Biology subjects

Allman, B. L.

Publications and source records attributed to Allman, B. L..

7 recordsLinked to original sources

bioRxiv2025

A simple, open-source restraint system for magnetic resonance imaging in awake rats

Magnetic resonance imaging (MRI) is a critical tool for translational neuroscience, offering cross-species insights into brain structure and function; however, its application in preclinical research is constrained by routine anesthesia use or sedation, which alters neural activity and limits comparisons to awake human imaging. Awake rodent functional MRI (fMRI) provides a powerful platform for investigating brain function under physiologically relevant conditions, but implementation is limited by technical challenges, particularly head motion and stress during scanning. Most restraint systems employ initial anesthesia, compromising translatability of findings, and highlighting the need for improved designs. We developed a novel restraint system optimized for awake rat fMRI. The system consists of modular 3D-printed components and can be assembled in under five minutes. It is accompanied by a protocol that includes head-post implantation followed by an 11-day habituation period post-surgical recovery. The system eliminates the need for isoflurane anesthesia, ear bars, and bite bars, reducing stress and improving animal comfort. It supports integration with behavioral paradigms such as pupil tracking and licking responses. High-resolution T2-weighted anatomical images and functional scans obtained using the system showed excellent spatial clarity and minimal motion artifacts. Quality control metrics, including head motion parameters and temporal signal-to-noise ratio, confirmed the systems stability and suitability for awake imaging. Functional connectivity analysis revealed robust positive correlations between functionally relevant regions. This system offers a scalable, reproducible, and animal-friendly solution for awake rat fMRI. While the current design limits direct cranial access for multimodal recordings, it enables high-quality, behaviorally enriched imaging without anesthesia. Significance Statement: Most rodent fMRI studies, including awake studies, rely on anesthesia, which profoundly alters brain activity and limits the interpretation of the data. This study presents a novel restraint system that enables high-quality fMRI in fully awake rats, eliminating the need for anesthesia, ear bars, and bite bars. By reducing stress and motion, this simple restraint system allows for investigation of neural activity and connectivity without confounds from sedation or anesthesia. Its open-source, modular design supports behavioral tasks and broad accessibility, making it a valuable tool for neuroscience research seeking to bridge the gap between preclinical imaging and real-world brain function.

neuroscience↗

bioRxiv2025

Microglial morphology reflects cognitive status in the aging rat brain

Age-related cognitive decline affects millions of individuals worldwide, but the cellular mechanisms underlying this decline remain incompletely understood. Microglia undergo significant changes with aging, including alterations in morphology, that may reflect or contribute to cognitive dysfunction. However, the relationship between specific microglial morphologies and cognitive performance in relevant brain regions remains poorly understood. To address this, we evaluated the relationship between morphology-based microglial phenotypes and cognitive performance across domains affected by aging. Microglial morphology was analyzed in four cognitive brain regions of male and female 3-, 9-, and 15-month-old rats and features were subjected to hierarchical clustering on principal components to identify microglial subtypes. Rats underwent cognitive testing using a radial arm water maze and a T-maze set-shifting task to assess spatial working and reference memory, striatal-based learning, and cognitive flexibility. We observed age-related cognitive impairments alongside region-specific changes in microglial morphotype abundance. Importantly, the relative abundance of distinct microglial clusters correlated with cognitive performance in functionally relevant brain regions including the prefrontal cortex, the orbitofrontal cortex, and the hippocampus. Taken together, these findings highlight the utility of morphological profiling in capturing microglial heterogeneity and suggest that morphological changes may reflect or contribute to cognitive decline during aging.

neuroscience↗

bioRxiv2025

Hypothalamic recurrent inhibition regulates functional states of stress effector neurons.

Stress triggers rapid and reversible shifts in vital physiological functions from homeostatic operation to emergency response. However, the neural mechanisms regulating such functional stress states remain poorly understood. Here we identify a novel recurrent inhibitory circuit governing functional states of key stress regulatory neurons: corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). Microendoscopic calcium imaging in freely behaving mice revealed synchronized low-activity state at baselines and a reversible high-activity state during mild stress. Ensemble analysis indicated increased dimensionality of network dynamics during high-activity state. Computational modeling of calcium ensemble data, together with independent modeling of single-unit CRHPVN neurons spiking dynamics, converged to show that recurrent inhibition is a key circuit motif for stress-induced functional state transitions. Guided by model predictions, chemogenetic manipulations of PVN-projecting GABAergic neurons (PVN[->]GABA) revealed their roles in constraining CRHPVN neurons to low-activity state at baselines via a prolonged feedback inhibition. Unexpectedly, slow CRHergic excitation was dispensable for driving this prolonged feedback, whereas glutamatergic transmission predominated at CRH[->]PVN[->]GABA excitatory synapses. Incorporating these findings, we refined our computational model to include fast excitation and slow inhibition, yielding new predictions for circuit operation. Together, our results establish recurrent inhibition as a fundamental circuit motif controlling CRHPVN neurons functional states and highlight the value of iterative experiment-model integration in advancing understanding of neural circuits functions.

neuroscience↗

bioRxiv2025

Increased circulating TREM2+ microglia extracellular vesicles in aged APP/PS1 Alzheimer's disease rats

INTRODUCTIONTREM2 is a microglial marker important in Alzheimers disease (AD) pathogenesis, but current methods to detect microglial TREM2 expression in vivo are limited. Circulating microglia-derived extracellular vesicles (EVs) show promise as potential biomarkers for AD and may offer insight into TREM2 activity. METHODSTMEM119+/TREM2+ EVs were assessed using nanoscale flow cytometry in plasma from wildtype and APP/PS1 rats aged to 3-, 9-, and 15-months-old. Molecular and histological assays were used to assess microglia markers in rat brain tissue and a radial arm water maze task was employed to evaluate spatial working and reference memory. RESULTSCirculating TMEM119+/TREM2+ EVs were increased in 15-month APP/PS1 rats and associated with severity of cognitive impairment. TREM2 brain expression varied by anatomical region, age, transgene, and assay. DISCUSSIONCollectively, this study provides the first assessment of TMEM119+/TREM2+ EVs as a biomarker of brain microglial expression and cognition in an AD rat model.

neuroscience↗

bioRxiv2025

Prefrontal parvalbumin neurons as a target for enhancing cognition in non-pathological and 22q11.2 microdeletion syndrome mice

A failure of organized communication in the PFC is thought to contribute to the emergence of cognitive impairments in psychiatric diseases, with attentional deficits occurring as a fundamental symptom across various conditions. The 22q11.2 microdeletion syndrome is a rare genetic condition that confers a high risk for developing psychiatric and neurodevelopmental disorders, and mouse models have been shown to display attention impairments and PFC pathology that are relevant to clinical populations. Abnormalities in prefrontal parvalbumin-expressing neurons (PVNs) are part of the observed pathophysiology, and studies in rodents have shown that the direct manipulation of these cells can induce behavioral deficits that align with the cognitive symptoms observed in psychiatric diseases. In the present study, we expanded on the role of PVNs in supporting cognition by investigating their involvement in multiple aspects of attentional functions using a translationally relevant task of focused visual attention, in both non-pathological mice and a model of the 22q11.2 microdeletion syndrome. We observed that task-evoked prefrontal PVN activity was reduced in mice that exhibited poorer attention and in 22q11.2 mutant mice. While PVN activity was shaped across learning in non-pathological mice, mutant mice exhibited a lack of signal dynamics that coincided with attentional deficits. Importantly, we observed that task performance in both poor performing wild-types and 22q11.2 mutants could be alleviated by gamma frequency stimulation of PVNs. Thus, PVNs appear to be involved in the acquisition of task rules and execution of attention and continue to be a promising therapeutic target for cognitive dysfunction in disease.

neuroscience↗

bioRxiv2022

State-dependent activity dynamics of hypothalamic stress effector neurons

The stress response necessitates an immediate boost in vital physiological functions from their homeostatic operation to elevated emergency response. However, neural mechanisms underlying this state-dependent change remain largely unknown. Using a combination of in vivo and ex vivo electrophysiology with computational modeling, we report that corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), the effector neurons of hormonal stress response, rapidly transition between distinct activity states through recurrent inhibition. Specifically, in vivo optrode recording shows that under non-stress conditions, CRHPVN neurons often fire with rhythmic brief bursts (RB), which, somewhat counterintuitively, constrains firing rate due to long ([~]2 s) inter-burst intervals. Stressful stimuli rapidly switch RB to continuous single spiking (SS), permitting a large increase in firing rate. A spiking network model shows that recurrent inhibition can control this activity-state switch, and more broadly the gain of spiking responses to excitatory inputs. In biological CRHPVN neurons ex vivo, the injection of whole-cell currents derived from our computational model recreates the in vivo-like switch between RB and SS, providing a direct evidence that physiologically relevant network inputs enable state-dependent computation in single neurons. Together, we present a novel mechanism for state-dependent activity dynamics in CRHPVN neurons.

neuroscience↗

bioRxiv2018

Dynamics of spontaneous alpha activity correlate with language ability in young children

Early childhood is a period of tremendous growth in both language ability and brain maturation. To understand the dynamic interplay between neural activity and spoken language development, we used resting-state EEG recordings to explore the relation between alpha oscillations (7-10 Hz) and oral language ability in 4- to 6-year-old children with typical development (N=41). Three properties of alpha oscillations were investigated: a) alpha power using spectral analysis, b) flexibility of the alpha frequency quantified via the oscillation's moment-to-moment fluctuations, and c) scaling behavior of the alpha oscillator investigated via the long-range temporal correlation in the alpha-amplitude time course. All three properties of the alpha oscillator correlated with children's oral language abilities. Higher language scores were correlated with lower alpha power, greater flexibility of the alpha frequency, and longer temporal correlations in the alpha-amplitude time course. Our findings demonstrate a cognitive role of several properties of the alpha oscillator that has largely been overlooked in the literature.

neuroscience↗