Biology subjects

Donaldson, Z. R.

Publications and source records attributed to Donaldson, Z. R..

12 recordsLinked to original sources

bioRxiv2026

Hypothalamic tauP301L pathology disrupts pair bonding in monogamous prairie voles

Although dementias primarily affect memory, they also disrupt our closest social relationships, resulting in elevated caregiver burden and worse patient outcomes. However, the mechanistic study of how pathology affects social attachments is limited by the use of laboratory rodents that do not form selective, long-term bonds. Here, in monogamous prairie voles, we expressed dementia-causing tauP301L in the paraventricular hypothalamus of 12- and 18-month-old animals, and separately, from birth through 18-months, across hippocampocortical regions. Hippocampocortical expression of tauP301L did not yield deficits in social or non-social dementia-related phenotypes. In contrast, tauP301L expressed in the hypothalamus yielded sex- and age-dependent social bonding deficits. 18-month males with hypothalamic tau pathology failed to form bonds and displayed blunted sociability, effects that converged across bonding assays. In addition, healthy 18-month males paired with a hypothalamic tau-expressing female also showed reduced partner preference, suggesting that pathology exerts vicarious effects on partners. Social behavior of both healthy females and those expressing tauP301L were unaffected. 18-month tauP301L males also showed elevated oxytocin fluorescence. These findings establish direct and vicarious disruptions to pair bonding induced by hypothalamic tau pathology in male prairie voles, potentially via altered oxytocin signaling.

neuroscience↗

bioRxiv2026

Social attachment shapes interbrain synchrony

Neural synchrony, or correlated neural activity across interacting individuals, scales with relationship quality in humans, yet how it evolves during social bond formation remains unknown. Using fiber photometry in monogamous prairie voles, we track prefrontal cortex synchrony across pair bond formation. Bonded voles show stronger synchrony with partners than strangers, mirroring human findings. A linear mixed model reveals that synchrony is jointly shaped by bond strength, inter-animal distance, and time since interaction onset, with relationship type modulating how each factor contributes. Using a machine-learning behavioral classification pipeline we developed for freely interacting voles, we demonstrate that the coupling between specific behaviors and synchrony depends on the nature of the dyadic relationship. These findings establish that neural synchrony is not a simple function of proximity or interaction time but is fundamentally shaped by relationship history--a conclusion with direct implications for understanding the synchrony in human social attachment.

neuroscience↗

bioRxiv2026

Synaptotagmin isoforms differentially regulate glutamate and GABA release in the lateral habenula

Neurotransmitter co-transmission contributes to diverse physiological processes throughout the mammalian brain, including sensory integration, motivational control, and social behaviors. Projections from the globus pallidus internus (GPi; the entopeduncular nucleus, EPN, in rodents) to the lateral habenula (LHb) are well-characterized by the co-transmission of both GABA and glutamate. These dual-release inputs modulate behavioral states in chronically learned helpless (cLH) rats, influencing both the onset and recovery of pathological phenotypes. Here, we employed confocal 3D reconstructions that confirmed the presence of both vesicular transporters VGAT and VGLUT2 in EPN axon terminals within the LHb. Further investigation revealed that GABA and glutamate are packaged in distinct vesicle populations within individual presynaptic terminals. Notably, the calcium (Ca{superscript 2}) sensors Synaptotagmin-2 (Syt2) and Synaptotagmin-3 (Syt3) are highly expressed in the EPN whereas expression of the canonical Ca{superscript 2} sensor, Synaptotagmin 1 (Syt1), is downregulated. Additionally, using confocal microscopy, we observed selective spatial correlations of Syt2 and VGLUT2 and between Syt3 and VGAT in LHb axon terminals. These observations strongly suggested that Syt2 serves as the predominant Ca{superscript 2} sensor for glutamatergic vesicle fusion, and Syt3 serves as the predominant Ca{superscript 2} sensor for GABAergic vesicle fusion in the LHb. To test this hypothesis, we employed targeted antisense oligonucleotide (ASO) knockdown of Syt2 and Syt3 in EPN neurons and measured LHb glutamatergic and GABAergic currents. Syt2 knockdown resulted in an increase in mEPSC frequency, amplitude, half-width and decay, suggesting increased glutamate vesicle release probability and increased glutamate vesicle packing. However, Syt2 knockdown had no influence on mIPSCs amplitude or frequency. On the other hand, Syt3 knockdown had no apparent effect on glutamate release but caused an increase in mIPSC frequency suggesting increased quantal release probability of GABA. Together, these findings identify a molecular mechanism by which synaptotagmin isoforms govern differential glutamate and GABA release at EPN dual-transmitter terminals in the LHb. These results provide evidence for presynaptic mechanisms regulating excitatory-inhibitory balance within this brain structure and importantly provide molecular targets for pharmacological intervention.

neuroscience↗

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↗

bioRxiv2025

Lentiviral CRISPRa/i in the adult Prairie Vole Brain: Modulating Neuronal Gene Expression Without DNA Cleavage

Prairie voles (Microtus ochrogaster) are a powerful model for studying the neurobiology of social bonding, yet tools for region- and cell type-specific gene regulation remain underdeveloped in this species. Here, we present a lentivirus-mediated CRISPR activation and interference (CRISPRa/i) platform for somatic gene modulation in the prairie vole brain. This system enables non-mutagenic, titratable regulation of gene expression in the adult brain without germline modification. Our dual-vector system includes one construct expressing dCas9-VPR (CRISPRa) or dCas9-KRAB-MeCP2 (CRISPRi) under a neuron-specific promoter, and a second construct delivering a U6-driven sgRNA alongside an EF1-driven mCherry reporter. We detail the design, production, and stereotaxic delivery of these tools and demonstrate their application by targeting four genes implicated in social behavior (Oxtr, Avpr1a, Drd1, Drd2) across two mesolimbic brain regions: the nucleus accumbens and ventral pallidum. Gene expression analyses confirmed robust, bidirectional transcriptional modulation for select targets, establishing proof of concept for CRISPRa/i in this non-traditional model. The dual-vector design is readily adaptable to other gene targets, cell types, and brain regions, and can be multiplexed to provide a flexible and scalable framework for investigating gene function in behaviorally relevant circuits. These advances represent the first successful implementation of somatic CRISPRa/i in prairie voles and expand the genetic toolkit available for this species.

molecular biology↗

bioRxiv2025

Oxytocin and Dopamine Receptor Expression: Cellular Level Implications for Pair Bonding

Oxytocin (Oxtr) and dopamine (Drd1, Drd2) receptors provide a canonical example for how differences in neuromodulatory receptors drive individual and species-level behavioral variation. These systems exhibit striking and functionally-relevant differences in nucleus accumbens (NAc) expression across monogamous prairie voles (Microtus ochrogaster) and promiscuous meadow voles (Microtus pennsylvanicus). However, their cellular organization remains largely unknown. Using multiplex in situ hybridization, we mapped Oxtr, Drd1, and Drd2 expression in sexually naive and mate-paired prairie and meadow voles. Prairie voles have more Oxtr+ cells than meadow voles, but Oxtr distribution across dopamine-receptor cell class was similar, indicating a general upregulation rather than cell class bias. Oxtr was enriched in cells that express both dopamine receptors (Drd1+/Drd2+) in prairie voles, suggesting these cells may be particularly sensitive to oxytocin. We found no species or pairing-induced differences in Drd1+ or Drd2+ cell counts, suggesting prior reports of expression differences may reflect upregulation in cells already expressing these receptors. Finally, we used single-nucleus sequencing to provide the first comprehensive map of Oxtr and Drd1-5 across molecularly-defined NAc cell types in the prairie vole. These results provide a critical framework for understanding how nonapeptide and catecholamine systems may recruit distinct NAc cell types to shape social behavior.

neuroscience↗

bioRxiv2024

Exposure to novel females increases fecundity in adult male prairie voles

Social circuitry of the mammalian brain can influence male reproductive physiology. This often manifests as plasticity in sperm production or allocation, particularly in response to male-male competition. However, socially mediated testicular plasticity has not been investigated with respect to mating and parental strategy. Testis mass and sperm production of sexually naive and female-exposed adult male individuals of three rodent species were compared: the socially monogamous and paternal prairie vole (Microtus ochrogaster), the promiscuous and non-paternal meadow vole (Microtus pennsylvanicus), and the promiscuous and non-paternal house mouse (Mus musculus). Monogamously paired prairie vole males exhibited significantly larger testes and greater sperm production than naive prairie vole males. Comparatively, there were no significant differences between naive and monogamously paired male meadow voles or mice. To investigate the role of olfactory cues for regulating this phenomenon in prairie voles, a group of naive males exposed to soiled bedding from novel females was used. These males were more similar to paired males than to naive males not exposed to novel female odors, demonstrating a strong role of the social olfactory system. Further, while the predictions of sperm competition theory (species with greater female promiscuity have larger testes than closely related species with less female promiscuity) are consistent between naive meadow voles and prairie voles, the prediction does not hold for monogamously paired prairie voles and meadow voles. This demonstrates the complexity of internal social dynamics and reproductive pressures which socially monogamous paternal males face and the evolutionary adaptions that may develop in response.

physiology↗

bioRxiv2024

Single nucleus RNA-sequencing reveals transcriptional synchrony across different relationships

As relationships mature, partners share common goals, improve their ability to work together, and experience coordinated emotions. However, the neural underpinnings responsible for this unique, pair-specific experience remain largely unexplored. Here, we used single nucleus RNA-sequencing to examine the transcriptional landscape of the nucleus accumbens (NAc) in socially monogamous prairie voles in peer or mating-based relationships. We show that, regardless of pairing type, prairie voles exhibit transcriptional synchrony with a partner. Further, we identify genes expressed in oligodendrocyte progenitor cells that are synchronized between partners, correlated with dyadic behavior, and sensitive to partner separation. Together, our data indicate that the pair-specific social environment profoundly shapes transcription in the NAc. This provides a potential biological mechanism by which shared social experience reinforces and strengthens relationships.

neuroscience↗

bioRxiv2021

Emergent intra-pair sex differences and behavioral coordination in pair bonded prairie voles

In pair bonding animals, coordinated behavior between partners is required for the pair to accomplish shared goals such as raising young. Despite this, experimental designs rarely assess the behavior of both partners within a bonded pair. Thus, we lack an understanding of the interdependent behavioral dynamics between partners that likely facilitate relationship success. To identify intra-pair behavioral correlates of pair bonding, we used socially monogamous prairie voles, a species in which females and males exhibit both overlapping and distinct pair bond behaviors. We tested both partners using social choice and non-choice tests at short- and long-term pairing timepoints. Females developed a preference for their partner more rapidly than males, with preference driven by different behaviors in each sex. Further, as bonds matured, intra-pair behavioral sex differences and coordinated behavior emerged - females consistently huddled more with their partner than males did, and partner huddle time became correlated between partners. When animals were allowed to freely interact with a partner or a novel in sequential free interaction tests, pairs spent more time interacting together than either animal did with a novel. Pair interaction was correlated with female, but not male, behavior. Via a social operant paradigm, we found that pair-bonded females, but not males, are more motivated to access and huddle with their partner than a novel vole. Together, our data indicate that as pair bonds mature, sex differences and coordinated behavior emerge, and that these intra-pair behavioral changes are likely organized and driven by the female animal.

animal behavior and cognition↗

bioRxiv2021

Prolonged partner separation erodes nucleus accumbens transcriptional signatures of pair bonding in male prairie voles

The loss of a spouse is often cited as the most traumatic event in a persons life. However, for most people, the severity of grief and its maladaptive effects subside over time via an understudied adaptive process. Like humans, socially monogamous prairie voles (Microtus ochrogaster) form opposite-sex pair bonds, and upon partner separation, show stress phenotypes that diminish over time. We test the hypothesis that extended partner separation diminishes pair bond-associated behaviors and causes pair bond transcriptional signatures to erode. Pairs were cohoused for 2 weeks and then either remained paired or were separated for 48hrs or 4wks before collecting fresh nucleus accumbens tissue for RNAseq. In a separate cohort, we assessed partner preference and selective aggression at these time points, finding that these behaviors persist despite prolonged separation in both same-sex and opposite-sex paired voles. Opposite-sex pair bonding led to changes in accumbal transcription that were stably maintained while animals remained paired but eroded following prolonged partner separation. Eroded genes are associated with gliogenesis and myelination, suggesting a previously undescribed role for glia in pair bonding and loss. Further, we pioneered neuron-specific translating ribosomal affinity purification in voles. Neuronally-enriched transcriptional changes revealed dopaminergic-, mitochondrial-, and steroid hormone signaling-associated gene clusters sensitive to acute pair bond disruption and loss adaptation. Our results suggest that partner separation erodes transcriptomic signatures of pair bonding despite core behavioral features of the bond remaining intact, revealing potential molecular processes priming a vole to be able to form a new bond.

neuroscience↗

bioRxiv2020

How prior pair-bonding experience affects future bonding behavior in monogamous prairie voles

Monogamous prairie voles (Microtus ochrogaster) form mating-based pair bonds. Although wild prairie voles rarely re-pair following loss of a partner, laboratory studies have shown that previous pairing and mating does not negate the ability to form a new partner preference. However, little is known about how prior bond experience may alter the trajectory and display of a new pair bond. In the present study, we disrupted an initial pair bond by separating partners and then varied the amount of time before a new partner was introduced. We assessed how separation time affected the stability of partner preference over time and influenced decision-making in male voles performing a head-to-head partner preference test in which they chose between the first and second partner. We found that the ability to consistently display a preference for the second partner, supplanting the initial pair bond, depended on how long the test animal was separated from their first partner. Prior bonding experience also shaped the subsequent effects of mating on partner preference. Partner preference strength was sensitive to latency to mate with the second partner but not the first partner, irrespective of separation time. These results suggest that the ability to form a consistent, strong preference for a new partner after an initial pair bond depends upon the amount of time that has passed since separation from the first partner. These results provide valuable insight into how social bonds are dynamically shaped by prior social experience and identify variables that contribute to recovery from partner loss and the ability to form a new pair bond.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

bioRxiv2019

Optogenetic reactivation of prefrontal social memory trace mimics social buffering of fear

Social buffering occurs when the presence of a companion attenuates the physiological and/or behavioral effects of a stressful or fear-provoking event. It represents a way in which social interactions can immediately and potently modulate behavior. As such, social buffering is one mechanism by which strong social support increases resilience to mental illness. While the behavioral and neuroendocrine impacts of social buffering are well studied in multiple species, including humans, the neuronal bases of this behavioral phenomenon remain largely unexplored. Previous work has shown that the infralimbic prefrontal cortex (IL-PFC) is important for processing social information and, in separate studies, for modulating fear and anxiety. Thus, we hypothesized that socially-active cells within the IL-PFC may integrate social information to modulate fear responsivity. To test this hypothesis, we employed social buffering paradigms in male and female mice. Similar to prior studies in rats, we found that the presence of a cagemate reduced freezing in fear and anxiety-provoking contexts. In accordance with previous work, we demonstrated that interaction with a novel or familiar conspecific induces activity in the IL-PFC as evidenced by increased immediate early gene (IEG) expression. We then utilized an activity-dependent tagging murine line, the ArcCreERT2 mice, to express channelrhodopsin (ChR2) in neurons active during the social encoding of a new cagemate. We found that optogenetic reactivation of these socially-active neuronal ensembles phenocopied the effects of cagemate presence in male and female mice in learned and innate fear contexts without being inherently rewarding or altering locomotion. These data suggest that a social neuronal ensemble within the IL-PFC may contribute to social buffering of fear. These neurons may represent a novel therapeutic target for fear and anxiety disorders.

neuroscience↗