Biology subjects

Bedbrook, C. N.

Publications and source records attributed to Bedbrook, C. N..

5 recordsLinked to original sources

bioRxiv2026

Engulfment by brain macrophages in a short-lived vertebrate

Engulfment by macrophages is critical for waste clearance in the vertebrate brain. Understanding clearance mechanisms may open new therapeutic possibilities to counter brain aging and neurodegenerative diseases. However, few in vivo models exist to study engulfment in the brain and characterize this process during aging and across species. Here we present a genetic model for secretion of a fluorescent protein by neurons in the brain of the African turquoise killifish, the shortest-lived vertebrate that can be bred in captivity. We use this model to identify a population of brain macrophages in the killifish responsible for engulfment of material from the brain extracellular space. Intriguingly, many of these cells bear similarities to mammalian border-associated and monocyte-derived macrophages, rare subsets of macrophages in mouse and human brains noted for their engulfment capabilities. We also find that in our model, killifish brain macrophages decline in engulfment capacity with age. This work highlights how vertebrate brain macrophages, particularly those at brain border regions, can play a critical role in clearance and provides an opportunity to test interventions that can boost engulfment by these macrophages to promote brain resilience in old age and disease.

cell biology↗

bioRxiv2025

Life-long behavioral screen reveals an architecture of vertebrate aging

Mapping behavior of individual vertebrate animals across lifespan is challenging, but if achieved, could provide an unprecedented view into the life-long process of aging. We created the first platform for high-resolution continuous behavioral tracking of a vertebrate animal across natural lifespan from adolescence to death--here, of the African killifish. This behavioral screen revealed that animals follow distinct individual aging trajectories. The behaviors of long-lived animals differed markedly from those of short-lived animals, even relatively early in life, and were linked to organ-specific transcriptomic shifts. Machine learning models accurately predicted age and even forecasted an individuals future lifespan, given only behavior at a young age. Finally, we found that animals progressed through adulthood in a sequence of stable and stereotyped behavioral stages with abrupt transitions suggesting a novel structure for the architecture of vertebrate aging.

animal behavior and cognition↗

bioRxiv2022

Rapid and precise genome engineering in a naturally short-lived vertebrate

The African turquoise killifish is a powerful vertebrate system to study complex phenotypes at scale, including aging and age-related disease. Here we develop a rapid and precise CRISPR/Cas9-mediated knock-in approach in the killifish. We show its efficient application to precisely insert fluorescent reporters of different sizes at various genomic loci, to drive cell-type- and tissue-specific expression. This knock-in method should allow the establishment of humanized disease models and the development of cell-type-specific molecular probes for studying complex vertebrate biology.

genetics↗

bioRxiv2021

An automated feeding system for the African killifish reveals effects of dietary restriction on lifespan and allows scalable assessment of associative learning

The African turquoise killifish is an exciting new vertebrate model for aging studies. A significant challenge for any model organism is the control over its diet in space and time. To address this challenge, we created an automated and networked fish feeding system. Our automated feeder is designed to be open-source, easily transferable, and built from widely available components. Compared to manual feeding, our automated system is highly precise and flexible. As a proof-of-concept for the feeding flexibility of these automated feeders, we define a favorable regimen for growth and fertility for the African killifish and a dietary restriction regimen where both feeding time and quantity are reduced. We show that this dietary restriction regimen extends lifespan in males (but not in females) and impacts the transcriptomes of killifish livers in a sex-specific manner. Moreover, combining our automated feeding system with a video camera, we establish a quantitative associative learning assay to provide an integrative measure of cognitive performance for the killifish. The ability to precisely control food delivery in the killifish opens new areas to assess lifespan and cognitive behavior dynamics and to screen for dietary interventions and drugs in a scalable manner previously impossible with traditional vertebrate model organisms.

physiology↗

bioRxiv2019

Machine learning-guided channelrhodopsin engineering enables minimally-invasive optogenetics

We have engineered light-gated channelrhodopsins (ChRs) whose current strength and light sensitivity enable minimally-invasive neuronal circuit interrogation. Current ChR tools applied to the mammalian brain require intracranial surgery for transgene delivery and implantation of invasive fiber-optic cables to produce light-dependent activation of a small volume of brain tissue [~1 mm3]. To enable optogenetics for large brain volumes and without the need for invasive implants, our ChR engineering approach leverages the significant literature of ChR variants to train statistical models for the design of new, high-performance ChRs. With Gaussian Process models trained on a limited experimental set of 102 functionally characterized ChR variants, we designed high-photocurrent ChRs with unprecedented light sensitivity; three of these, ChRger1, ChRger2, and ChRger3, enable optogenetic activation of the nervous system via minimally-invasive systemic transgene delivery with rAAV-PHP.eB, which was not possible previously due to low per-cell transgene copy produced by systemic delivery. These engineered ChRs enable light-induced neuronal excitation without invasive intracranial surgery for virus delivery or fiber optic implantation, i.e. they enable minimally-invasive optogenetics.

bioengineering↗