-matrix organization and conserved dorsolateral-ventromedial gene expression gradients. This atlas provides a foundational molecular and spatial framework for studying human basal ganglia architecture, offering a multi-centimeter scale resource that links cell types, spatial architecture, and subcellular transcript topography across multiple nuclei. HighlightsO_LIOur multi-centimeter scale spatial taxonomy identifies the precise locations of 60 neuronal and glial cell types of human basal ganglia. C_LIO_LIMERFISH+ and Stereo-seq platforms map consistent spatial modules that align with classical neuroanatomical nuclei. C_LIO_LID1D2 hybrid MSNs and primate-expanded interneurons show regional and domain specific organization C_LIO_LISubcellular RNA localization reports soma morphology and projection-inferred signatures. C_LI

neuroscience↗

bioRxiv2025

The Innexin 7 gap junction protein contributes to synchronized activity in the Drosophila antennal lobe and regulates olfactory function

In the mammalian olfactory bulb (OB), gap junctions coordinate synchronous activity among mitral and tufted cells to process olfactory information. In insects, gap junctions are also present in the Antennal Lobe (AL), a structure homologous to the mammalian OB. The invertebrate gap junction protein ShakB contributes to electrical synapses between AL Projections Neurons (PNs) in Drosophila. Other gap junction proteins, including Innexin 7 (Inx7), are also expressed in the Drosophila AL, but little is known about their contribution to intercellular communication during olfactory information processing. Here we report spontaneous calcium transients in PNs grown in cell culture that are highly synchronous when these neurons are physically connected. RNAi-mediated knock down of Inx7 in cultured PNs blocks calcium transient neuronal synchronization. In vivo, downregulation of Inx7 in the AL impairs both vinegar-induced electrophysiological calcium responses and behavioral responses to this appetitive stimulus. These results demonstrate that Inx7-encoded gap junctions functionally coordinate PN activity and modulate olfactory information processing in the adult Drosophila AL.

neuroscience↗

bioRxiv2022

Longitudinal dynamics of microvascular recovery after acquired cortical injury

Acquired brain injuries due to trauma damage cortical vasculature, which in turn impairs blood flow to injured tissues. There are reports of vascular morphological recovery following traumatic brain injury (TBI), but the remodeling process has not been examined longitudinally in detail after injury in vivo. Understanding the dynamic processes that influence recovery is thus critically important. We evaluated the longitudinal and dynamic microvascular recovery and remodeling up to 2 months post injury using live brain miniscope and 2-photon microscopic imaging. The new imaging approaches captured dynamic morphological and functional recovery processes at high spatial and temporal resolution in vivo. Vessel painting documented the initial loss and subsequent temporal morphological vascular recovery at the injury site. Miniscopes were used to longitudinally image the temporal dynamics of vascular repair in vivo after brain injury in individual mice across each cohort. We observe near-immediate nascent growth of new vessels in and adjacent to the injury site that peaks between 14-21 days post injury. 2-photon microscopy confirms new vascular growth and further demonstrates differences between cortical layers after cortical injury: large vessels persist in deeper cortical layers (>200 m), while superficial layers exhibit a dense plexus of fine (and often non-perfused) vessels displaying regrowth. Functionally, blood flow increases mirror increasing vascular density. Filopodia development and endothelial sprouting is measurable within 3 days post injury that rapidly transforms regions devoid of vessels to dense vascular plexus in which new vessels become increasingly perfused. Within 7 days post injury, blood flow is observed in these nascent vessels. Behavioral analysis reveals improved vascular modulation after 9 days post injury, consistent with vascular regrowth. We conclude that morphological recovery events are closely linked to functional recovery of blood flow to the compromised tissues, which subsequently leads to improved behavioral outcomes.

neuroscience↗

bioRxiv2020

Subanesthetic ketamine reactivates adult cortical plasticity to restore vision from amblyopia

Subanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamines effects remains elusive, but ketamine may broadly modulate brain plasticity processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces down-regulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons in vitro and in vivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia. Highlights{circ} Disinhibition of excitatory cells by ketamine occurs in a fast and sustained manner {circ}Ketamine evokes NRG1 downregulation and excitatory input loss to PV cells {circ}Ketamine induced plasticity is blocked by exogenous NRG1 or its receptor knockout {circ}PV inhibitory cells are the initial functional locus underlying ketamines effects

neuroscience↗

bioRxiv2020

Weekend light shifts evoke persistent Drosophila circadian neural network desynchrony

Billions of people subject themselves to phase-shifting light signals on a weekly basis by remaining active later at night and sleeping in later on weekends relative to weekday for up to a 3hr weekend light shift (WLS). Unnatural light signals disrupt circadian rhythms and physiology and behavior. Real-time light responses of mammalian suprachiasmatic nucleus are unmeasurable at single cell resolution. We compared Drosophila whole-circadian circuit responses between unshifted daytime/nighttime schedule and a 3hr WLS schedule at the single-cell resolution in cultured adult Drosophila brains using real-time bioluminescence imaging of the PERIOD protein for 11 days to determine how light shifts alter biological clock entrainment and stability. We find that circadian circuits show highly synchronous oscillations across all major circadian neuronal subgroups in unshifted light schedules. In contrast, circadian circuits exposed to a WLS schedule show significantly dampened oscillator synchrony and rhythmicity in most circadian neurons during, and after exposure. The WLS schedule first desynchronizes lateral ventral neuron (LNv) oscillations and the LNv are the last to resynchronize upon returning to a simulated weekday schedule. Surprisingly, one circadian subgroup, the dorsal neuron group-3 (DN3s), robustly increase their within-group synchrony in response to WLS exposure. Intact adult flies exposed to the WLS schedule show post-WLS transient defects in sleep stability, learning, and memory. Our findings suggest that WLS schedules disrupt circuit-wide circadian neuronal oscillator synchrony for much of the week, thus leading to observed behavioral defects in sleep, learning, and memory. Significance StatementThe circadian clock controls numerous aspects of daily animal physiology, metabolism and behavior. Shift work in humans is harmful. Our understanding of circadian circuit-level oscillations stem from ex vivo imaging of mammalian suprachiasmatic nucleus (SCN) brain slices. However, our knowledge is limited to investigations without direct interrogation of phase-shifting light signals. We measured circuit-level circadian responses to a WLS protocol in light sensitive ex vivo Drosophila whole-brain preparation and find robust sub-circuit-specific oscillator desynchrony/resynchrony responses to light. These circuit-level behaviors correspond to our observed functional defects in learning and memory, and sleep pattern disruption in vivo. Our results reflect that WLS cause circadian-circuit desynchronization and correlate with disrupted cognitive and sleep performance.

neuroscience↗

bioRxiv2019

Circadian regulation of light-evoked attraction/avoidance in day- vs. night-biting mosquitoes

Mosquitoes pose widespread threats to humans and other animals as disease vectors. Day- vs. night-biting mosquitoes occupy distinct time-of-day niches and exhibit very different innate temporal attraction/avoidance behavioral responses to light, yet little is known about their circuit or molecular mechanisms. Day-biting diurnal mosquitoes Aedes aegypti are attracted to light during the day regardless of spectra. In contrast, night-biting nocturnal mosquitoes Anopheles coluzzii avoid short, but not long wavelength light. Attraction/avoidance behavioral responses to light in both species change with time-of-day and show distinct sex and circuit differences. The basis of diurnal versus nocturnal behavior is driven by clock timing, which cycle anti-phase between day-biting versus night-biting mosquito species. Disruption of the circadian molecular clock severely interferes with light-evoked attraction/avoidance behavior in mosquitoes. In summary, attraction/avoidance mosquito behaviors are circadian and light regulated, which may be applied towards species specific control of harmful mosquitoes.

neuroscience↗