Biology subjects

Arefin, T. M.

Publications and source records attributed to Arefin, T. M..

9 recordsLinked to original sources

bioRxiv2026

Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the most common form of central nervous system (CNS) injury and is often characterized by persistent neuroinflammation, metabolic dysregulation, and oxidative stress. Repetitive injuries compound these pathologies and lead to multifocal axonal injuries and long-term functional deficits. Despite the prevalence of mTBIs, the cellular mechanisms that facilitate or prevent recovery following injury remain poorly defined. Here, we extend our previous work on the role of the protein transglutaminase 2 (TG2) in CNS injury and we hypothesize that transcriptional regulation by TG2 restricts metabolic versatility in astrocytes following TBI, thereby impairing neuronal energetic support and worsening pathological outcomes. We utilized an established weight-drop model of repetitive mTBI followed by multi-parametric analysis of TBI pathology in complete TG2 knockout (TG2-/-) and wild type mice. At 28 days post-injury, TG2-/- mice showed marked attenuation of TBI pathology, compared to wild type mice, in vulnerable white matter and default mode network (DMN) regions, as assessed by diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and immunohistochemistry. Integrated epigenomic, proteomic, and metabolomic profiling of cortical astrocytes isolated 28 days after injury revealed a pronounced metabolic restriction in wild type astrocytes which was remarkably attenuated in the TG2-/- mice. This rescue was associated with a de-repression of gene networks involved in glutamate recycling, lipid metabolism, and metabolic homeostasis. Together, these studies provide novel mechanistic insights into the metabolic dysregulation that characterizes persistent TBI pathology, and establish a foundation for evaluating TG2 as a therapeutic target for TBI.

neuroscience↗

bioRxiv2025

Non-invasive modulation of brain activity and behavior by transcranial radio frequency stimulation

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSAchieving non-invasive, targeted modulation of deep brain tissue remains a major challenge in neurotechnology. Current non-invasive brain stimulation methods--such as transcranial electrical (TES), magnetic (TMS), and focused ultrasound (TFUS) stimulation--suffer from limitations in spatial focality, penetration depth, or skull-related distortions. Radio frequency (RF) energy, which penetrates biological tissue effectively, offers an alternative avenue for neural modulation. This study introduces Transcranial Radio Frequency Stimulation (TRFS) as a novel, contactless neuromodulation technique that leverages RF-induced thermal effects to modulate neural activity in vivo. MethodsWe developed a custom RF stimulation system using 945 MHz stub antennas optimized for localized brain heating in mice. Using our unique experimental setup, we developed and tested two operational modes of TRFS: Pristine mode: RF stimulation applied to intact brain tissue. RF-genetics mode: RF stimulation applied to brain regions virally transduced to overexpress the thermosensitive TRPV1 ion channel. Neural activity was recorded using metal-free one-photon fiber photometry with GCaMP calcium indicators. Behavioral effects were assessed through a rotational test in freely moving mice after MK-801-induced hyperlocomotion. Local temperature changes were monitored by optical thermometry. ResultsIn pristine mode, RF exposure induced temperature rises leading to dose-dependent suppression of cortical parvalbumin (PV) interneuron activity. This neural suppression translated behaviorally into a unilateral rotational bias ipsilateral to the stimulated hemisphere in hyperlocomotive freely moving mice. In RF-genetics mode, RF stimulation of TRPV1-overexpressing regions produced temperature-dependent excitation of neural activity once local change in temperatures exceeded {Delta}T {approx} 1.5 {degrees}C. Behaviorally, this excitation reversed the direction of rotation in hyperlocomotive freely moving mice, yielding a contralateral bias. ConclusionsTRFS represents a conceptual advance in neuromodulation, uniting the inherent capability of RF energy to target deep brain tissue with the biophysical reliability of thermal modulation. TRFS applications are bimodal, capable of influencing the pristine brain by suppressing the activity of specific neuronal populations in targeted regions, or of exciting selectively transfected neural ensembles expressing thermosensitive TRPV1 ion channels. The latter modality, first introduced here, represents a novel concept termed "RF-genetics." TRFS represents a promising platform for next-generation non-invasive brain stimulation with potential translational applications in treating various neurological and psychiatric disorders.

neuroscience↗

bioRxiv2025

Dissecting the strain and sex specific connectome signatures of unanesthetized C57BL/6J and DBA/2J mice using magnetic resonance imaging

Mouse models are an essential tool for understanding behavior and disease states in neuroscience research. While genetic and sex-specific effects have been reported in many neurodegenerative and psychiatric illnesses, these factors may also alter baseline neuroanatomical features of mice. This raises the question of whether the observed changes are related to the disease being studied (i.e., pathological differences) or if there are baseline strain or sex differences that may potentially predispose animals to different responses. Over the past decade, tremendous effort has been made in mapping neural architecture at various scales; however, the complex relationships including identifying genetic and sex-specific differences in brain structure and function remain understudied. To bridge this gap, we used C57BL/6J and DBA/2J mice, two of the most widely used inbred mouse strains in neuroscience research, to investigate strain and sex-specific features of the brain connectome in awake animals using magnetic resonance imaging (MRI). By combining resting-state fMRI and diffusion MRI, we found that the motor, sensory, limbic, and salience networks exhibit significant differences in both functional and structural domains between C57BL/6J and DBA/2J mice. Further, functional and structural properties of the brain were significantly correlated in both strains. Our results underscore the importance of considering these baseline differences when interpreting the brain-behavior interactions in mouse models of human disorders.

neuroscience↗

bioRxiv2024

Cerebellar output neurons impair non-motor behaviors by altering development of extracerebellar connectivity

The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the minimum requirement for these neurons is for motor coordination and not learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.

neuroscience↗

bioRxiv2023

Early Deprivation Impairs Perforant Pathway Connectivity and Contextual Memory in Adolescent Male Mice

Early-life adversity causes reduced hippocampal volume and abnormal hippocampal connectivity and function, with evidence indicating more prominent deficits in males compared to females. Reelin-positive projections from the lateral entorhinal cortex (LEC) to the dorsal hippocampus are essential for encoding contextual and semantic memories in diverse mammalian species, including humans and rodents. However, the impact of early-life adversity on these projections and their contribution to hippocampal-dependent deficits have not been reported. Using a modified limited bedding (LB) mouse model of early adversity that extends the impoverished conditions from birth to postnatal day 25 (P25), we found severe impairment in contextual fear conditioning for adolescent LB male but not LB female mice. Using retrograde tracing, we found that the number of reeling-positive projections from the LEC to the dorsal hippocampus is significantly reduced in LB males but not LB females. Further, the number of projections was highly correlated with deficits in contextual memory and hypomyelination in perforant pathway terminals located in the dorsal hippocampus. Ex vivo high-resolution diffusion magnetic resonance imaging confirmed reduced structural connectivity between the entorhinal cortex and the dorsal hippocampus and revealed extensive cortical atrophy that resembled abnormalities reported in children exposed to severe deprivation. Given the essential role that reelin-positive projections play in contextual memory, these findings suggest a novel mechanism to explain the pronounced contextual memory deficits seen in LB males.

neuroscience↗

bioRxiv2022

Towards reliable reconstruction of the mouse brain thalamocortical connectivity using diffusion MRI

Diffusion magnetic resonance imaging (dMRI) tractography has yielded intriguing insights into brain circuits and their relationship to behavior in response to gene mutations or neurological diseases across a number of species. Still, existing tractography approaches suffer from limited sensitivity and specificity, leading to uncertain interpretation of the reconstructed connections. Hence, in this study, we aimed to optimize the imaging and computational pipeline for reliable reconstruction of the mouse brain thalamocortical network. We developed a dMRI-based atlas of the mouse forebrain with structural labels imported from the Allen Mouse Brain Atlas (AMBA). Using the atlas and tracer data from the Allen Mouse Brain Connectivity Atlas (AMBCA) as ground truth, we investigated the accuracy of reconstructed node-to-node thalamocortical structural connectivity and effects of imaging and tractography parameters. Our results suggest that these parameters significantly affect tractography outcomes and our atlas can be used to investigate macroscopic structural connectivity in the mouse brain. Furthermore, tractography in mouse brain gray matter still face challenges and need improved imaging and tractography methods.

bioengineering↗

bioRxiv2022

Open-source versatile 3D-print animal conditioning platform design for in-vivo preclinical brain imaging in awake mice and anesthetized mice and rats

Proper animal conditioning is a key factor in the quality and success of preclinical neuroimaging applications. We introduce an open-source easy-to-modify multi-modal 3D printable design for rodent conditioning for magnetic resonance imaging (MRI) or other imaging modalities. Our design can be used for brain imaging in anesthetized or awake mice and anesthetized rats. We show ease-of-use and reproducibility of subject conditioning with anatomical T2-weighted imaging for both mice and rats. We also demonstrate application of our design for awake fMRI in mice using both visual evoked potential and olfactory stimulation paradigms. In addition, we demonstrate that our proposed cradle design can be extended to multiple imaging modalities combining MRI, Positron emission tomography and X-ray computed tomography.

neuroscience↗

bioRxiv2022

Deep Learning Guided Diffusion MRI Tractography in the Mouse Brain

Diffusion MRI (dMRI) tractography is the only tool for non-invasive mapping of macroscopic structural connectivity over the entire brain. Although it has been successfully used to reconstruct large white matter tracts in the human and animal brains, the sensitivity and specificity of dMRI tractography remained limited. Especially, the fiber orientation distributions (FODs) estimated from dMRI signals, key to tractography, may deviate from histologically measured fiber orientation in crossing fibers and gray matter regions. In this study, we demonstrated that a deep learning network, trained using mesoscopic tract-tracing data from the Allen Mouse Brain Connectivity Atlas, was able to improve the estimation of FODs from mouse brain dMRI data. Tractography results based on the network generated FODs showed improved specificity while maintaining sensitivity comparable to results based on FOD estimated using a conventional spherical deconvolution method. Our result is a proof-of-concept of how mesoscale tract-tracing data can guide dMRI tractography and enhance our ability to characterize brain connectivity.

bioengineering↗

bioRxiv2020

Inferring Maps of Cellular Structures from MRI Signals using Deep Learning

1H MRI maps brain structure and function non-invasively through versatile contrasts that exploit inhomogeneity in tissue micro-environments. Inferring histopathological information from MRI findings, however, remains challenging due to absence of direct links between MRI signals and cellular structures. Here, we show that deep convolutional neural networks, developed using co-registered multi-contrast MRI and histological data of the mouse brain, can estimate histological staining intensity directly from MRI signals at each pixel. The results provide three-dimensional maps of axons and myelin with tissue contrasts that closely mimics target histology and enhanced sensitivity and specificity compared to conventional MRI markers. Furthermore, the relative contribution of each MRI contrast within the networks can be used to optimize multi-contrast MRI acquisition. We anticipate our method to be a starting point for translation of MRI results into easy-to-understand virtual histology for neurobiologists and provide resources for validating novel MRI techniques.

bioengineering↗