Biology subjects

Hike, D.

Publications and source records attributed to Hike, D..

5 recordsLinked to original sources

bioRxiv2024

Ongoing loss of viable neurons for weeks after mild perinatal hypoxia-ischemia

Mild hypoxic-ischemic encephalopathy is common in neonates with no evidence-based therapies, and 30-40% of patients experience adverse outcomes. The nature and progression of mild injury is poorly understood. Thus, we studied the evolution of mild perinatal brain injury using longitudinal two-photon imaging of transgenic fluorescent proteins as a novel readout of neuronal viability and activity at cellular resolution. In vitro, perinatal murine organotypic hippocampal cultures underwent 15-20 minutes of oxygen-glucose deprivation. In vivo, mild hypoxia-ischemia was completed in post-natal day 10 mouse pups of both sexes with carotid ligation and 15 minutes of hypoxia. Consistent with a mild injury, minimal immediate neuronal death was seen and there was no volumetric evidence of injury by ex vivo MRI 2.5 weeks after injury. In both the hippocampus and neocortex, these mild injuries resulted in a significantly delayed and progressive neuronal loss in the second week after injury, measured by fluorophore quenching. Mild hypoxia-ischemia transiently suppressed cortical network activity followed by normal maturation. No post-injury seizures were seen. The participation in network activity of individual neurons destined to die was indistinguishable from those that survived for 4 days post-injury. In conclusion, our results showed that mild perinatal brain injury resulted in a prolonged increase of neuronal death. Neurons that died late were functioning normally for days after injury, suggesting a new pathophysiology of neuronal death. Critically, the neurons destined to die late demonstrated multiple biomarkers of viability long after mild injury, suggesting their later death may be modified with neuroprotective interventions. SIGNIFICANCE STATEMENTNeonatal encephalopathy due to peripartum hypoxia-ischemia (HI) is a major cause of neonatal mortality and morbidity worldwide. Of these infants, most are categorized as having mild HI. Infants with mild HI have significant long-term disabilities. There are currently no evidence-based therapies, largely because the progression and pathophysiology of mild injury is poorly understood. We have identified, for the first time, that mild perinatal HI results in a delayed and prolonged increase in neuronal death. The cortical and hippocampal neurons that die over a week after injury participate normally in neural network activity and exhibit robust viability for many days after injury, indicating a novel pathophysiology of neuronal death. Clinically, these data suggest an extended therapeutic window for mild perinatal HI.

neuroscience↗

bioRxiv2024

Mapping the Cerebrovascular Abnormality in Transgenic Alzheimer's Disease (AD) Mice with deep-learning-based super-resolution cerebral blood volume (CBV)-MRI

To measure the brain-wide vascular density (VD) alteration in degenerated brains with Alzheimers Disease (AD), deep learning-based super-resolution approach was developed to assist the segmentation of micro-vessels from the Monocrystalline Iron Oxide Nanoparticle (MION)-based CBV MRI images of transgenic mouse brains. Iron-induced T2* amplification effect well separated micro-vessels with tens of microns from capillary-enriched parenchyma voxels, enabling vascular compartment-specific VD differential analysis between AD and wildtype control mice. The differential maps based on segmented micro-vessels identified decreased VD in the anterior cingulate cortex (ACC) and medial entorhinal cortex (mEC) and increased VD in several highlighted brain regions, including dentate gyrus (DG) of the hippocampus, central and geniculate thalamus, medial septal area (MS), ventral tegmental area (VTA), and lateral entorhinal cortex (lEC). In contrast, the T2*-weighted capillary density mapping from parenchyma voxels showed increased VD in several cortical regions, including somatosensory and visual cortex, retrosplenial cortex, as well as piriform area and lEC in AD brains. However, dramatic capillary VD decrease was observed in the subcortical areas including hippocampus, thalamus, hypothalamus, and pontine areas. These high-resolution MION-based CBV MRI elucidates altered vascular compartments in degenerated AD brains, reconciling the various region-specific vascular impairment and angiogenesis in functional areas critical for cognitive decline of AD.

neuroscience↗

bioRxiv2023

Mapping the bioimaging marker of Alzheimer's disease based on pupillary light response-driven brain-wide fMRI in awake mice

Pupil dynamics has emerged as a critical non-invasive indicator of brain state changes. In particular, pupillary-light-responses (PLR) in Alzheimers disease (AD) patients may be used as biomarkers of brain degeneration. To characterize AD-specific PLR and its underlying neuromodulatory sources, we combined high-resolution awake mouse fMRI with real-time pupillometry to map brain-wide event-related correlation patterns based on illumination-driven pupil constriction (Pc) and post-illumination pupil dilation recovery (amplitude, Pd, and time, T). The Pc-driven differential analysis revealed altered visual signal processing coupled with reduced thalamocortical activation in AD mice compared with the wild-type normal mice. In contrast, the post-illumination pupil dilation recovery-based fMRI highlighted multiple brain areas related to AD brain degeneration, including the cingulate cortex, hippocampus, septal area of the basal forebrain, medial raphe nucleus, and pontine reticular nuclei (PRN). Also, brain-wide functional connectivity analysis highlighted the most significant changes in PRN of AD mice, which serves as the major subcortical relay nuclei underlying oculomotor function. This work combined non-invasive pupil-fMRI measurements in preclinical models to identify pupillary biomarkers based on neuromodulatory dysfunction coupled with AD brain degeneration.

neuroscience↗

bioRxiv2023

High-resolution awake mouse fMRI at 14 Tesla

High-resolution awake mouse fMRI remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radiofrequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Furthermore, this study provides a thorough acclimation method used to accustom animals to the MRI environment minimizing motion induced artifacts. Using a 14T scanner, high-resolution fMRI enabled brain- wide functional mapping of visual and vibrissa stimulation at 100x100x200{micro}m resolution with a 2s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust BOLD responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 seconds prior to the air-puff in awake mice with repetitive stimulation, which was not detected using a randomized stimulation paradigm. This early BC activation indicated a learned anticipation through the vibrissa system and association cortices in awake mice under continuous training of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas. Significance StatementThis awake mouse fMRI platform was developed by implementing an advanced implantable radiofrequency (RF) coil scheme, which simultaneously served as a headpost to secure the mouse head during scanning. A thorough acclimation method was used to accustom animals to the MRI environment minimizing motion induced artifacts. The ultra-high spatial resolution (100x100x200{micro}m) BOLD fMRI enabled the brain-wide mapping of activated visual and vibrissa systems during sensory stimulation in awake mice, including association cortices, e.g. anterior cingulate cortex and retrosplenial cortex, for high order sensory processing. Also, the activation of barrel cortex at 2 s prior to the air-puff indicated a learned anticipation of awake mice under continuous training of the repetitive vibrissa stimulation.

neuroscience↗

bioRxiv2023

Alpha-180 spin-echo based line-scanning method for high resolution laminar-specific fMRI

Laminar-specific functional magnetic resonance imaging (fMRI) has been widely used to study circuit-specific neuronal activity by mapping spatiotemporal fMRI response patterns across cortical layers. Hemodynamic responses reflect indirect neuronal activity given limit of spatial and temporal resolution. Previous gradient-echo based line-scanning fMRI (GELINE) method was proposed with high temporal (50 ms) and spatial (50 {micro}m) resolution to better characterize the fMRI onset time across cortical layers by employing 2 saturation RF pulses. However, the imperfect RF saturation performance led to poor boundary definition of the reduced region of interest (ROI) and aliasing problems outside of the ROI. Here, we propose (alpha)-180 spin-echo-based line-scanning fMRI (SELINE) method to resolve this issue by employing a refocusing 180{degrees} RF pulse perpendicular to the excitation slice. In contrast to GELINE signals peaked at the superficial layer, we detected varied peaks of laminar-specific BOLD signals across deeper cortical layers with the SELINE method, indicating the well-defined exclusion of the large drain-vein effect with the spin-echo sequence. Furthermore, we applied the SELINE method with 200 ms TR to sample the fast hemodynamic changes across cortical layers with a less draining vein effect. In summary, this SELINE method provides a novel acquisition scheme to identify microvascular-sensitive laminar-specific BOLD responses across cortical depth.

neuroscience↗