Biology subjects

Steinwand, S.

Publications and source records attributed to Steinwand, S..

4 recordsLinked to original sources

bioRxiv2024

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice

Our study elucidates functional roles for conserved cis-elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity (Fto) locus. Some hibernation-linked cis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis-elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis-element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control. One-sentence summaryDeletions of conserved cis-elements tied to hibernator evolution causes diverse metabolic traits in mice.

genomics↗

bioRxiv2024

Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus

Elucidating the genetic basis of mammalian metabolism could help define mechanisms central to health and disease. Here, we define conserved cis-regulatory elements (CREs) and programs for mammalian metabolic control. We delineate gene expression and chromatin responses in the mouse hypothalamus for 7 steps of the Fed-to-Fasted-to-Refed (FFR) response process. Comparative genomics of hibernating versus non-hibernating lineages then illuminates cis-elements showing convergent changes in hibernators. Hibernators accumulated loss-of-function effects for specific CREs regulating hypothalamic FFR responses. Multi-omics approaches pinpoint key CREs, genes, regulatory programs, and cell types in the divergence of hibernating and homeothermic lineages. The refeeding period after extended fasting is revealed as one critical period of chromatin remodeling with convergent genomic changes. This genetic framework is a step toward harnessing hibernator adaptations in medicine. One sentence summaryConvergent signals define cis-regulatory mechanisms behind food scarcity responses and hibernator-homeotherm divergence.

genomics↗

bioRxiv2022

Arc Regulates a "Second-Guessing" Cognitive Bias During Naturalistic Foraging

Foraging involves innate decision heuristics that are adapted for the wild but can cause economically suboptimal cognitive biases in some contexts. The mechanisms underlying cognitive biases are poorly understood but are likely genetic. Here, we investigate foraging in fasted mice using a naturalistic paradigm and uncover an innate "second-guessing" cognitive bias that involves repeatedly investigating an empty former food patch instead of consuming available food. Second-guessing prevents mice from maximizing feeding benefits in the task. Since learning and memory are involved, we tested roles for the synaptic plasticity gene, Arc, and found that Arc-/- mice show a specific lack of second-guessing. Arc-/- males reap benefits by increasing food consumption. Unsupervised machine learning decompositions of foraging show that Arc affects discrete, stereotyped foraging sequences that we call modules within a rich naturalistic behavioral landscape. Thus, our study reports a second- guessing cognitive bias, ethological roles for Arc in naturalistic foraging, and links between genetically determined foraging modules and cognitive bias in decision making.

neuroscience↗

bioRxiv2020

Dopa decarboxylase is a genetic hub of parental control over offspring behavior

Dopa decarboxylase (DDC) regulates the synthesis of monoaminergic neurotransmitters and is linked to psychiatric and metabolic disorders. Ddc exhibits complex genomic imprinting effects that have not been functionally studied. Here, we investigate different noncanonical imprinting effects at the cellular level with a focus on Ddc. Using allele-specific reporter mice, we found Ddc exhibits dominant expression of the maternal allele in subpopulations of cells in 14 of 52 brain regions, and dominant paternal or maternal allele expression in adrenal cell subpopulations. Maternal versus paternal Ddc allele null mutations differentially affect offspring social, foraging and exploratory behaviors. Machine learning analyses of naturalistic foraging in Ddc-/+ and +/- offspring uncovered finite behavioral sequences controlled by the maternal versus paternal Ddc alleles. Additionally, parental Ddc genotype is revealed to affect behavior independent of offspring genotype. Thus, Ddc is a hub of maternal and paternal influence on behavior that mediates diverse imprinting and parental effects. HIGHLIGHTSO_LIDopa decarboxylase (Ddc) allelic expression resolved at the cellular level C_LIO_LICells differentially express maternal versus paternal Ddc alleles C_LIO_LIMaternal and paternal Ddc alleles control distinct behavioral sequences C_LIO_LIParental Ddc genotype affects offspring independent of mutation transmission C_LI eTOCAllelic reporter mice and machine learning analyses reveal dopa decarboxylase is affected by diverse imprinting and parental effects that shape finite behavioral sequences in sons and daughters.

neuroscience↗