Biology subjects

Fisher, H. S.

Publications and source records attributed to Fisher, H. S..

9 recordsLinked to original sources

bioRxiv2026

Data-driven prioritization of mouse strains for improved preclinical modeling of rare and common disease

Choosing an appropriate mouse genetic background is a persistent challenge for successful translation of preclinical disease modeling. We present Strain Recommender, a genomic framework that prioritizes inbred mouse strains as relatively vulnerable or resilient to a disease state using disease-associated gene signatures and strain-specific transcriptome predictions. The method represents disease states as weighted gene scores, ranks 657 strains based on resemblance to the disease state, and estimates uncertainty via a permutation-derived false positive rate (FPR). In a prospective validation of connective tissue disorder predictions, vulnerable and resilient Collaborative Cross strains showed significantly different cardiovascular abnormalities. In a global retrospective validation predicting previously reported strain background effects, Strain Recommender achieved [≥] 90% sensitivity for 86.6% of diseases with 94.4% mean sensitivity (95% CI: 94.0-94.8%) across 5,890 diseases, including 92.3% (95% CI: 91.6-93.0%) for 2,598 rare diseases, demonstrating its potential to improve the validity of mouse models of human disease.

bioinformatics↗

bioRxiv2025

A shared genetic regulator of metabolism and addiction-related behavior in mice and humans

Substance use disorders and other mental health conditions often co-occur with metabolic disorders, suggesting shared biological underpinnings1. These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments2. The genetic mechanisms linking these traits have remained elusive. Here, we show that a variable gene enhancer in mice jointly regulates genes encoding an epigenetic factor (Eed) and a mitochondrial enzyme (Me3) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating EED and ME3 associated with substance use, psychiatric and metabolic disorders. These findings reveal a convergent genetic regulatory network linking mitochondrial biology to behavioral and metabolic risk, offering insight into how genetic variation in beneficial regulatory pathways can predispose individuals to substance use disorders and related conditions.

genetics↗

bioRxiv2025

Behavioral variation across multiple phases of intravenous cocaine self-administration among genetically diverse mouse populations

Genetic and other predisposing factors can influence the progression from initiation of drug intake to compulsive substance use through distinct biobehavioral processes. Operant cocaine self-administration studies in laboratory mice offer a powerful method to dissect the biology of this progression from initiation, dose-response, extinction, and cued reinstatement in a controlled, tractable system. However, many such studies encompass limited genetic diversity and rarely examine self-administration behaviors beyond the acquisition stage. Here, we study three high-diversity mouse populations - 50 strains from the Collaborative Cross (CC) reference panel, a large sample of Diversity Outbred (J:DO) population and their eight founder strains - to characterize the varied phenotypic manifestation of behaviors across multiple phases of cocaine intravenous self-administration (IVSA) in both sexes. We observed distinct strain differences among the founders and CC strains in all phases of self-administration, with heritability estimates ranging from 0 to 0.585 and many CC and J:DO phenotypic values exceeding the range of founders including the C57BL/6J strain. Sex differences were common across behaviors, some manifesting as main effects, others as strain interactions. Finally, by adopting a multi-stage design, we identified extreme strains for various cocaine intake and response traits and evaluated whether these strains exhibited differences in behavioral assays that model compulsive drug seeking. Together, these findings demonstrate the utility of extended self-administration protocols in advanced mouse populations for discovery and characterization of biological mechanisms of substance use traits and for preclinical studies in relevant, complex mouse models.

genetics↗

bioRxiv2024

Reproductive experience drives changes in behavior and physiology in male California mice (Peromyscus californicus)

Paternal experience improves memory and reduces anxiety-like behavior in males, but it is unclear whether these changes are due to mating, siring offspring, or caregiving behavior. Likewise, paternal males have larger testes, a measure of sperm production, but again, the effects of siring and caregiving experience are difficult to disentangle. We examined behavioral and physiological outcomes in three groups of male mice: 1) virgins, 2) males paired with sterile females ( non-fathers), and 3) experienced fathers (Experiment 1). Compared to virgins and non-fathers, experienced fathers exhibited increased recognition memory (novel object recognition) and decreased anxiety-like behavior (elevated plus maze). Virgin males, however, had smaller testes and fewer sperm compared to non-fathers. We then compared the same traits in three additional groups of male mice: 1) non-fathers, 2) non-fathers with experience caring for unrelated pups ( pup-sensitized non-fathers), and 3) first-time fathers, to determine whether the behavioral and physiological observations in Experiment 1 were due to siring offspring or caregiving, and how rapidly these changes occur (Experiment 2). Recognition memory and anxiety-like behavior did not differ among these three groups, suggesting that caring for a single litter does not recapitulate the behavioral changes observed in experienced fathers (Experiment 1). Despite equal mating opportunity, we observed larger testes in first-time fathers compared to non-fathers, suggesting that investment in sperm production may be more plastic than behavioral changes. Finally, we compared pup interactions in pup-sensitized non-fathers and first-time fathers. While pup-sensitized non-fathers were slower to approach pups than first-time fathers, they spent more time grooming pups, whereas first-time fathers invested more time in nest building, suggesting different caregiving behaviors in pup-sensitized males and biological fathers. Taken together, our study revealed that mating, siring, and caregiving experience contributes to changes in memory, anxiety-like behavior, and reproductive investment in males of a biparental species.

animal behavior and cognition↗

bioRxiv2023

Centriole Remodeling Evolved into Centriole Degradation in Mouse Sperm

Centrioles are subcellular organelles found at the cilia base with an evolutionarily conserved structure and a shock absorber-like function. In sperm, centrioles are found at the flagellum base and are essential for embryo development in basal animals. Yet, sperm centrioles have evolved diverse forms, sometimes acting like a transmission system, as in cattle, and sometimes becoming dispensable, as in house mice. How the essential sperm centriole evolved to become dispensable in some organisms is unclear. Here, we test the hypothesis that this transition occurred through a cascade of evolutionary changes to the proteins, structure, and function of sperm centrioles and was possibly driven by sperm competition. We found that the final steps in this cascade are associated with a change in the primary structure of the centriolar luminal protein FAM161A in rodents. This information provides the first insight into the molecular mechanisms and adaptive evolution underlying a major evolutionary transition within the internal structure of the mammalian sperm neck. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/532086v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@bdbe1eorg.highwire.dtl.DTLVardef@10cc2b9org.highwire.dtl.DTLVardef@c42734org.highwire.dtl.DTLVardef@1e9c750_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- Barrel-shaped centrioles are present in all rodents except members of the Muridae taxonomical family. - The FAM161A sequence evolved selectively in rodents and specifically in a murid subgroup. - The evolution of centriole degradation is correlated with the expression of a novel FAM161A isoform. - The ancestral centriole remodeling program involves elongation followed by redistribution. - The mouse centriole degradation program involves elongation followed by elimination.

cell biology↗

bioRxiv2020

The social shape of sperm: Using an integrative machine-learning approach to examine sperm ultrastructure and collective motility

Sperm are one of the most morphologically diverse cell types in nature, yet they also exhibit remarkable behavioral variation, including the formation of collective groups of cells that swim together for motility or transport through the female reproductive tract. Here we take advantage of the natural variation in sperm traits observed across Peromyscus mice to test the hypothesis that the morphology of the rodent sperm head influences their sperm aggregation behavior. Using machine learning and traditional morphometric approaches to quantify and analyze their complex shapes, we show that the elongation of the sperm head is the most distinguishing morphological trait in these rodents and, as predicted, significantly associates with collective sperm movements obtained from in vitro observations. We then successfully use neural network analysis to predict the size and proportion of sperm aggregates from sperm head morphology and show that species whose sperm feature relatively wider heads aggregate more often and form larger groups, providing support for the theoretical prediction that an adhesive region around the equatorial region of the sperm head mediates these unique gametic interactions. Together these findings advance our understanding of how even subtle variation in sperm design can drive differences in sperm function and performance. Subject AreasEvolution, Cellular Biology, Behavior

evolutionary biology↗

bioRxiv2020

Collective sperm movements are shaped by post-copulatory sexual selection and phylogenetic history in Peromyscus mice

In some species, sperm form coordinated groups that are hypothesized to improve their swimming performance in competitive contexts or to navigate through the viscous fluids of the female reproductive tract. Here we investigate sperm aggregation across closely-related species of Peromyscus mice that naturally vary by mating system to test the predictions that sperm aggregates (1) are faster than solitary sperm in species that females mate multiply to aid cells in sperm competition, and (2) outperform solitary sperm cells in viscous environments. We find significant variation in the size of sperm aggregates, which negatively associates with relative testis mass, a proxy for sperm competition risk, suggesting that post-copulatory sexual selection has a stabilizing effect on sperm group size. Moreover, our results show that sperm aggregates are faster than solitary sperm in some, but not all, species, and this can vary by fluid viscosity. Of the two species that produce the largest and most frequent groups, we find that sperm aggregates from the promiscuous P. maniculatus are faster than solitary sperm in every experimentally viscous environment but aggregation provides no such kinematic advantage under these same conditions for the monogamous P. polionotus. The reduced performance of P. polionotus aggregates is associated with less efficient aggregate geometry and the inclusion of immotile or morphological abnormal sperm. Our cross-species comparison yields insight into the evolution of sperm social behaviors, provides evidence of extensive variation in the Peromyscus lineage, and reveals that differences in sperm aggregate quality associate with post-copulatory sexual selection.

evolutionary biology↗

bioRxiv2018

Sibling rivalry: Males with more brothers develop larger testes

When females mate with multiple partners in a reproductive cycle, the relative number of competing sperm from rival males is often the most critical factor in determining paternity. Gamete production is directly related to testis size in most species, and is associated with both mating behavior within a system and perceived risk of competition. Peromyscus maniculatus is naturally promiscuous and males invest significantly more in sperm production than males of P. polionotus, their monogamous sister-species. Here we show that the relatively larger testes in P. maniculatus are retained, even after decades of enforced monogamy in captivity. While these results suggest that differences in sperm production between species with divergent evolutionary histories can be maintained, we also show that the early rearing environment of males can strongly influence their testis size as adults. Using a second-generation hybrid population to increase variation in testis size, we show that males reared in litters with more brothers develop larger testes as adults. Importantly, this difference in testis size is also associated with increased fertility. Together, our findings suggest that sperm production may be both broadly shaped by natural selection over evolutionary timescales and also finely tuned during early development.

evolutionary biology↗

bioRxiv2018

Cellular geometry controls the efficiency of motile sperm aggregates

Teams of cooperating sperm have been found across several vertebrate and invertebrate species, ranging from sperm pairs to massive aggregates containing hundreds of cells. Although the biochemical mechanisms involved in sperm-sperm adhesion are unclear, aggregation can enhance the motility of the cells. Here, we report a thorough computational investigation on the role of cellular geometry in the performance of sperm aggregates. The sperm head is modeled as a persistent random walker characterized by a non-trivial three-dimensional shape and equipped with an adhesive region where cell-cell binding occurs. By considering both a simple parametric head shape and a computer reconstruction of a real head shape based on morphometric data, we demonstrate that the geometry of the head and the structure of the adhesive region crucially affect both the stability and motility of the aggregates. Our analysis further suggests that the apical hook, commonly found in the sperm of most muroid rodents, might serve to shield portions of the adhesive region and promote efficient alignment of the velocities of the interacting cells.

evolutionary biology↗