Biology subjects

Russell, G. A.

Publications and source records attributed to Russell, G. A..

4 recordsLinked to original sources

bioRxiv2026

Ventral tegmental area acetylcholine generates appetitive and aversive incentive motivation

Ventral tegmental area neurons participate in reward learning, motivation, and movement but also have an emerging role in the regulation of aversive behaviors. While these diverse contributions have been attributed to distinct projections of ventral tegmental area neurons, it remains unresolved how these neurons inherit their array of behavioral functions. The ventral tegmental area is rich with acetylcholine receptors and receives dense cholinergic input from the mesopontine tegmentum. While it is known that acetylcholine release in the ventral tegmental area can increase dopamine output we lack an understanding of the scenarios which necessitate ventral tegmental area acetylcholine release. We sought to provide a comprehensive overview of the participation of ventral tegmental area acetylcholine signaling across valence to motivated behavior. Rats were trained on a diverse array of tasks that allowed for the isolation of the contribution of acetylcholine release in the ventral tegmental area to cue- and context-driven behavior. We used intracranial pharmacology to determine the receptor mechanisms that contribute to acetylcholines effects. Ultimately, we found that acetylcholine release in the ventral tegmental area is necessary for appetitive and aversive states to become motivationally relevant and spur reward-seeking and threat-avoidance. We propose that this state-dependent contribution allows ventral tegmental area acetylcholine to act as a motivational gate for behavior across valence. This work expands our view of the interaction between neuromodulatory systems in the brain and opens new directions to the understanding of ventral tegmental area neurons in health and disease.

neuroscience↗

bioRxiv2026

Complementary constraints in germ and immune cells shape evolution of gene regulation and phenotype

New mutations arise in germ cells and must preserve fertility while altering somatic phenotype to confer a fitness advantage. To understand how whole organisms balance these constraints, we generated mice with humanized noncoding promoter sequence at Traf6, an NF-{kappa}B pathway component with recently diverged chromatin state in mouse germ cells. The humanized allele (Traf6h) reinstated human-like expression in germ and immune cells, which we traced to a 13 base pair deletion that impairs CTCF binding. Traf6h had no effect on fertility but induced a sensitized innate immune response to endotoxin. Other NF-{kappa}B pathway genes followed a similar pattern, suggesting that their expression has evolved in tandem and consistent with known mouse-human differences in inflammatory response. Our results reveal distinct roles for germ and immune cells in shaping gene regulatory evolution, where immune cells quickly adjust phenotype, enabling selection, while germ cells robustly maintain fertility despite changing expression levels, enabling inheritance.

genetics↗

bioRxiv2025

HKU5 bat merbecoviruses use divergent mechanisms to engage bat and mink ACE2 as entry receptors

Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness. While Middle East respiratory syndrome coronavirus (MERS-CoV) uses DPP4 for entry, the receptors of many MERS-related betacoronaviruses remain unknown. The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells. Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy (cryo-EM) analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2, revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use and underscore the need for continued surveillance of bat and mustelid species.

microbiology↗

bioRxiv2020

The gut microbiota limits Th2 immunity to Heligmosomoides polygyrus bakeri infection

Helminth-induced alterations to the gut microbiota have been shown to affect immune responses at local and peripheral sites. Studies examining helminth-microbiota interactions, however, have been limited due to the practical constraints of performing germ-free experiments with parasites that thrive in microbial-rich conditions to complete their development. The infectious (L3) larvae of the murine helminth Heligmosomoides polygyrus bakeri (Hpb), for example, are normally reared using a fecal-culture method and therefore are inherently unsuitable for germ-free studies in vivo. Herein, we detail an adapted methodology for rearing effectively germ-free Hpb larvae that are able to maintain the axenic status of a germ-free host during infection. We validate that these larvae do not display any fitness defects relative to fecal-grown larvae and evoke a comparable immune response in vivo. Characterization of axenic Hpb infection reveals that the commensal microbiota play a multifaceted role during infection - curbing the anti-Hpb Th2 response and directing the resolution of tissue granulomas, while simultaneously promoting parasite fitness. Overall these data demonstrate a mutualistic relationship between commensal microbes, enteric helminths and the infected host.

immunology↗