Biology subjects

See, D. L.

Publications and source records attributed to See, D. L..

2 recordsLinked to original sources

bioRxiv2024

Oxytocin receptor function regulates neural signatures of pair bonding and fidelity in the nucleus accumbens

The formation of enduring relationships dramatically influences future behavior, promoting affiliation between familiar individuals. How such attachments are encoded to elicit and reinforce specific social behaviors in distinct ethological contexts remains unknown. Signaling via the oxytocin receptor (Oxtr) in the nucleus accumbens (NAc) facilitates social reward as well as pair bond formation between mates in socially monogamous prairie voles1-9. How Oxtr function influences activity in the NAc during pair bonding to promote affiliative behavior with partners and rejection of other potential mates has not been determined. Using longitudinal in vivo fiber photometry in wild-type prairie voles and those lacking Oxtr, we demonstrate that Oxtr function sex-specifically regulates pair bonding behaviors and associated activity in the NAc. Oxtr function influences prosocial behavior in females in a state-dependent manner. Females lacking Oxtr demonstrate reduced prosocial behaviors and lower activity in the NAc during initial chemosensory investigation of novel males. Upon pair bonding, affiliative behavior with partners and neural activity in the NAc during these interactions increase, but these changes do not require Oxtr function. Conversely, males lacking Oxtr display increased prosocial investigation of novel females. Using the altered patterns of behavior and activity in the NAc of males lacking Oxtr during their first interactions with a female, we can predict their future preference for a partner or stranger days later. These results demonstrate that Oxtr function sex-specifically influences the early development of pair bonds by modulating prosociality and the neural processing of sensory cues and social interactions with novel individuals, unmasking underlying sex differences in the neural pathways regulating the formation of long-term relationships.

neuroscience↗

bioRxiv2024

Atomically accurate de novo design of single-domain antibodies

Despite the central role that antibodies play in modern medicine, there is currently no method to design novel antibodies that bind a specific epitope entirely in silico. Instead, antibody discovery currently relies on animal immunization or random library screening approaches. Here, we demonstrate that combining computational protein design using a fine-tuned RFdiffusion network alongside yeast display screening enables the generation of antibody variable heavy chains (VHHs) and single chain variable fragments (scFvs) that bind user-specified epitopes with atomic-level precision. To verify this, we experimentally characterized VHH binders to four disease-relevant epitopes using multiple orthogonal biophysical methods, including cryo-EM, which confirmed the proper Ig fold and binding pose of designed VHHs targeting influenza hemagglutinin and Clostridium difficile toxin B (TcdB). For the influenza-targeting VHH, high-resolution structural data further confirmed the accuracy of CDR loop conformations. While initial computational designs exhibit modest affinity, affinity maturation using OrthoRep enables production of single-digit nanomolar binders that maintain the intended epitope selectivity. We further demonstrate the de novo design of single-chain variable fragments (scFvs), creating binders to TcdB and a Phox2b peptide-MHC complex by combining designed heavy and light chain CDRs. Cryo-EM structural data confirmed the proper Ig fold and binding pose for two distinct TcdB scFvs, with high-resolution data for one design additionally verifying the atomically accurate conformations of all six CDR loops. Our approach establishes a framework for the rational computational design, screening, isolation, and characterization of fully de novo antibodies with atomic-level precision in both structure and epitope targeting.

bioengineering↗