Biology subjects

Lim, M. M.

Publications and source records attributed to Lim, M. M..

13 recordsLinked to original sources

bioRxiv2026

Temporal Trajectories of Motor and Cognitive Dysfunction After Combined PTSD and TBI in Mice: Implications for Neurodegenerative Disease Vulnerability

Post-Traumatic Stress Disorder (PTSD) commonly occurs alongside Traumatic Brain Injury (TBI), yet the chronic behavioral consequences of combined neurotrauma (i.e., PTSD and TBI) across the sexes remain unclear. Using a mouse model combining Single Prolonged Stress (SPS) as a model for PTSD and Controlled Cortical Impact (CCI) as a model for TBI, we assessed gait, anxiety-like behavior, and contextual fear learning and extinction at 2, 4, and 12-weeks post-injury. Combined neurotrauma produced early and persistent gait impairments in both sexes, delayed changes to anxiety-like behavior characterized by reduced avoidance of an anxiogenic environment, and long-lasting contextual fear recall deficits. Impaired learning was observed in males, where they demonstrated reduced fear acquisition and diminished extinction rates at later time points while females showed no deficits. Across testing and sex, peak deficits emerged at 4 weeks post-neurotrauma. Together, these findings define a sex- and time-dependent behavioral phenotype following combined neurotrauma and underscore the importance of modeling comorbidity to capture the temporal and neurobehavioral consequences of trauma exposure that more closely reflect clinical populations.

animal behavior and cognition↗

bioRxiv2025

Neurotype matching in monogamous rodents is modulated by early-life sleep experience

Studies of human sociability indicate stronger social affinity in matched-neurotype dyads (e.g., two individuals with autism or two without) compared to mixed-neurotype dyads (e.g., one individual with autism paired with one without). Is this neurotype matching phenomenon also quantifiable in non-human animals? Using deep learning tools, we analyzed dyadic male-female interactions in prairie voles, a highly social rodent species. To simulate "neurotypes", voles were exposed to either control conditions or early-life sleep disruption (ELSD) during a critical neurodevelopmental period (postnatal days 14-21), recapitulating two features of human autism: developmental sleep disruption and later-life atypical sociability. Analogous to human studies, voles showed signs of reduced social affinity in mixed dyads compared to matched dyads, including sex-specific changes in aggression and body orientation toward the conspecific. These findings advance our understanding of social affinity, providing a framework for new studies in both animal models and humans.

animal behavior and cognition↗

bioRxiv2025

Developmental time course of social touch, parvalbumin interneurons, perineuronal nets and Mef2c expression reveals a sensitive period of somatosensory cortex development in prairie voles

Social touch facilitates our attachment to others, especially early in life, which may be linked to the maturation of parvalbumin interneurons (PVI) in the somatosensory cortex (S1). These neurons respond to social touch, mature in a sensory experience-dependent manner, and influence both somatosensory processing and social behavior in models of Autism Spectrum Disorder. Prairie voles (Microtus ochrogaster) are an ideal rodent model for studying these concepts since they engage in a species-typical social touch called "huddling". This study first showed that over development from juvenile to adult, same-sex siblings huddled less and explored more. Next, we tracked two markers of plasticity indicative of PVI maturation, extracellular perineuronal nets (PNNs) and nuclear transcription factor Myocyte enhancing factor 2C (Mef2c) - across seven developmental timepoints. We found that, while PV expression in S1 was stable by P21, PNNs and Mef2c continued to shift afterwards, indicating a protracted development. Four unique clusters of PVIs converge during development between P14-P21, suggesting a sensitive period of PVI development. Finally, to determine environmental factors affecting these processes, environmental enrichment between P21-P28 led to accelerated PVI maturation. This developmental mapping provides a particularly salient model to investigate the molecular underpinnings of cortical and social development.

neuroscience↗

bioRxiv2024

Heart rate variability impairment during sleep in Veterans with REM sleep behavior disorder, traumatic brain injury, and posttraumatic stress disorder: An early potential window into autonomic dysfunction?

Individuals with comorbid REM sleep behavior disorder (RBD) and neurotrauma (defined by traumatic brain injury and post-traumatic stress disorder) have an earlier age of RBD symptom onset, increased RBD-related symptom severity and more neurological features indicative of prodromal synucleinopathy compared to RBD only. An early sign of neurodegenerative condition is autonomic dysfunction, which we sought to evaluate by examining heart rate variability during sleep. Participants with overnight polysomnography were recruited from the VA Portland Health Care System. Veterans without neurotrauma or RBD (controls; n=19), with RBD only (RBD, n=14), and with RBD and neurotrauma (RBD+NT, n=19) were evaluated. Eligible 5-minute NREM and REM epochs without apneas/hypopneas, microarousals, and ectopic beats were analyzed for frequency and time domain (e.g. low frequency power, LF; high frequency power, HF; root mean square of successive RR intervals, RMSSD; % of RR intervals that vary [≥]50 ms, pNN50) heart rate variability outcomes. Heart rate did not significantly differ between groups in any sleep stage. Time domain and frequency domain variables (e.g., LF power, HF power, RMSSD, and pNN50) were significantly reduced in the RBD and RBD+NT groups compared to controls and RBD only during NREM sleep. There were no group differences detected during REM sleep. These data suggest significant reductions in heart rate variability during NREM sleep in RBD+NT participants, suggesting greater autonomic dysfunction compared to controls or RBD alone. Heart rate variability during sleep may be an early, promising biomarker, yielding mechanistic insight for diagnosis and prognosis of early neurodegeneration in this vulnerable population. STATEMENT OF SIGNIFICANCEComorbid REM sleep behavior disorder (RBD) and neurotrauma (NT, traumatic brain injury + post-traumatic stress disorder; RBD+NT) is associated with increased neurodegenerative symptom burden and worsened health. Sleep and autonomic function are integrally and bidirectionally related to neurodegenerative processes. In the current study, we sought to determine if early signs of autonomic dysfunction, measured via heart rate variability (HRV), were present during sleep in comorbid RBD+NT compared to RBD only and controls. Our data show reduced time and frequency domain HRV during NREM sleep in RBD+NT Veterans compared to RBD only and controls. These data contribute evidence that participants with RBD and comorbid NT demonstrate significantly worse autonomic dysfunction compared to age/sex matched participants with RBD alone.

physiology↗

bioRxiv2024

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation

The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimers disease and Parkinsons disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of -synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits -synuclein clearance and facilitates -synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical -synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein -syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of -synuclein from intersititial to cerebrospinal fluid. Using a mouse model of -synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased -synuclein aggregates. Our results indicate -synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinsons disease. SummaryIn a human postmortem case series, we observe that neocortical Lewy body pathology is associated with mis-localization of the astroglial water channel aquaporin-4 (AQP4). In mice, -synuclein is cleared from the brain along perivascular pathways, while loss of perivascular AQP4 localization impairs glymphatic -synuclein clearance to the CSF. Furthermore, loss of perivascular AQP4 localization promotes the development and propagation of -synuclein aggregates.

neuroscience↗

bioRxiv2024

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces

Background and PurposeAn association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and MethodsThis analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3). ResultsOn average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a persons BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a persons average BMI was associated with a 0.021 mm3/cm3 increase in MV-PVS volume (p<0.001). ConclusionThis longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a persons mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

neuroscience↗

bioRxiv2024

Quantifying social roles in multi-animal videos using subject-aware deep-learning

Analyzing social behaviors is critical for many fields, including neuroscience, psychology, and ecology. While computational tools have been developed to analyze videos containing animals engaging in limited social interactions under specific experimental conditions, automated identification of the social roles of freely moving individuals in a multi-animal group remains unresolved. Here we describe a deep-learning-based system - named LabGym2 - for identifying and quantifying social roles in multi-animal groups. This system uses a subject-aware approach: it evaluates the behavioral state of every individual in a group of two or more animals while factoring in its social and environmental surroundings. We demonstrate the performance of subject-aware deep-learning in different species and assays, from partner preference in freely-moving insects to primate social interactions in the field. Our subject-aware deep learning approach provides a controllable, interpretable, and efficient framework to enable new experimental paradigms and systematic evaluation of interactive behavior in individuals identified within a group.

animal behavior and cognition↗

bioRxiv2024

Maternal cannabis use alters excitatory inputs to corticostriatal efferent neurons in rat offspring

With the recent surge in cannabis legalization across North America, there is legitimate concern that rates of cannabis use during pregnancy will dramatically increase in the coming years. However, the long-term impacts of prenatal cannabis exposure (PCE) on the brain and behavior remain poorly understood. Using a model of passive cannabis vapor exposure, we have previously shown that PCE impairs behavioral flexibility in an attentional set-shifting task in adult offspring, which is orchestrated in part by excitatory inputs from the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAc). Given the fundamental role of these corticostriatal inputs in coordinating flexible reward-seeking strategies, we used a combination of retrograde tracing and ex vivo electrophysiology to test the hypothesis that maternal cannabis use alters the synaptic and intrinsic membrane properties of corticostriatal efferent neurons in exposed male and female rat offspring. Specifically, pregnant rat dams were trained to self-administer vaporized cannabis (69.7% THC; 150 mg/ml) twice daily throughout mating and gestation and offspring were subsequently injected with fluorescent retrobeads into the NAc core prior to conducting whole-cell ex vivo recordings of spontaneous excitatory and inhibitory post-synaptic currents (EPSC and IPSC, respectively) in retrolabeled mPFC neurons in adulthood. Our results indicate that PCE increases the frequency of spontaneous glutamatergic events (EPSCs) in NAc-projecting mPFC neurons in a sex-specific manner, which drives changes in excitatory to inhibitory (EPSC/IPSC) ratio, particularly in females. Furthermore, the amplitude of phasic glutamatergic events was reduced in cannabis-exposed offspring of both sexes, suggesting changes in postsynaptic receptor function. Altogether, these data demonstrate that PCE shifts the balance of excitatory/inhibitory inputs onto NAc-projecting mPFC neurons with limited effects on membrane conductance in females, resulting in reduced sex differences following maternal cannabis self-administration. These results provide putative neurophysiological mechanisms mediating previously observed behavioral changes, and future studies will need to test if these cannabis-induced changes are causal to long-term deficits in behavioral flexibility that have been previously documented in exposed offspring.

neuroscience↗

bioRxiv2022

Early life sleep disruption has long lasting, sex specific effects on later development of sleep in prairie voles

In mammals, sleep duration is highest in the early postnatal period of life and is critical for shaping neural circuits that control the development of complex behaviors. The prairie vole is a wild, highly social rodent that serves as a unique model for the study of complex, species-typical social behaviors. Previous work in our laboratory has found that early life sleep disruption (ELSD) in prairie voles during a sensitive window of postnatal development leads to long lasting changes in social and cognitive behaviors as well as structural changes in excitatory and inhibitory neural circuits in the brain. However, it is currently unknown how later sleep is impacted by ELSD, both shortly after ELSD and over the long term. Therefore, the aim of this study was to describe the effects of ELSD on later life sleep, compared to sleep in normally developing prairie voles. First, we conducted tethered electroencephalogram/electromyogram (EEG/EMG) recordings in juvenile prairie voles undergoing ELSD, compared to Control conditions. Second, we conducted 24 hours of home cage tethered EEG/EMG recordings in either adolescent or adult male and female prairie voles that had previously undergone ELSD or Control conditions as juveniles. We found that, as adults, male ELSD prairie voles showed persistently lower REM sleep duration and female ELSD prairie voles showed persistently higher NREM sleep duration compared to Controls, but no other sleep parameters differed. We concluded that 1) persistent effects of ELSD on sleep into adulthood may contribute to the social and cognitive deficits observed in adult voles, and 2) sleep disruption early in life can influence later sleep patterns in adulthood.

neuroscience↗

bioRxiv2022

Early-life sleep disruption impairs subtle social behaviors during pair bond formation in prairie voles: A computer vision study

Early life sleep disruption (ELSD) has been shown to have long lasting effects on social behavior in adult prairie voles (Microtus ochrogaster), including impaired expression of pair bond behavior during partner preference testing (e.g., reduced huddling with a pair bonded partner). However, due to the limitations of manual behavior tracking, the behavioral effects of ELSD across the entire time course of pair bond formation have not yet been described, hindering our ability to trace mechanisms. Here, we used computer vision to precisely track multiple behaviors during opposite-sex cohabitation of prairie voles. Male-female pairs were allowed to interact through a mesh divider in the home cage for 72 h, providing variables of body direction, distance-to-divider, and locomotion speed, with temporal resolution as high as the video frame rate (20-25 Hz). We found that control males displayed periodic, stereotyped patterns of body orientation towards females during pair bond formation. In contrast, ELSD males showed reduced duration and ultradian periodicity of these body orientation behaviors towards females. Furthermore, in both sexes, ELSD altered stereotypical spatial and temporal patterns of locomotion seen in control animals that typically varied across days of cohabitation and light/dark periods. This study highlights the utility of computer vision in deep characterization of subtle behaviors and allows a more comprehensive behavioral assessment of the profound and persistent effects of ELSD on later life social behavior. Our findings may shed light on causal mechanisms underlying human neurodevelopmental disorders featuring sleep disruption and social deficits, such as autism spectrum disorder.

animal behavior and cognition↗

bioRxiv2022

REM sleep has minute-scale rhythms in mice and humans: A non-binary continuum between phasic and tonic microstates

Rapid eye movement sleep (REM) is believed to have a binary temporal structure with "phasic" and "tonic" microstates, defined by motoric activity versus quiescence, respectively. However, we observed in mice that the frequency of theta activity (a marker of rodent REM) fluctuates in a non-binary fashion, with the extremes of that fluctuation correlating with phasic-type and tonic-type facial motricity. This demonstrates that phasic and tonic REM rather represent ends of a continuum. These cycles of brain physiology and facial movement occurred at 0.01-0.06 Hz, or infraslow frequencies, and affected cross-frequency coupling and neuronal assembly activity in the neocortex, suggesting network functional impact. We then confirmed that humans also demonstrate non-binary phasic/tonic microstates, with continuous 0.01-0.04 Hz respiratory rate cycles matching the incidence of eye movements. Thus, we discovered a fundamental property of REM, which can yield new insights into our understanding of sleep health.

neuroscience↗

bioRxiv2021

Sleep Dependent Changes of Lactate Concentration in Human Brain

Lactate is an important cellular metabolite that is present at high concentrations in the brain, both within cells and in the extracellular space between cells. Small animal studies demonstrated high extracellular concentrations of lactate during wakefulness with reductions during sleep and/or anesthesia with a recent study suggesting the glymphatic activity as the mechanism for the reduction of lactate concentrations. We have recently developed a rigorous non-invasive imaging approach combining simultaneous magnetic resonance spectroscopy (MRS) and polysomnography (PSG) measurements, and here, we present the first in-vivo evaluation of brain lactate levels during sleep-wake cycles in young healthy humans. First, we collected single voxel proton MRS (1H-MRS) data at the posterior cingulate with high temporal resolution (every 7.5 sec), and simultaneously recorded PSG data while temporally registering with 1H-MRS time-series. Second, we evaluated PSG data in 30 s epochs, and classified into four stages Wake (W), Non-REM sleep stage 1 (N1), Non-REM sleep stage 2 (N2), and Non-REM sleep stage 3 (N3). Third, we determined lactate signal intensity from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epoch. In examinations of nine healthy participants (four females, five males; mean age 24.2 ({+/-}2; SD) years; age range: 21-27 years) undergoing up to 3-hour simultaneous MRS/PSG recordings, we observed a group mean reduction of [4.9 {+/-} 4.9] % in N1, [10.4 {+/-} 5.2] % in N2, and [24.0 {+/-} 5.8] % in N3 when compared to W. Our finding is consistent with more than 70 years of invasive lactate measurements from small animal studies. In addition, reduced brain lactate was accompanied by a significant reduction the apparent diffusion coefficient of brain lactate. Taken together, these findings are consistent with the loss of lactate from the extracellular space during sleep while suggesting lactate metabolism is altered and/or lactate clearance via glymphatic exchange is increased during sleep. Significance StatementThis study describes a non-invasive magnetic resonance spectroscopy/polysomnography technique that allows rigorous measurement of brain metabolite levels together with simultaneous characterization of brain arousal state as either wakeful or one of the several sleep states. The results provide the first in-vivo demonstration of reductions in brain lactate concentration and diffusivity during sleep versus wakefulness in young healthy human brain. These findings are consistent with invasive small-animal studies showing the loss of extracellular lactate during sleep, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain.

neuroscience↗

bioRxiv2021

Immediate Impact of Yogic Breathing on Pulsatile Cerebrospinal Fluid Dynamics

Cerebrospinal fluid (CSF), a clear fluid bathing the central nervous system (CNS), undergoes pulsatile movements, and plays a critical role for the removal of waste products from the brain including amyloid beta, a protein associated with Alzheimers disease. Regulation of CSF dynamics is critical for maintaining CNS health, and increased pulsatile CSF dynamics may alter brains waste clearance due to increased mixing and diffusion. As such, understanding the mechanisms driving CSF movement, and interventions that influence its resultant removal of wastes from the brain is of high scientific and clinical impact. Since pulsatile CSF dynamics is sensitive and synchronous to respiratory movements, we are interested in identifying potential integrative therapies such as yogic breathing to regulate and enhance CSF dynamics, which has not been reported before. Here, we investigated the pre-intervention baseline data from our ongoing randomized controlled trial, and examined whether yogic breathing immediately impacts pulsatile CSF dynamics compared to spontaneous breathing. We utilized our previously established non-invasive real-time phase contrast magnetic resonance imaging (RT-PCMRI) approach using a 3T MRI instrument, and computed and rigorously tested differences in CSF velocities (instantaneous, respiratory, cardiac 1st and 2nd harmonics) at the level of foramen magnum during spontaneous versus four yogic breathing patterns. In examinations of 18 healthy participants (eight females, ten males; mean age 34.9 {+/-} 14 (SD) years; age range: 18-61 years), we discovered immediate increase in cranially-directed velocities of instantaneous-CSF 16% - 28% and respiratory-CSF 60% - 118% during yogic versus spontaneous breathing, with most statistically significant changes during deep abdominal breathing (28%, p=0.0008, and 118%, p=0.0001, respectively). Further, cardiac pulsation was the primary source of pulsatile CSF during all breathing conditions except during deep abdominal breathing, when there was a comparable contribution of respiratory and cardiac 1st harmonic power [0.59 {+/-} 0.78], demonstrating respiration can be the primary regulator of CSF depending on individual differences in breath depth and location. Further work is needed to investigate the impact of sustained training yogic breathing on increased pulsatile CSF dynamics and brain waste clearance for CNS health.

neuroscience↗