Biology subjects

Fassihi, A.

Publications and source records attributed to Fassihi, A..

3 recordsLinked to original sources

bioRxiv2024

Astrocyte transcriptomic analysis identifies glypican 5 downregulation as a contributor to synaptic dysfunction in Alzheimer disease models

Synaptic dysfunction is an early feature in Alzheimers disease (AD) and correlates with cognitive decline. Astrocytes are essential regulators of synapses, impacting synapse formation, maturation, elimination and function. To understand if synapse-supportive functions of astrocytes are altered in AD, we used astrocyte BacTRAP mice to generate a comprehensive dataset of hippocampal astrocyte transcriptional alterations in two mouse models of Alzheimers pathology (APPswe/PS1dE9 and Tau P301S), characterizing sex and age-dependent changes. We found that astrocytes from both models downregulate genes important for synapse regulation and function such as the synapse-maturation factor Glypican 5. This transcriptional signature is shared with human post-mortem AD patients. Manipulating a key component of this signature by in vivo overexpression of Glypican 5 in astrocytes is sufficient to prevent early synaptic dysfunction and improve spatial learning in APPswe/PS1dE9 mice. These findings open new avenues to target astrocytic factors to mitigate AD synaptic dysfunction.

neuroscience↗

bioRxiv2021

The sensory code within sense of time

Sensory experiences are accompanied by the perception of the passage of time; a cell phone vibration, for instance, is sensed as brief or long. The neuronal mechanisms underlying the perception of elapsed time remain unknown1. Recent work agrees on a role for cortical processing networks2,3, however the causal function of sensory cortex in time perception has not yet been specified. We hypothesize that the mechanisms for time perception are embedded within primary sensory cortex and are thus governed by the basic rules of sensory coding. By recording and optogenetically modulating neuronal activity in rat vibrissal somatosensory cortex, we find that the percept of stimulus duration is dilated and compressed by optogenetic excitation and inhibition, respectively, during stimulus delivery. A second set of rats judged the intensity of tactile stimuli; here, optogenetic excitation amplified the intensity percept, demonstrating sensory cortex to be the common gateway to both time and stimulus feature processing. The coding algorithms for sensory features are well established4-10. Guided by these algorithms, we formulated a 3-stage model beginning with the membrane currents evoked by vibrissal and optogenetic drive and culminating in the representation of perceived time; this model successfully replicated rats choices. Our finding that stimulus coding is intrinsic to sense of time disagrees with dedicated pacemaker-accumulator operation models11-13, where sensory input acts only to trigger the onset and offset of the timekeeping process. Time perception is thus as deeply intermeshed within the sensory processing pathway as is the sense of touch itself14,15 and can now be treated through the computational language of sensory coding. The model presented here readily generalizes to humans14,16 and opens up new approaches to understanding the time misperception at the core of numerous neurological conditions17,18.

neuroscience↗

bioRxiv2020

A sensory integration account for time perception

The connection between stimulus perception and time perception remains unknown. The present study combines human and rat psychophysics with sensory cortical neuronal firing to construct a computational model for the percept of elapsed time embedded within sense of touch. When subjects judged the duration of a vibration applied to the fingertip (human) or whiskers (rat), increasing stimulus mean speed led to increasing perceived duration. Symmetrically, increasing vibration duration led to increasing perceived intensity. We modeled spike trains from vibrissal somatosensory cortex as input to dual leaky integrators - an intensity integrator with short time constant and a duration integrator with long time constant - generating neurometric functions that replicated the actual psychophysical functions of rats. Returning to human psychophysics, we then confirmed specific predictions of the dual leaky integrator model. This study offers a framework, based on sensory coding and subsequent accumulation of sensory drive, to account for how a feeling of the passage of time accompanies the tactile sensory experience.

neuroscience↗