Biology subjects

Theint, A. T.

Publications and source records attributed to Theint, A. T..

3 recordsLinked to original sources

bioRxiv2025

Cortical α-synuclein pathology induces cell autonomous neuronal hypoactivity and compensatory circuit changes in a model of early Lewy Body Dementia

Posterior cortical impairments in visuospatial/perceptual function are common non-motor symptoms of the Lewy Body Dementias (LBD) and are relatively specific for LBDs compared to other dementias. Across populations, cognitive impairments correlate with the presence of -synuclein (-syn) pathology in limbic and neocortical brain regions. However, the specific role that -syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing -syn pathology in primary visual cortex (V1) in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this, we injected -syn pre-formed fibrils (PFF) into V1, causing the formation of sparse Lewy-like pathology. Using longitudinal in vivo two-photon (2P) calcium imaging over 6 months, we recorded visually evoked activity of pyramidal cells in layer 2/3 (L2/3) and quantified -syn pathology using C05-05, a fluorescent ligand that binds aggregated -syn. Measuring population activity, we found a greater percentage of neurons in PFF-injected mice were responsive to visual stimuli with lower direction selectivity compared to controls at 4-5 months post-injection (MPI). Neurons with somatic Lewy-like inclusions showed reduced activity compared to neighboring neurons without inclusions. Conversely, neurons without somatic inclusions showed increased activity, positively correlated with the local burden of -syn pathology. Using a coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice. Our results demonstrate that -syn pathology leads to reductions in neuronal activity in cells with somatic inclusions and reciprocal changes in local population activity but does not impair visuoperceptual function. Reflecting the early stages of neocortical -syn pathology, our model provides a framework for future studies to better understand the heterogeneity of cognitive symptoms and -syn pathology across patients.

neuroscience↗

bioRxiv2025

The Pesticide Chlorpyrifos Increases the Risk of Parkinson's Disease

Background and PurposePesticides have been associated with an increased risk of Parkinsons disease (PD), but it is unclear which specific pesticides contribute to this association and whether it is causal. Since chlorpyrifos (CPF) exposure has been implicated as a risk factor for PD, we investigated its association to incident PD and if this association is biologically plausible using human, rodent, and zebrafish (ZF) studies. MethodsThe association of CPF with PD was assessed using the UCLA PEG study (829 PD and 824 control subjects), and proximity-based exposure estimates from living or working near agricultural CPF use. For the mammalian studies, 6 months old male C57BL/6 mice were divided into two groups, CPF and controls, for open field, rotarod, and wire hang behavioral testing. Mice were then exposed to CPF in an inhalation chamber (0.65-2.9 mg/m3/day) for 6 hrs./day 5 days/wk., whereas control mice were exposed to vehicle alone. Behavioral tests were performed before and 2.5 months after CPF exposure following a 3-day washout. Mice were then perfused for immunohistochemical analysis. For the mechanistic studies, ZF embryos were treated with CPF (250 nM) 24 hours post fertilization for 5-7 days. Behavioral testing was performed using the Viewpoint Imaging System. Neuronal loss and microglial activation were determined using immunohistochemistry. Neuronal autophagic flux was determined using autophagy modulators in GFP-LC3 transgenic ZF and Western blots. ResultsLong-term residential CPF exposure was linked to an increased risk of developing PD with an odds ratio of 2.68 (CI 1.58-4.55). Mice exposed to aerosolized CPF developed motor impairment and a significant loss of dopaminergic neurons in the substantia nigra and activation of microglia. TH positive neurons in the substantia nigra (SN) had significantly higher levels of phosphoserine 129 (pS129) -synuclein (-syn), a marker for pathological phosphorylated -syn, and ubiquitin. In contrast, neither pS129 -syn or ubiquitin accumulated in TH neurons in the VTA after CPF exposure. Consistent with the mice data, CPF exposure resulted in impairment of locomotor activity and selective loss of aminergic neurons in ZF. We also found an increase in neuronal apoptosis and microglial activation. Importantly, dopamine neuron loss was found to be at least partially dependent on {gamma}1-synuclein (closest functional homologue to human -syn) as neuronal loss did not occur in {gamma}1-synuclein knockout ZF. Using an in vivo ZF assay, we found impaired autophagic flux and an increase in lysosomal labelling within the zebrafish brain. CPF exposure also led to elevated {gamma}1-synuclein and p62 (autophagic cargo protein) levels consistent with impaired degradation. Furthermore, induction of autophagy was protective, supporting the hypothesis that impaired autophagic flux is at least partially responsible for neuron loss following CPF exposure. ConclusionsCPF exposure is associated with an increased risk of developing PD and this association is likely causal since PD-like pathology was recapitulated in animal models. Furthermore, impaired autophagic flux appears to underly this toxicity, a pathway implicated in the pathogenesis of PD.

neuroscience↗

bioRxiv2022

High sensitivity intrinsic optical signal imaging through flexible, low-cost adaptations of an upright microscope

Intrinsic optical signal imaging (IOSI) is a staple technique in modern neuroscience. Pioneered over thirty years ago, IOSI allows macroscopic mapping of neuronal activity throughout the cortex. The technique has been used to study sensory processing and experience-dependent plasticity, and is often used as an adjunctive procedure to localize cortical areas for subsequent targeting by other imaging or physiology techniques. Despite the ubiquity of IOSI in neuroscience there are few commercially available IOSI systems. As a result, investigators have typically resorted to building their own imaging systems. Over the years, simplified systems built on existing microscope platforms have been proposed. Still, these often require additional, sometimes costly, custom-built hardware, which presents challenges for investigators without significant experience in optics or microscopy design. Here we present a straightforward set of adaptations that can be applied to any standard upright microscope, using readily available, inexpensive, commercial parts for illumination, optics, and signal detection, that enables high sensitivity IOSI. Using these adaptations, we are able to readily map sensory-evoked signals across the somatosensory and visual cortex, including single-whisker barrel cortical activity maps in mice. We show that these IOSI maps are highly reproducible across animals and can be used to study plasticity mechanisms in the somatosensory cortex. We also provide open-source applications to control illumination and analyze raw data to generate activity maps. We anticipate these resources will be particularly useful for neuroscience investigators from broad technical backgrounds looking to add IOSI capabilities to an existing microscope on a budget.

neuroscience↗