Biology subjects

Young, L. J.

Publications and source records attributed to Young, L. J..

12 recordsLinked to original sources

bioRxiv2026

Interplay between ferroptosis and guttae in an early-onset murine model of Fuchs endothelial corneal dystrophy (FECD)

Col8a2Q455K/Q455K (Q455K) mice exhibit features of early-onset Fuchs endothelial corneal dystrophy (FECD), including decreased endothelial cell density (ECD) and guttae formation. Within the context of these clinical features, this study longitudinally evaluates ferroptosis in Q455K and wild-type (WT) mice using in vivo imaging, PCR and immunohistochemistry. Fifty-six Q455K and 56 WT mice were evaluated from 3 to 24 months of age with in vivo confocal microscopy; ECD and guttae were measured. Ferroptosis marker expression was determined with PCR and immunohistochemistry (IHC). Data were analyzed using two-way ANOVA with Tukeys post hoc test, Chi-square test and a paired t-test. The ECD significantly decreased in both groups from 3 to 24 months of age, but more markedly in Q455K (2285 {+/-} 317 to 1012 {+/-} 58 cells/mm{superscript 2}) versus WT mice (2714 {+/-} 139 to 2057 {+/-} 149 cells/mm{superscript 2}, P<0.0001). Guttae were observed exclusively in Q455K mice beginning at 3 months of age and increased over time (P=0.0003). The Q455K mice demonstrate guttae at the vertices of corneal endothelial cells rather than their centers (74.3% vs. 25.7%P<0.001). Expression of ferroptosis-related genes (Tfrc, Slc40a1, Ftl1, Gpx4) were significantly increased in the Q455K versus WT mice (P<0.05). Furthermore, corresponding protein expression (transferrin receptor 1, ferroportin, ferritin and glutathione peroxidase 4) was significantly elevated adjacent to guttae in Q455K versus WT mice (P<0.05). These findings implicate guttae in the initiation of ferroptosis as it relates to the pathophysiology of FECD and provide an optimal window for testing novel FECD therapies using this murine model, particularly those that target ferroptosis. Significance StatementFuchs endothelial corneal dystrophy (FECD) is a major cause of corneal blindness, yet the mechanisms driving endothelial cell loss remain unclear. Using an early-onset Q455K murine model, we show that disease onset occurs by 3 months of age and progresses with characteristic corneal guttae, endothelial cell loss, and morphological abnormalities replicating human FECD. By identifying ferroptosis adjacent to guttae in the Q455K, we demonstrate this mechanism is not specific to genetic mutations, but rather a conserved driver of corneal endothelial loss within the context of guttae formation. These findings establish an FECD progression timeline and reveal a mechanistic link between ferroptosis and guttae, validating this model as a critical tool for evaluating targeted therapeutic strategies.

developmental biology↗

bioRxiv2025

Natural variation in the oxytocin receptor gene predicts social observation in female prairie voles

Genetic variation in the oxytocin receptor gene (Oxtr) has been linked to differences in brain OXTR expression and long-term social bonds, but whether it shapes the moment-to-moment dynamics of early social interactions is unclear. Here we examined how the intronic Oxtr single nucleotide polymorphism (SNP) NT213739 in female prairie voles (Microtus ochrogaster) shapes their dynamic social interactions with an opposite-sex conspecific. Leveraging a computational pipeline to analyze the movements of freely interacting voles, we found that C/C females, which expressed higher OXTR levels in the nucleus accumbens than T/T females, spent more time socially observing novel males from a distance, especially early in interactions. This genotype-phenotype relationship persisted in multiple contexts, including the social preference test. Thus, natural Oxtr variation biases social observation in females toward unfamiliar males before bonds form, consistent with models where accumbens OXTR enhances the salience of social cues. These findings show that SNPs can shape subtle behavioral dimensions in early social encounters, with important implications for the role of oxytocin in the study of social attachment.

neuroscience↗

bioRxiv2025

Nonlinear hippocampal coding of the pair-bonded partner in prairie voles

Neural representation of specific opposite-sex partners remains largely unexplored. Using monogamous prairie voles, we demonstrated that partner preference required the ventral hippocampus, in which 3-4 Hz oscillations were enhanced following partner interaction. We identified ventral hippocampal neurons responding selectively to the pair-bonded partner and stranger, which encoded identity-related information in a nonlinear manner, shedding light upon how mammalian brains create distinct neural representations of romantic opposite-sex partners.

neuroscience↗

bioRxiv2025

The Relationship between Social Reward Behavior and Mesolimbic Dopamine Release

Deficits in social behavior, such as reduced motivation and social avoidance, are key symptoms in several psychiatric disorders. Distinct modes of reward, such as drug and social, may rely on different dopamine release patterns in the mesolimbic pathway. We investigated the relationship between social reward behaviors and dopamine release elicited by phasic and tonic stimulation patterns in C57BL/6J mice. Social conditioned place preference was used to assess motivation for social interaction, and in vivo fixed potential amperometry was used to measure nucleus accumbens dopamine release before and after cocaine (10 mg/kg, ip). Additional measures included the frequency and duration of social interactions during conditioning sessions, with the first and last session representing novel and familiar social interactions respectively. No relationship was found between baseline (pre-cocaine) dopamine and social place preference in either sex. However, in males, social place preference negatively correlated with cocaine-induced phasic dopamine release, indicating that increased social motivation was associated with a reduced phasic dopaminergic response to cocaine. In contrast, greater novel interaction was associated with increased baseline dopamine elicited by tonic stimulations. These relationships were not observed in females. Overall, these findings suggest distinct, sex-dependent roles for phasic and tonic dopamine release in mediating social reward.

neuroscience↗

bioRxiv2024

Different Roles of D1/D2 Medium Spiny Neurons in the Nucleus Accumbens in Pair Bond Formation of Male Mandarin Voles

The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, involvements of DA release, real time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.

neuroscience↗

bioRxiv2024

Vocal recognition of partners by female prairie voles

Recognizing conspecifics is vitally important for differentiating kin, mates, offspring and social threats.1 Although often reliant upon chemical or visual cues, individual recognition across the animal kingdom is also facilitated by unique acoustic signatures in vocalizations.2-4 However, amongst the large Muroidea superfamily of rodents that encompasses laboratory species amenable to neurobiological studies, there is scant behavioral evidence for individual vocal recognition despite individual acoustic variation.5-10 Playback studies have found evidence for coarse communicative functions like mate attraction and territorial defense, but limited finer ability to discriminate known individuals vocalizations.11-17 Such a capacity would be adaptive for species that form lifelong pair bonds requiring partner identification across timescales, distances and sensory modalities, so to improve the chance of finding individual vocal recognition in a Muroid rodent, we investigated vocal communication in the prairie vole (Microtus ochrogaster) - one of the few socially monogamous mammals.18 We found that the ultrasonic vocalizations of adult prairie voles can communicate individual identity. Even though the vocalizations of individual males change after cohabitating with a female to form a bond, acoustic variation across individuals is greater than within an individual so that vocalizations of different males in a common context are identifiable above chance. Critically, females behaviorally discriminate their partners vocalizations over a strangers, even if emitted to another stimulus female. These results establish the acoustic and behavioral foundation for individual vocal recognition in prairie voles, where neurobiological tools19-22 enable future studies revealing its causal neural mechanisms. HighlightsO_LIMuroid rodents can display individual vocal recognition C_LIO_LIAdult prairie vole USVs are more variable across individuals than social experience C_LIO_LIIndividual vole identity can be decoded from their vocalizations C_LIO_LICarefully constructed protocol sustains voles interest in vocal playback C_LIO_LIFemale prairie voles behaviorally recognize their mates vocalizations C_LI

animal behavior and cognition↗

bioRxiv2023

Natural variation in oxytocin receptor signaling causes widespread changes in brain transcription: a link to the natural killer gene complex

Oxytocin (OXT) is a highly conserved neuropeptide that modulates social cognition, and genetic variation in its receptor gene (Oxtr) is linked to divergent social phenotypes. However, the molecular mechanisms connecting Oxtr genotype to behavioral outcomes remain obscure. Here, we leverage naturally occurring Oxtr polymorphisms in the prairie vole that associate with striatal-specific OXTR density to investigate how OXTR signaling influences brain function. Specifically, we identify OXTR-dependent transcriptomic changes in the natural killer gene complex (NKC) - a genomic region classically associated with peripheral immune function. Centrally, OXTR-regulated NKC genes are positioned to influence microglia-neuron interactions. Consistent with a role for these genes in shaping neuronal connectivity, we show that genetic reduction of OXTR levels leads to increased dendritic spine density on striatal Oxtr-expressing neurons. In addition, we provide support for a similar relation between variation in OXTR mRNA levels and NKC transcription in humans. Together, our findings suggest a role for OXTR signaling in the shaping of neural circuits through transcriptional control of the NKC, outlining a mechanism via which variation in OXTR signaling may influence circuit connectivity to generate diversity in social behaviors.

neuroscience↗

bioRxiv2022

Transcriptional lability of brain oxytocin receptor (Oxtr) generates diversity in brain OXTR distribution and social behaviors

Although oxytocin (OXT) exhibits a highly conserved neuroanatomical pattern among vertebrates, the distribution of OXT receptor (OXTR) in brain varies considerably across species and is associated with species-typical social behavior. To investigate the genomic basis of the phylogenetic plasticity in brain Oxtr expression and its social behavioral consequences, we generated transgenic mice carrying a bacteria artificial chromosome (BAC) harboring the entire prairie vole Oxtr locus and flanking intergenic regulatory regions. We established eight independent "volized" mouse lines expressing prairie vole Oxtr (pvOxtr). Strikingly, despite conserved Oxtr expression in mammary gland of all transgenic mouse lines, each line displayed a unique pattern of brain expression distinct from both mice and prairie voles. Together with topologically associating domain (TAD) structure analysis with mouse genome, our findings suggest that unlike Oxt, Oxtr expression patterns in brain, involve contributions of distal regulatory elements beyond the BAC insert. In contrast, Oxtr expression in peripheral tissues appears resistant to such distal influences. Moreover, the "volized" mouse lines with different brain Oxtr expression patterns showed differences in partner preference and maternal behaviors, providing direct functional evidence that variation in brain Oxtr expression can drive differences in social behaviors. We propose that brain Oxtr expression is transcriptionally sensitive to long-range interactions with distal genomic elements, rendering it more susceptible to diverse regulatory influences. This supports a model in which regulatory flexibility facilitates the evolutionary diversification of social behavior, while maintaining essential peripheral Oxtr expression.

neuroscience↗

bioRxiv2021

Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles

Social relationships are dynamic and evolve with shared and personal experiences. Whether the functional role of social neuromodulators also evolves with experience to shape the trajectory of relationships is unknown. We utilized pair bonding in the socially monogamous prairie voles as an example of socio-sexual experience that dramatically alters behaviors displayed toward other individuals. We investigated oxytocin-dependent modulation of excitatory synaptic transmission in the nucleus accumbens as a function of pair bonding status. We found that an oxytocin receptor agonist decreases the amplitude of spontaneous Excitatory Postsynaptic Currents (EPSCs) in sexually naive virgin, but not pair-bonded, female voles, while it increases the amplitude of electrically evoked EPSCs in paired voles, but not in virgins. This oxytocin-dependent potentiation of synaptic transmission relies on the de novo coupling between oxytocin receptor signaling and endocannabinoid CB1 receptor signaling in pair bonded voles. Blocking CB1 receptors after pair bond formation increases the occurrence of a specific form of social rejection - defensive upright response - that is displayed towards the partner but not towards a novel individual. Altogether, our results demonstrate that oxytocins action in the nucleus accumbens is changed through social experience in a way that regulates the trajectory of social interactions as the relationship with the partner unfolds, potentially promoting the maintenance of a pair bond by inhibiting aggressive responses. These results provide a mechanism by which social experience and context shift oxytocinergic signaling to impact neural and behavioral responses to social cues.

neuroscience↗

bioRxiv2020

Limb-clasping, cognitive deficit and increased vulnerability to kainic acid -induced seizures in neuronal GPI anchor deficiency mouse models

Post-translational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, more than 150 human GPI anchored proteins have been discovered and about 30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko), or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid (KA)-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities.

neuroscience↗

bioRxiv2019

Social bonding induces changes in brain functional connectivity in male and female monogamous voles: a longitudinal fMRI study

Previous studies have related pair bonding in Microtus ochrogaster, the prairie vole, with plastic changes in several brain regions. However, their socially-relevant interactions have yet to be described. In this study, we used resting state magnetic resonance imaging to explore longitudinal changes in functional connectivity of brain regions associated with pair bonding. Male and female prairie voles were scanned at baseline, after 24 hours and two weeks of cohabitation with mating. Network based statistics revealed a common network with significant longitudinal changes including prefrontal and cortical regions, the hippocampus, the anterior olfactory nucleus, the lateral septum, the paraventricular nucleus, and the ventral tegmental area. Furthermore, baseline functional connectivity of three sub-networks predicted the onset of affiliative behavior, and a relationship was found between partner preference with long-term changes in the functional connectivity between the medial amygdala and ventral pallidum. Overall, our findings revealed the association between network-level changes and social bonding.

animal behavior and cognition↗

bioRxiv2018

MiLeSIM: combining super-resolution and machine learning permits high-throughput virus structure analysis

Optical super-resolution microscopy techniques enable high molecular specificity with high spatial resolution and constitute a set of powerful tools in the investigation of the structure of supramolecular assemblies such as viruses. Here, we report on a new methodology which combines Structured Illumination Microscopy (SIM) with machine learning algorithms to image and classify the structure of large populations of biopharmaceutical viruses with high resolution. The method offers information on virus morphology that can ultimately be linked with functional performance. We demonstrate the approach on viruses produced for oncolytic viriotherapy (Newcastle Disease Virus) and vaccine development (Influenza). This unique tool enables the rapid assessment of the quality of viral production with high throughput obviating the need for traditional batch testing methods which are complex and time consuming. We show that our method also works on non-purified samples from pooled harvest fluids directly from the production line.

biophysics↗