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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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Molecular Properties And Transport Mechanism Of Vesicular Nucleotide Transporter (VNUT)

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Dr. Rishabh Pathak

The Vesicular Nucleotide Transporter (VNUT), also known as SLC17A9, is a transmembrane protein responsible for packaging nucleotides, particularly ATP, into synaptic vesicles for release as neurotransmitters. Here is an overview of the molecular properties and transport mechanism of VNUT:


1.      Molecular Properties:

o    Gene and Protein Structure: The VNUT gene, SLC17A9, encodes the VNUT protein, a member of the SLC17 transporter family. VNUT is a transmembrane protein with 12 transmembrane domains and cytoplasmic N- and C-termini.

o    Subcellular Localization: VNUT is primarily localized to synaptic vesicles in neurons and secretory vesicles in other cell types, where it facilitates the packaging of nucleotides for vesicular release.

2.     Transport Mechanism:

o Substrate Specificity: VNUT is selective for nucleotides, with a preference for ATP as the primary substrate for vesicular packaging. It can also transport other nucleotides like ADP and UTP.

oProton Coupling: VNUT operates through a proton-coupled transport mechanism, where the uptake of nucleotides into vesicles is coupled to the electrochemical gradient of protons across the vesicular membrane.

o Vesicular Acidification: The acidic pH inside synaptic vesicles created by the vesicular H+-ATPase is essential for the transport activity of VNUT, as it drives the nucleotide uptake process.

3.     Regulation:

o pH Sensitivity: VNUT activity is sensitive to changes in vesicular pH, with optimal transport efficiency observed under acidic conditions typical of synaptic vesicles.

o Modulation by Cations: Cations like calcium (Ca2+) and zinc (Zn2+) can modulate VNUT activity, potentially influencing nucleotide loading and synaptic vesicle release.

4.    Physiological Functions:

o Neurotransmission: VNUT plays a crucial role in purinergic neurotransmission by packaging ATP into synaptic vesicles for release as a neurotransmitter or a co-transmitter with classical neurotransmitters like glutamate.

o Synaptic Plasticity: ATP release via VNUT-mediated vesicular exocytosis can modulate synaptic transmission, plasticity, and neuronal excitability, contributing to various physiological processes in the nervous system.

5.     Pathophysiological Implications:

o Neurological Disorders: Dysregulation of VNUT function and purinergic signaling has been implicated in neurological disorders such as chronic pain, epilepsy, and neurodegenerative diseases, highlighting VNUT as a potential therapeutic target.

o  Immune Responses: Extracellular ATP released through VNUT-mediated vesicular exocytosis can also modulate immune responses, inflammation, and the activation of immune cells in the brain and periphery.

Understanding the molecular properties and transport mechanism of VNUT provides insights into the fundamental processes of nucleotide packaging and release in synaptic vesicles, with implications for neurotransmission, synaptic function, and the pathophysiology of neurological and immune-related disorders. Further research on VNUT regulation and its role in health and disease may uncover novel therapeutic strategies targeting purinergic signaling pathways.

 

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