Biology subjects

Tollkuhn, J.

Publications and source records attributed to Tollkuhn, J..

6 recordsLinked to original sources

bioRxiv2026

Single-library chromosome-scale diploid assemblies of vole genomes resolve a species-specific duplication implicated in pair bonding

Comparing prairie voles (Microtus ochrogaster), a species that forms lasting pair bonds and exhibits biparental care, with meadow voles (Microtus pennsylvanicus), a non-monogamous species showing maternal care only, provides a framework to examine the genomic basis of behavioral divergence over short evolutionary time. Here, we develop a simplified assembly approach combining PacBio HiFi and CiFi sequencing in a single library and run, producing high-quality contiguous chromosome-scale diploid prairie and meadow vole genomes (2.3 Gbp). Comparative analysis reveals substantial differences, including near-complete Y chromosome divergence and a prairie-vole-specific duplication of Avpr1a, a vasopressin receptor gene implicated in social bonding and autism in humans. These extensive genomic changes suggest rapid chromosome evolution as a driver of the dramatic Microtus radiation, generating [~]60 vole species in >2 million years. This single-library approach facilitates a simplified and more affordable assembly workflow, producing near-complete genomes of diverse species using one sequencing platform.

genomics↗

bioRxiv2023

Comparative analysis of gonadal hormone receptor expression in the house mouse, meadow vole, and prairie vole brain

The socially monogamous prairie vole (Microtus ochrogaster) and promiscuous meadow vole (Microtus pennsylvanicus) are closely related, but only prairie voles display long-lasting pair bonds, biparental care, and selective aggression towards unfamiliar individuals after pair bonding. These social behaviors in mammals are largely mediated by steroid hormone signaling in the social behavior network (SBN) of the brain. Hormone receptors are reproducible markers of sex differences that can provide more information than anatomy alone, and can even be at odds with anatomical dimorphisms. We reasoned that behaviors associated with social monogamy in prairie voles may emerge in part from unique expression patterns of steroid hormone receptors in this species, and that these expression patterns would be more similar across males and females in prairie than in meadow voles or the laboratory mouse. To obtain insight into steroid hormone signaling in the developing prairie vole brain, we assessed expression of estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), and androgen receptor (Ar) within the SBN, using in situ hybridization at postnatal day 14 in mice, meadow, and prairie voles. We found species-specific patterns of hormone receptor expression in the hippocampus and ventromedial hypothalamus, as well as species differences in the sex bias of these markers in the principal nucleus of the bed nucleus of the stria terminalis. These findings suggest the observed differences in gonadal hormone receptor expression may underlie species differences in the display of social behaviors.

neuroscience↗

bioRxiv2023

Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia1-15. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia16-20. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-61-5,15,18,21-23, leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing of Gfral-expressing AP neurons also ameliorates the cancer-associated cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer-associated cachexia.

neuroscience↗

bioRxiv2020

Regulation of neural gene expression by estrogen receptor alpha

The transcription factor estrogen receptor (ER) is a principal regulator of sex differences in the vertebrate brain and can modulate mood, behavior, and energy balance in females and males. However, the genes regulated by ER in the brain remain largely unknown. Here we reveal the genomic binding of ER within a sexually dimorphic neural circuit that regulates social behaviors. We profiled gene expression and chromatin accessibility and show ER induces a neurodevelopmental gene program in adulthood. We further demonstrate that ER binds with Nuclear factor I X-type (Nfix) to regulate a male-biased gene expression program that initiates in early life. Our results reveal a neural strategy for ER-mediated gene regulation and provide molecular targets that underlie estrogens effects on brain development, behavior, and disease.

neuroscience↗

bioRxiv2019

Estrogen Drives Melanocortin Neurons To Reduce Sedentary Behavior

Estrogen depletion in rodents and humans leads to inactivity, unhealthy fat accumulation, and diabetes1,2, underscoring the conserved metabolic benefits of estrogen that inevitably decline with aging. In rodents, the preovulatory surge in 17{beta}-estradiol (E2) temporarily allows energy expenditure to outpace energy intake, thus coordinating increased physical activity with peak sexual receptivity. To investigate how estrogen rebalances energy allocation in females, we examine estrogen receptor alpha (ER) signaling in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)3-7. We uncover a small population of VMHvlER neurons expressing the melanocortin-4 receptor (MC4R) that integrates estrogen and melanocortin signals and projects to arousal centers in the hippocampus and hindbrain, enabling bursts of physical activity. ER recruitment to the Mc4r gene promotes upregulation of Mc4r in VMHvl neurons during the preovulatory surge or following E2 treatment. We leveraged three models to stimulate VMHvlMC4R neurons, restore MC4R signaling in the VMHvl of hyperphagic MC4R null females, or increase Mc4r levels in the VMHvl by CRISPR-mediated activation. All models increase spontaneous activity, whereas silencing VMHvlMC4R neurons blunts normal activity. Direct activation of the VMHvlMC4R node overrides the inactivity and hypometabolism following hormone depletion. These data extend the impact of MC4R signaling - the most common cause of monogenic human obesity8 - beyond the regulation of food intake. Our findings also rationalize reported sex differences in melanocortin signaling, including the greater disease severity of MC4R insufficiency in women9. The hormone-dependent node identified here illuminates the power of estrogen in motivating behavior during the female reproductive cycle and for maintaining an active lifestyle.

neuroscience↗

bioRxiv2017

Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize the brain

Masculinization of the rodent brain is driven by estrogen signaling during a perinatal critical period. Genetic deletion of estrogen receptor alpha (Esr1/ER) results in altered hypothalamic-pituitary-gonadal (HPG) axis signaling and a dramatic reduction of male sexual and territorial behaviors. However, the requirement of ER function in masculinizing distinct classes of neurons, and if these populations mediate components of male-typical behavior, remains unexplored. We deleted ER in excitatory or inhibitory neurons using either a Vglut2 or Vgat driver and assessed male behaviors. We find that Vglut2-Cre;Esr1lox/lox mutant males lack ERa in the ventrolateral region of the ventromedial hypothalamus (VMHvl) and posterior ventral portion of the medial amygdala (MePV). These mutants recapitulate the increased serum testosterone levels seen with constitutive ER deletion, but have none of the behavioral deficits. In contrast, Vgat-Cre;Esr1lox/lox males with substantial ER deletion in inhibitory neurons, including those of the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr), posterior dorsal MeA (MePD), and medial preoptic area (MPOA) have normal testosterone levels, but display alterations in mating and territorial behaviors. These mutants also show demasculinized expression of androgen receptor (AR) and estrogen receptor beta (Esr2). Our results demonstrate that ER masculinizes GABAergic neurons that gate the display of male-typical behaviors.

neuroscience↗