Biology subjects

Dearborn, J. T.

Publications and source records attributed to Dearborn, J. T..

6 recordsLinked to original sources

bioRxiv2026

Intrastriatal injection of amplified Lewy body dementia (LBD) fibrils in mice results in accumulation of fibrils with LBD structure and neurodegeneration

The defining neuropathologic feature of Lewy body dementia (LBD) and Parkinson's disease (PD) is alpha-synuclein (Asyn) fibril accumulation in Lewy bodies (LBs) and Lewy neurites (LNs). Recently, we developed a method to amplify Asyn fibrils derived from human post-mortem LBD brain tissue and determined that the structure of amplified Asyn fibrils is highly similar to the structure of fibrils directly isolated from LBD brain tissue. We examined whether injection of these fibrils into humanized Asyn mice recapitulates pathologic Asyn fibril accumulation with human LBD Asyn fibril structure. We utilized mice containing a null allele in the mouse Snca gene and a human SNCA transgene. Intrastriatal injection of amplified Asyn fibrils derived from 3 different LBD autopsy cases resulted in cytoplasmic and neuritic phospho-Asyn accumulation in the striatum, cortex, and amygdala bilaterally at 3mpi. Fibril injections produced a reduction in the number of dopaminergic neurons in the substantia nigra, with LB-like inclusions in surviving neurons, and produced impaired sensorimotor function as measured on the accelerating rotarod test. Fibril accumulation increased 3.6-fold between 1 and 3 months post-injection (mpi) and was relatively stable between 3 and 5 mpi. We amplified fibrils from mouse brain tissue 5 mpi and collected single-particle cryo-EM data. High resolution 3D structural information could not be obtained because of the lack of helical twist, but comparison of the cryo-EM 2D class averages with those derived from amplified fibrils prepared from human LBD tissue revealed multiple matching classes, indicating that the Lewy fold is maintained in the fibrils that accumulate in mouse brain tissue. Our findings demonstrate an approach to model the accumulation of Asyn fibrils with LBD structure in mice, providing a platform for investigating disease mechanisms, imaging biomarkers, and therapeutics targeting Asyn in PD/LBD.

neuroscience↗

bioRxiv2026

In vivo optical clearing of the mouse brain

Light microscopy is one of the most powerful tools for understanding living systems, but the opacity of tissue prevents visualization of all but superficial layers. Several methods to clarify tissue have been developed, but most require fixed specimens. To address the challenge of improving resolution in functioning neuronal circuits, we developed a biocompatible clearing agent, iodixanol-ACSF, which is capable of increasing the transparency of living neuronal tissue. Brain-cleared mice were motile and unimpaired on a variety of behavioral tasks, and extracellular recordings showed that many cellular and circuit phenomena were well-preserved. In live iodixanol-ACSF cleared mouse brain tissue, both transmission and cellular-resolution fluorescence microscopy indicate improvements of 150-200% in penetration depth with one-third to one-half the laser intensity when compared to untreated tissue. Our results show that iodixanol-ACSF clearing will enable deeper imaging and extend our understanding of neuronal circuit function.

neuroscience↗

bioRxiv2025

Chronic oral cannabidiol delays or prevents seizures in a mouse model of CLN2 disease

A growing body of literature describes the anti-inflammatory, neuroprotective, and anti-epileptic properties of the cannabis sativa constituent cannabidiol, suggesting that it might play a useful role in the treatment of neurodegenerative diseases. Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare pediatric neurodegenerative disorder resulting from an inherited dysfunction of the lysosome. CLN2 disease, and its representative animal models, display neuroimmune response, neuroinflammation, neurodegeneration, and epileptic seizures, and these symptoms are all touted as potential targets of cannabidiol therapeutic benefit. Here, we treated a valid model of CLN2 disease with long-term daily cannabidiol (300mg/kg) from 1 month of age until disease end stage and evaluated epileptic seizures, lifespan, and markers of neuroimmune response. Chronic cannabidiol treatment significantly delayed or fully eliminated seizures in CLN2 mice compared to those treated with vehicle only, and the treatment led to a nearly significant extension of lifespan. These effects occurred in the absence of any therapeutic benefit to physiological markers of disease such as GFAP, CD68, and cytokine/chemokine reactivity. Taken together, we show that chronic treatment with cannabidiol confers significant anti-seizure benefit to the mouse model of CLN2 disease, and that it does not appear to do so by altering the inflammatory and neuroimmune markers traditionally used to track CLN2 disease progression.

neuroscience↗

bioRxiv2022

Cortical interneuron loss and seizure generation as novel clinically relevant disease phenotypes in Cln2R207X mice

AimsCLN2 disease is a fatal inherited childhood neurodegenerative disorder. Although a disease-modifying therapy now exists, a fundamental lack of understanding of disease pathogenesis has hampered development of more effective therapies. To better understand the cellular pathophysiology of CLN2 disease, we investigated the nature and progression of neuropathological and neurological changes in the recently generated Cln2R207X mouse. MethodsWe have detailed microglial activation, astrogliosis, cytokine and chemokine expression, and neuron loss across the forebrain and spinal cords of Cln2R207X mice, along with quantitative gait analysis. We also performed long-term electroencephalography (EEG) recordings to characterize seizure activity, a clinically-relevant phenotype yet to be defined in any CLN2 disease model. ResultsHistology revealed early localized microglial activation months before neuron loss in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. These pathological changes were more pronounced and occurred in the cortex before the thalamus or spinal cord. There were early-onset and progressive changes in the expression of specific chemokines and cytokines including IL-33, IP-10, and MIP-1. Gait analysis revealed impaired performance only at disease end stage. EEG recordings revealed robust and progressive epileptiform activity from disease mid-stage including spontaneous seizures, which were accompanied by a profound loss of cortical GABAergic interneurons. ConclusionsOur data reveal novel phenotypes in Cln2R207X mice that differ markedly in their timing and progression through the CNS from other NCL mouse models. Our findings provide new insights on CLN2 disease pathogenesis and clinically-relevant readouts for future therapeutic studies.

neuroscience↗

bioRxiv2022

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1-/-) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1-/- mice compared to normal animals. Cln1-/- mice received an oral dose (100mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency.

neuroscience↗

bioRxiv2020

A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral anomalies including hyperactivity, muscle weakness and fatigue, and social alterations with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

neuroscience↗