Biology subjects

McCullagh, E. A.

Publications and source records attributed to McCullagh, E. A..

16 recordsLinked to original sources

bioRxiv2026

Oxytocin and Vasopressin Immunoreactivity Differs Across Auditory Brainstem Nuclei in Rodents with Distinct Social Systems

Oxytocin (OT) and vasopressin (AVP) are neuropeptide hormones involved in regulating animal social behavior and a broad spectrum of physiological processes. Although their distributions are well documented in neuroendocrine regions of the forebrain and midbrain, their expression in the hindbrain remains poorly understood. Here, we used immunohistochemistry to quantify OT and AVP immunoreactive puncta within three auditory brainstem nuclei, the lateral superior olive (LSO), the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB) in six wild-caught rodent species differing in sociality. We also quantified the volume of these nuclei and examined variation in total brain volume across species and sociality. OT and AVP puncta count differed among species and social groups. Group-living species exhibited higher OT and AVP puncta counts than monogamous and solitary species in the LSO and MNTB. In the MSO, OT puncta counts did not differ among social groups, whereas AVP puncta counts were higher in group-living than in monogamous and solitary species. Total brain volume and the volumes of the MNTB and MSO differed among species, but not across social groups, whereas LSO volume did not differ among species or sociality. These findings revealed sociality-related variation in OT and AVP immunoreactive puncta within auditory brainstem circuits and suggest that neuropeptide signaling within early auditory brainstem pathways may contribute to the neural integration of social and auditory information.

neuroscience↗

bioRxiv2026

Sociality Drives Sex Differences in Auditory Brainstem Processing Across Rodent Species

Although social behavior has been predicted to correlate with increased complexity in vocal signals, its relationship with auditory sensitivity between the sexes remains poorly understood. Here, we used phylogenetic comparative analyses to examine sex-specific differences in auditory processing across rodent species representing different social lifestyle strategies. We detected significant sex differences in click and frequency evoked auditory brainstem response (ABR) thresholds across sociality, with social female rodents exhibiting lower thresholds than solitary males. Males generally exhibited higher ABR wave I and IV amplitude ratios than females, whereas interpeak latencies were similar between the sexes across social groups. Females exhibited significantly higher binaural interaction component (BIC) relative amplitudes and faster BIC normalized latencies than males across tested interaural time differences (ITDs). Together, these findings demonstrate that sociality plays an important role in shaping differences in auditory physiology between male and female rodents and highlights the potential influence of social behavior on the evolution of mammalian auditory systems.

physiology↗

bioRxiv2026

Fmr1 mutation reshapes gut microbiome structure, diversity, intestinal barrier integrity, and function in a sex and genotype-dependent manner

Fragile X Syndrome (FXS) is the leading monogenic cause of autism spectrum disorder (ASD), caused by mutation in the Fmr1 gene. In addition to cognitive and behavioral challenges, FXS patients often experience altered gut microbiome-induced gastrointestinal (GI) problems. Evidence suggests that an altered gut microbiome can disrupt mucosal barrier and promote inflammation, leading to impaired intestinal barrier integrity and function. However, the mechanisms by which the gut microbiome alters the barrier integrity and contributes to GI pathology in FXS remain poorly understood. To address this gap, we tested the hypothesis that Fmr1 mutation reshapes the gut microbiome composition, altering transcriptional markers of intestinal barrier regulation and gut barrier physiology in mice. To test our hypothesis, we used an Fmr1 knockout (KO) mouse model with wild-type (WT) littermates as controls. First, we performed 16S ribosomal RNA sequencing to characterize gut microbial community structure and diversity across genotypes and sexes. Among the alpha-diversity metrics, only Chao1 showed significant differences across female genotypes in both fecal and cecal contents. Additionally, qRT-PCR analysis of ileal samples revealed reduced barrier and mucosal defense gene expression in female KO and Het mice compared with WT females. Next, we utilized a Ussing chamber assay to test gut epithelial permeability and function. Our physiological data showed that female Het mice had increased transepithelial resistance compared to WT females, indicating a tighter epithelial barrier. Overall, FXS is associated with modest genotype and sex-specific microbiome variation, impaired gut barrier integrity, and altered epithelial barrier function in female mice.

microbiology↗

bioRxiv2026

Loss of Fmr1 reorganizes the multi-elemental composition of neural and somatic tissues in Fragile X mice

Fragile X Syndrome (FXS) results from a genetic mutation which silences the expression of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP serves various roles regulating cellular protein synthesis including mRNAs that code for proteins regulating ion flux. However, there are few studies measuring the elemental balance between FXS genotypes and tissues. Here, we measured the multivariate balance of 10 elements in tissues of wild-type and Fmr1-knockout mice to compare elemental composition of brain and somatic tissues within and across genotypes. Using a Bayesian mixed model approach, we found that the main differences between groups were between tissues, with significant effects of genotype and interaction of tissue on genotype. Wild-type feces were significantly higher in magnesium and sodium than knockout. Fur was significantly higher in potassium in wild-type, which was supported by the interaction effect of genotype with tissue. These results align with previous work showing FXS pathologies alter electrolytic and metal ion regulation, neuronal excitability, and gastrointestinal function. Future work should additionally test how elemental differences relate to function at the cellular level, as well as patterns of individual intake, digestion, assimilation, and/or excretion.

neuroscience↗

bioRxiv2025

In-vivo optogenetic manipulation approach for gerbil medial nucleus of trapezoid body

PurposeThis study introduces an in-vivo optogenetic manipulation approach for the medial nucleus of the trapezoid body (MNTB) in Mongolian gerbils, a species with a hearing range similar to humans. The MNTB is crucial for sound localization, but traditional methods lack temporal precision and reversibility. The aim of this study is to develop a specific, reversible method for controlling MNTB activity with fast and precise temporal control, an approach vital for studying sound localization. MethodsWe stereotactically injected adeno-associated viral vectors encoding opsins into the gerbil MNTB. Precise targeting was achieved despite the MNTBs location in a deep, heavily myelinated area of the brainstem. Opsin expression was confirmed via confocal microscopy. In-vivo electrophysiology combined with optical stimulation was used to test optical activation and suppression of MNTB activity during sound stimuli. ResultsOpsin expression was strong and stable in MNTB neurons over weeks and months. Laser stimulation during in-vivo recordings successfully induced both activation and suppression of MNTB neurons, demonstrating fast and precise control over neural activity. ConclusionThis in-vivo optogenetic method provides specific, reversible control of MNTB activity in gerbils with rapid, real-time modulation. It offers a powerful tool for investigating sound localization and auditory processing with high temporal precision.

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

VARIATION IN HEAD AND PINNA MORPHOLOGY OF PRESERVED PEROMYSCUS SPP. SPECIMENS AND IMPLICATIONS FOR AUDITORY FUNCTION

The characteristics of an animals head and pinna mark the beginning of auditory communication. Auditory communication is broadly achieved by receiving sounds from the environment and plays a vital role in an animals ability to perceive and localize sounds. Natural history museums and collections along with their vast repositories of specimens provide a unique resource for examining how the variability in both the size and shape of the head and pinna cause variability in the detection of acoustic signals across species. Using this approach, we measured the dimensions of the head and pinna of over 1,200 preserved specimens of Peromyscus boylii, P. californicus, P. gossypinus, P. leucopus, P. maniculatus, and P. truei, followed by a series of head-related transfer functions (HRTFs) on several individuals to study the relationship between morphology and available auditory information. Our morphological results show significant variation in pinna length and width, as well as in the distance between the two ears across the six species. ITDs and ILDs were calculated and demonstrated consistent results across species, suggesting the differences in head and pinna size do not significantly modify these cues. Not only does this study contribute to existing research on external morphology and auditory function, but it also provides valuable insight into the use of preserved specimens in auditory research, an area that is currently understudied. Summary statementThis work aims to provide insight into using natural history museum specimens for morphological research pertaining to the auditory system in small mammals.

evolutionary biology↗

bioRxiv2024

Sex Differences in Auditory Brainstem Responses in the Hispid Pocket Mouse (Chaetodipus hispidus)

The hispid pocket mouse (C. hispidus) is a solitary semi-fossorial rodent that has been the subject of various ecological and genetic studies. However, no previous studies have characterized its hearing ability, which is important for its survival and fitness. We collected auditory brainstem responses (ABRs) from C. hispidus and measured craniofacial and pinna morphological features to assess hearing ability and test differences in hearing thresholds, monaural and binaural ABR amplitudes and latencies between the sexes. ABR recordings revealed that similar to other small mammals, C. hispidus displayed the lowest threshold to sounds between 8-16 kHz, indicating best hearing across those frequencies. We found significant differences in auditory thresholds of the ABRs between the sexes, with females showing lower frequency hearing compared to males. However, no significant differences were detected in monaural and binaural ABR amplitudes and latencies between the sexes. We also found no significant differences in craniofacial and pinna dimensions between the sexes. These findings shed novel insights into the auditory systems across species and highlighted for the first time sex differences in auditory thresholds for this rodent species.

neuroscience↗

bioRxiv2024

Hearing in Two Closely Related Peromyscus Species (Peromyscus maniculatus and P. leucopus)

The genus Peromyscus has been extensively used as a model for ecological, behavioral, and evolutionary studies. We used auditory brainstem responses (ABRs), craniofacial morphology, and pinna measurements to compare characteristics that could impact the threshold, amplitude, and latency of ABRs in two wild-caught species, P. leucopus and P. maniculatus. We observed significant differences in craniofacial and pinna attributes between species, with P. leucopus exhibiting larger features and bigger overall size compared to P. maniculatus. ABR recordings showed similar hearing thresholds with peak sensitivity between 8 to 46 kHz for both species. We found that amplitude of ABR wave I and IV increased significantly with increasing intensity, while no main effect of species was detected. Latency of wave I and IV significantly decreased with increasing intensity in both species. Finally, we observed longer latencies of the binaural interaction component (BIC) at longer interaural time differences (ITDs) in P. leucopus, while no differences were observed across relative BIC amplitude between species. These results provide additional ABR related data that expands the use of both Peromyscus species as future models for auditory research.

neuroscience↗

bioRxiv2024

Sex-specific loss of mitochondrial membrane integrity and mass in the auditory brainstem of a mouse model of Fragile X syndrome

Sound sensitivity is one of the most common sensory complaints for people with autism spectrum disorders (ASDs). How and why sounds are perceived as overwhelming by affected people is unknown. To process sound information properly, the brain requires high activity and fast processing, as seen in areas like the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem. Recent work has shown dysfunction in mitochondria, which are the primary source of energy in cells, in a genetic model of ASD, Fragile X syndrome (FXS). Whether mitochondrial functions are also altered in sound-processing neurons, has not been characterized yet. To address this question, we imaged the MNTB in a mouse model of FXS. We stained MNTB brain slices from wild-type and FXS mice with two mitochondrial markers, TOMM20 and PMPCB, located on the Outer Mitochondrial Membrane and in the matrix, respectively. These markers allow exploration of mitochondrial subcompartments. Our integrated imaging pipeline reveals significant sex-specific differences between genotypes. Colocalization analyses between TOMM20 and PMPCB reveal that the integrity of mitochondrial subcompartments is most disrupted in female FXS mice compared to female wildtype mice. We highlight a quantitative fluorescence microscopy pipeline to monitor mitochondrial functions in the MNTB from control or FXS mice and provide four complementary readouts. Our approach paves the way to understanding how cellular mechanisms important to sound encoding are altered in ASDs.

neuroscience↗

bioRxiv2022

Evaluating risk-taking behaviors in Lycosidae: are the nutritional benefits of sugar water worth the risk of predation?

The risk-taking tendencies and addiction in small vertebrates are often used to understand the processes of larger vertebrates, such as humans. We set out to find whether certain risk-taking behaviors characteristic of addiction remain consistent between vertebrates and invertebrates. Different animals will gorge on sugar water, and addiction-like tendencies are often associated with the overconsumption of sucrose. The goal of my study was to evaluate those risk-taking behaviors and compare invertebrate risk-taking behaviors to vertebrate risk-taking behaviors. The risk-taking behavior we observed was the process of relieving cravings while the risk of predation was present. Through this study we document evidence of wolf spiders feeding on a 25% sucrose solution and explain the wolf spiders preference to a sugar water solution over filtered tap water. To evaluate if wolf spiders exhibit addiction like behaviors associated with sucrose, we placed a green-colored, sugar water-soaked cotton ball on the silk of a large, predatory Tigrosa helluo wolf spider and a regular, filtered water-soaked cotton ball on the "safe" side of a plastic trial arena and then evaluated the behaviors of the prey spiders. We used a mixture of Pardosa milvina and Rabidosa rabida as test spiders, with one group given a sugar-water treatment beforehand and the other group was given a green colored control cotton ball with filtered tap water (n=14 for both the sugar water treatment and control groups). The wolf spiders who were predisposed to the sugar water treatment were more likely to cross through their predators silk in order to gain access to the sugar water cotton ball than their counterparts who were not given a sugar water treatment prior. These results suggest the risk for predation of the wolf spider is not worth the benefits of the sugar water, unless a wolf spider has been allowed unlimited access to sugar water in advance. When a wolf spider who was allowed unlimited access to sugar water beforehand is presented with a risky situation, they will increase their risk-taking behaviors via crossing through a predators silk in order indulge in the sugar water. These results suggest the addictive properties of sugar spans across vertebrates and invertebrates, and potentially opens the door for a cost-efficient and ethically acceptable invertebrate model-organism for examining the risk-taking behaviors associated with addiction.

animal behavior and cognition↗

bioRxiv2021

Auditory Brainstem Responses in the C57BL/6J Fragile X Syndrome Knockout Mouse Model

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X Syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brainstem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure hearing range, monaural and binaural auditory responses in hemizygous males, homozygous females and heterozygous females compared to wildtype mice. Consistent with previous work we showed no difference in morphological parameters across genotypes or sexes. Male FXS mice had increased threshold for high frequency hearing at 64 kHz compared to wildtype males, while females had no difference in hearing range between genotypes. In contrast, female homozygous FXS mice had decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Lastly, FXS males had increased latency of the binaural interaction component (BIC) at 0 ITD compared to wildtype males. These findings further clarify auditory brainstem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

neuroscience↗

bioRxiv2021

Hearing Ability of Prairie Voles (Microtus ochrogaster)

Hearing ability of mammals can be impacted by many factors including social cues, environment, and physical properties of animal morphology. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been fully characterized. In this study, we measure morphological head and pinna features and use auditory brainstem responses to measure auditory capabilities of prairie voles characterizing monaural and binaural hearing and hearing range. Additionally, we measured unbonded male and female voles to characterize differences due to sex. We found that prairie voles show a hearing range with greatest sensitivity between 8 - 32 kHz, robust binaural hearing, and characteristic monaural ABRs. We show no differences between the sexes for binaural hearing or hearing range, however female voles have increased amplitude of peripheral ABR waves I and II and increased latency of wave IV. Our results confirm that prairie voles have both low and high frequency hearing, binaural hearing, and despite biparental care and monogamy, differences in processing of sound information between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in behavioral responses between sexes. HighlightsO_LIMonogamous prairie voles hear across both low and high frequencies. C_LIO_LIFemale prairie voles show differences in monaural hearing compared to males. C_LIO_LIThere is no difference in binaural hearing or pinna/head size morphology between the sexes. C_LI

neuroscience↗

bioRxiv2021

Myelination deficits in the auditory brainstem of a mouse model of Fragile X Syndrome, a possible mechanism for auditory phenotypes

1Auditory symptoms are one of the most frequent sensory issues described in people with Fragile X Syndrome (FXS), the most common genetic form of intellectual disability. However, the mechanisms that lead to these symptoms are under explored. In this study, we examined whether alterations in myelination in auditory brainstem circuitry contribute to auditory impairments in FXS mice. Specifically, we studied myelinated fibers that terminate in the Calyx of Held, which encode temporally precise sound arrival time, and are some of the most heavily myelinated axons in the brain. We measured anatomical myelination characteristics using coherent anti-stokes Raman spectroscopy (CARS) and electron microscopy (EM) in a FXS mouse model in the medial nucleus of the trapezoid body (MNTB) where the Calyx of Held synapses. We measured number of mature oligodendrocytes (OL) and oligodendrocyte precursor cells (OPCs) to determine if changes in myelination were due to changes in the number of myelinating or immature glial cells. The two microscopy techniques (EM and CARS) showed a decrease in fiber diameter in FXS mice. Additionally, EM results indicated reductions in myelin thickness and axon diameter, and an increase in g-ratio, a measure of structural and functional myelination. Lastly, we showed an increase in both OL and OPCs in MNTB sections of FXS mice suggesting that the myelination phenotype is not due to an overall decrease in number of myelinating OLs. This is the first study to show that a potential myelination mechanism can explain alterations seen in FXS at the level of the auditory brainstem.

neuroscience↗

bioRxiv2019

Auditory binaural and spatial hearing impairments in a Fragile X Syndrome mouse model

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in Fragile X Syndrome (FXS) it is not known whether these changes cause sound localization impairments in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with sound source location as the prepulse stimulus, was used to show that Fmr1 knockout mice have decreased inhibition of their startle responses. Specifically, Fmr1 mice show decreased PPI compared to wildtype during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared to wildtype. Lastly, Fmr1 mice have increased latency to respond in these tasks suggesting additional impairments in the pathway responsible for reacting to a startling sound.

neuroscience↗

bioRxiv2019

De novo assembly of the Mongolian gerbil genome and transcriptome

BACKGROUNDThe Mongolian gerbil (Meriones unguiculatus) has historically been used as a model organism for the auditory and visual systems, stroke/ischemia, epilepsy and aging related research since 1935 when laboratory gerbils were separated from their wild counterparts. In this study we report genome sequencing, assembly, and annotation further supported by transcriptome data from 27 different tissues samples. FINDINGSThe genome was assembled using Illumina HiSeq 2000 and resulted in a final genome size of 2.54 Gbp with contig and scaffold N50 values of 31.4 Kbp and 500.0 Kbp, respectively. Based on the k-mer estimated genome size of 2.48 Gbp, the assembly appears to be complete. The genome annotation was supported by transcriptome data that identified 36 019 predicted protein-coding genes across 27 tissue samples. A BUSCO search of 3023 mammalian groups resulted in 86% of curated single copy orthologs present among predicted genes, indicating a high level of completeness of the genome. CONCLUSIONSWe report a de novo assembly of the Mongolian gerbil genome that was further enhanced by annotation of transcriptome data from several tissues. Sequencing of this genome increases the utility of the gerbil as a model organism, opening the availability of now widely used genetic tools. The data sets supporting the results of this article are available in the China National GeneBank CNSA repository, Accession id: CNP0000340.

genomics↗