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Unveiling Hidden Neural Codes: SIMPL – A Scalable and Fast Approach for Optimizing Latent Variables and Tuning Curves in Neural Population Data

Dr. Rishabh Pathak
This research paper presents SIMPL (Scalable Iterative Maximization of Population-coded Latents), a novel, computationally efficient algorithm designed to refine the estimation of latent variables and tuning curves from neural population activity. Latent variables in neural data represent essential low-dimensional quantities encoding behavioral or cognitive states, which neuroscientists seek to identify to understand brain computations better. Background and Motivation Traditional approaches commonly assume the observed behavioral variable as the latent neural code. However, this assumption can lead to inaccuracies because neural activity sometimes encodes internal cognitive states differing subtly from observable behavior (e.g., anticipation, mental simulation). Existing latent variable models face challenges such as high computational cost, poor scalability to large datasets, limited expressiveness of tuning models, or difficulties interpreting complex neural network-based functio...
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Endoplasmic Reticulum Stress Is Associated with A Synucleinopathy in Transgenic Mouse Model

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Dr. Rishabh Pathak

In a transgenic mouse model of a-synucleinopathy, endoplasmic reticulum (ER) stress has been implicated as a key pathological mechanism associated with the accumulation of a-synuclein aggregates. Here are the key points related to ER stress and a-synucleinopathy in the context of the transgenic mouse model:


1.      Transgenic Mouse Model of a-Synucleinopathy:

o    Transgenic mouse models expressing human a-synuclein have been developed to study the pathogenesis of synucleinopathies, including Parkinson's disease and related disorders characterized by the accumulation of a-synuclein aggregates.

2.     Endoplasmic Reticulum Stress and a-Synucleinopathy:

o    ER Stress Induced by a-Synuclein Aggregates: Accumulation of misfolded proteins, such as a-synuclein aggregates, can trigger ER stress, leading to the activation of the unfolded protein response (UPR) in cells. ER stress is a cellular condition caused by the accumulation of misfolded proteins, altered calcium homeostasis, and impaired proteasomal activity.

o    Implications of ER Stress in a-Synucleinopathy: In the context of a-synucleinopathy, ER stress may contribute to neuronal dysfunction and degeneration by disrupting protein homeostasis, impairing cellular functions, and promoting cell death pathways. The presence of a-synuclein aggregates in the ER may exacerbate ER stress and cellular toxicity.

3.     Pathological Consequences:

o    Neuronal Degeneration: Prolonged ER stress and UPR activation in response to a-synuclein aggregation can lead to neuronal dysfunction and degeneration, contributing to the progression of a-synucleinopathies. ER stress-induced cell death pathways may exacerbate neurodegeneration in the context of a-synuclein pathology.

o    Protein Misfolding and Aggregation: The presence of misfolded a-synuclein proteins in the ER lumen can disrupt ER function, impair protein folding processes, and promote the formation of toxic protein aggregates. ER stress-induced dysfunction may further exacerbate a-synuclein aggregation and cellular toxicity.

4.    Therapeutic Implications:

o    Targeting ER Stress: Strategies aimed at alleviating ER stress and restoring ER homeostasis may have therapeutic potential for mitigating the pathological consequences of a-synucleinopathy in neurodegenerative disorders. Modulating ER stress responses and enhancing protein quality control mechanisms could help protect neurons from ER stress-induced damage.

In summary, in a transgenic mouse model of a-synucleinopathy, endoplasmic reticulum stress is associated with the accumulation of a-synuclein aggregates and neuronal dysfunction. Understanding the interplay between ER stress, protein misfolding, and neurodegeneration in the context of a-synucleinopathies is crucial for developing targeted therapeutic interventions aimed at preserving ER function, mitigating protein aggregation, and protecting neurons from ER stress-induced toxicity. Further research into the mechanisms linking ER stress to a-synucleinopathy will advance our understanding of disease pathogenesis and guide the development of novel strategies for treating synucleinopathies and related neurodegenerative disorders.

 

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