Biology subjects

Raghuraman, R.

Publications and source records attributed to Raghuraman, R..

3 recordsLinked to original sources

bioRxiv2024

Tau load in select brainstem neurons predicts the severity and nature of balance deficits in the absence of cell death

Patients with tauopathies present with profoundly different clinical symptoms1, even within the same disorder2. A central hypothesis in the field, well-supported by biomarker studies3,4 and post-mortem pathology5-7, is that clinical heterogeneity reflects differential degeneration of vulnerable neuronal populations responsible for specific neurological functions. Recent work has revealed mechanisms underlying susceptibility of particular cell types8-10, but relating tau load to disrupted behavior -- es- pecially before cell death -- requires a targeted circuit-level approach. Here we studied two distinct balance behaviors in larval zebrafish11 expressing a human 0N/4R-tau allele12 in select populations of evolutionarily-conserved and well-characterized brainstem vestibular circuits13,14. We observed that human tau load predicted the severity of circuit-specific deficits in posture and navigation in the ab- sence of cell death. Targeting expression to either mid- or hindbrain balance neurons recapitulated these particular deficits in posture and navigation. By parametrically linking tau load in specific neu- rons to early behavioral deficits, our work moves beyond cell type to close the gap between pathological and neurological conceptions of tauopathy.

neuroscience↗

bioRxiv2024

Lateral Entorhinal Cortex Dysfunction in Alzheimers Disease Mice

In Alzheimers disease (AD), the formation of amyloid beta (A{beta}) and neurofibrillary tangles (NFTs) leads to neuronal loss in entorhinal cortex (EC), a crucial brain region for memory and navigation. These pathological changes are concurrent with the onset of memory impairments in AD patients with symptoms of forgetfulness such as misplacing items, disorientation in familiar environments etc. The lateral EC (LEC) is associated with non-spatial memory processing including object recognition. Since some LEC neurons fire in response to objects (object cells) while others fire at locations previously occupied by objects (trace cells), pathology in this region could lead to dysfunction in object-location coding. In this paper we show that a transgenic AD mouse model, EC-App/Tau, which expresses both APP and tau primarily in the EC region, have deficits in LEC-specific memory tasks. Using in vivo single-unit electrophysiology recordings we show that LEC neurons are hyperactive with low information content and high sparsity compared to the controls indicating poor firing fidelity. We finally show that object cells and trace cells fire less precisely in the EC-App/Tau mice compared to controls indicating poor encoding of objects. Overall, we show that AD pathology causes erratic firing of LEC neurons and object coding defects leading to LEC-specific memory impairment.

neuroscience↗

bioRxiv2022

Imaging the structure and dynamic activity of retinal microglia and macrophage-like cells in the living human eye

PurposeWe recently showed how a refined sequential detection pattern and image processing pipeline for multi-offset adaptive optics scanning light ophthalmoscopy (AOSLO) can increase the contrast of weakly scattering inner retinal structures, including microglia. However, sequential detection was still time-consuming, preventing dynamics from being monitored over short intervals (< 3 mins). Here we show that simultaneous fiber-bundle (FB) detection can overcomes this limitation to reveal the structure and dynamic activity of microglia and macrophage-like cells in healthy and diseased retinae. MethodsWe designed and implemented a custom 7-fiber optical FB with one central confocal fiber and six larger fibers for multi-offset detection in AOSLO at a single focal plane. We imaged the ganglion cell layer at several locations at multiple timepoints (from minutes to weeks) in 8 healthy participants and in 4 patients with ocular infections or inflammation, including ocular syphilis and posterior uveitis. Microglia and immune cells were manually segmented to quantify cell morphometry and motility. ResultsFiber-bundle detection reduced single acquisition time to 20-30 seconds, enabling imaging over larger areas and monitoring of dynamics over shorter intervals. Presumed microglia in healthy retinas had an average diameter of 12.8 m and with a spectrum of morphologies including circular cells and elongated cells with visible processes. We also detected the somas of putative macroglia, potentially astrocytes, near the optic nerve head. Microglia moved slowly in normal eyes (0.02m/sec, on average) but speed increased in patients with active infections or inflammation (up to 2.37m/sec). Microglia activity was absent in a patient with chronic uveitis that was quiescent but apparent over short intervals in an active uveitis retina. In a patient with ocular syphilis imaged at multiple timepoints during treatment, macrophage-like cells containing granular internal structures were seen. Decreases in the quantity and motility of these immune cells were correlated with improvements to vision and other structural and systemic biomarkers. ConclusionsFB-AOSLO enable simplified optical setup with easy alignment and implementation. We imaged the fine-scale structure and dynamics of microglia and macrophage-like cells during active infection and inflammation in the living eye for the first time. In healthy eyes we also detected putative glia cell near the optic nerve head. FB-AOSLO offers promise as a powerful tool for detecting and monitoring retinal inflammation and infection in the living eye over short response to treatment.

bioengineering↗