Biology subjects

Hope, K. T.

Publications and source records attributed to Hope, K. T..

4 recordsLinked to original sources

bioRxiv2026

Lysosomal Glycosaminoglycan Catabolism Regulates Microglial Cell State in the Developing CNS

Remodeling of the extracellular matrix (ECM), a complex structural and signaling network of the nervous system, is essential for CNS development, plasticity, and injury responses, yet how individual neural cell types contribute to this process remains poorly understood. Here, we show that phagocytic clearance of glycosaminoglycans (GAGs), major components of the ECM, is an intrinsic function of microglia in the developing CNS. Our studies reveal an unexpected finding that impaired GAG clearance shifts microglia toward a non-homeostatic cell state seen in immature and disease-associated microglia (DAM), supporting a reciprocal relationship between the ECM and microglia. Using mouse models of Mucopolysaccharidosis VII, we examined the consequences of deleting {beta}-glucuronidase (GUSB), a lysosomal enzyme required for GAG degradation. Loss of GUSB causes early accumulation of undegraded chondroitin sulfate within microglial lysosomes, as confirmed by LC-MS analysis of intracellular GAGs isolated from cortical microglia. Single-cell RNA sequencing identified Gusb-null microglia as a distinct transcriptional population enriched for a core transcriptome shared by immature and disease-associated microglia. Together, these findings establish lysosomal GAG catabolism as a pathway that links ECM remodeling to the acquisition of adult homeostatic microglial identity during CNS development.

neuroscience↗

bioRxiv2023

An output-null signature of inertial load in motor cortex

Coordinated movement requires the nervous system to continuously compensate for changes in mechanical load across different contexts. For voluntary movements like reaching, the motor cortex is a critical hub that generates commands to move the limbs and counteract loads. How does cortex contribute to load compensation when rhythmic movements are clocked by a spinal pattern generator? Here, we address this question by manipulating the mass of the forelimb in unrestrained mice during locomotion. While load produces changes in motor output that are robust to inactivation of motor cortex, it also induces a profound shift in cortical dynamics, which is minimally affected by cerebellar perturbation and significantly larger than the response in the spinal motoneuron population. This latent representation may enable motor cortex to generate appropriate commands when a voluntary movement must be integrated with an ongoing, spinally-generated rhythm.

neuroscience↗

bioRxiv2021

Midbrain microglia exhibit early proliferative and inflammatory responses during aging that are modulated by CX3CR1 and microglial ablation and repopulation

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to insults, positioning these cells to have profound impact on the functional integrity of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions and CNS insults in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. We demonstrate that microglia in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) exhibit unique and premature responses to aging, compared to microglia elsewhere. This is associated with pockets of VTA/SNc neuroinflammation that are likely to compromise local synaptic function as early as middle age. Surprisingly, these early aging responses of VTA and SNc microglia do not appear to be driven by systemic inflammation, local neuron death, or early responses of astrocytes to aging. Finally, CX3CR1 receptor knockout can exacerbate and microglial ablation/repopulation can suppress early VTA microglial aging; these manipulations have been shown to affect brain-wide microglial aging, and our data demonstrate that their impact is not uniform throughout the CNS. Our findings reveal a previously unappreciated regional variation in the onset and magnitude of microglial aging responses and suggest that there may be important links between local microglial aging and vulnerability of nearby neurons to functional decline and disease.

neuroscience↗

bioRxiv2019

Mesolimbic microglia display regionally distinct developmental trajectories

Microglia play critical roles during CNS development and undergo dramatic changes in tissue distribution, morphology, and gene expression as they transition from embryonic to neonatal to adult microglial phenotypes. Despite the magnitude of these phenotypic shifts, little is known about the time course and dynamics of these transitions and whether they vary across brain regions. Here we define the time course of microglial maturation in key regions of the basal ganglia in mice where significant regional differences in microglial phenotype are present in adults. We found that microglial density peaks in the ventral tegmental area (VTA) and nucleus accumbens (NAc) during the third postnatal week, driven by a burst of microglial proliferation. Microglial abundance is then refined to adult levels through a combination of tissue expansion and microglial programmed cell death. This overproduction and refinement of microglia was significantly more pronounced in the NAc and was accompanied by a sharp peak in NAc microglial lysosome abundance in the third postnatal week. Collectively, these data identify a key developmental window when elevated microglial density in discrete basal ganglia nuclei may support circuit refinement and could increase susceptibility to inflammatory insults.

neuroscience↗