Gao, V. D. | bioRxiv Science

bioRxiv2025

Macrophage depletion restores the DRG microenvironment and prevents axon degeneration in bortezomib-induced neuropathy

Peripheral neuropathy is a common and debilitating side effect of the chemotherapeutic bortezomib (BTZ). To explore the mechanisms underlying BTZ-induced neuropathy (BIPN), we developed a mouse model that replicates the route of administration and approximates the prolonged BTZ exposure experienced by patients. We find that male mice treated with BTZ experience more severe sensorimotor dysfunction and axon loss compared to females and observed similar results when analyzing human data. Using single cell RNA-sequencing, we reveal that BTZ significantly alters the dorsal root ganglia (DRG) microenvironment in mice, producing pronounced sex-specific changes in satellite glial cells (SGCs) in males and females and dysregulation of the extracellular matrix (ECM), particularly in males. These changes are accompanied by expansion of macrophages, which is more pronounced in males. We identify four macrophage subtypes in the DRG, including a pro-fibrotic population that is exclusively associated with BIPN. Depletion of macrophages via anti-CSF1R treatment in male mice prevents BTZ-induced SGC activation and aberrant collagen deposition in DRGs, potently preserves peripheral axons, and improves functional outcomes. These findings highlight SGCs, neuroinflammation and dysregulation of the ECM as drivers of sex-specific differences in BIPN and suggest that targeting neuroinflammation is a promising therapeutic strategy to treat this disease. One Sentence SummaryInflammation and neurofibrosis in DRGs underlie sex-specific differences in bortezomib-induced neuropathy and are promising treatment targets.

neuroscience↗

bioRxiv2020

Resource competition shapes biological rhythms and promotes temporal niche differentiation in a community simulation

Competition for resources often contributes strongly to defining an organisms ecological niche. Biological rhythms are important adaptations to the temporal dimension of niches, but the role of other organisms in determining such temporal niches have not been much studied, and the role specifically of competition even less so. We investigate how interspecific and intraspecific competition for resources shapes an organisms activity rhythms. For this, communities of one or two species in an environment with limited resource input were simulated. We demonstrate that when organisms are arrhythmic, one species will always be competitively excluded from the environment, but the existence of activity rhythms allows niche differentiation and indefinite coexistence of the two species. Two species which are initially active at the same phase will differentiate their phase angle of entrainment over time to avoid each other. When only one species is present in an environment, competition within individuals of the species strongly selects for niche expansion through arrhythmicity, but the addition of an interspecific competitor facilitates evolution of increased rhythmic amplitude when combined with additional adaptations for temporal specialization. Finally, if individuals preferentially mate with others who are active at similar times of day, then disruptive selection by intraspecific competition can split one population into two reproductively isolated groups. In summary, these simulations suggest that biological rhythms are an effective method to temporally differentiate ecological niches, and that competition is an important ecological pressure promoting the evolution of rhythms and sleep. Author summaryWhy do we sleep? We are interested in the ecological factors which promote the evolution of biological rhythms like the sleep-wake cycle, focusing especially on competition. When animals compete with each other for resources, they often evolve to avoid each other by specializing to use different resources or separating their activity in other ways. To test hypotheses about how competition shapes rest-activity rhythms, we performed computer simulations of a community of animals who move, reproduce, and compete for resources. We show that biological rhythms let two species divide time so that one species is active while its competitor is resting, thus avoiding depleting shared resources. When a species has no competitors in the simulation, competition between members of the same species cause population and individual rhythms to decrease, since resource availability is low when everybody is active at the same time. However, having competitors allows strong rhythms to evolve from originally arrhythmic organisms. Competition can even cause a single population to split into two species which are separated in time. In summary, these results suggest that competition is a strong factor promoting rest-activity rhythms.

ecology↗