Nazari, S. | bioRxiv Science

bioRxiv2025

Induction of Chimera States in Hindmarsh-Rose Neurons through Astrocytic Modulation: Implications for Learning Mechanisms

Chimera states, a form of partial synchronization in neural networks, are characterized by the coexistence of synchronized and asynchronous regions. These states are crucial for various cognitive functions, such as learning and information processing. Conversely, abnormal synchronization--often referred to as hyper-synchronization--can lead to pathological conditions such as epilepsy and Parkinsons disease. Understanding the mechanisms underlying synchronization can provide valuable insights for developing effective therapeutic strategies for these disorders. Astrocyte, a primary type of glial cell, plays a pivotal role in modulating neural synchrony. They influence the synchronization threshold of neurons by providing feedback through the release of gliotransmitters, promoting group firing of neurons within the astrocytes domain. This research aims to explore how astrocytes can facilitate the conversion of hyper-synchronized states into healthy chimera states within neural networks. This process is vital for maintaining normal brain function and may be critical to advancing treatments for neurological conditions. We analyzed how astrocytes can induce chimera states in nonlocally two-dimensional Hindmarsh-Rose neurons, which serve as realistic models of neuronal ensembles. Our findings demonstrate that astrocytes can effectively transition unhealthy hyper-synchronization states into healthy chimera states. Furthermore, by analyzing time spans, spatiotemporal patterns, inter-spike interval distributions (ISI), and phase plane diagrams of 2D H-R neurons, we validated our hypothesis about the crucial role of astrocytes in the development of chimera states. The outcomes may pave the way for innovative therapeutic approaches to restore normal neural activity patterns, ultimately improving patient outcomes in conditions such as epilepsy and Parkinsons disease.

neuroscience↗

bioRxiv2021

{-}Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease{-}

Gaucher disease (GD) is caused by the deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase), and the subsequent accumulation of its substrate, glucosylceramide substrate (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) lead to GCase misfolding and inhibiting the lysosomes proper trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway. GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes the GC biosynthesis, reducing a GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density. The effects of EGT and ABX on GCase activity and autophagy-lysosomal pathway (ALP) were assessed in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. While both compounds enhanced GCase activity in control cells, an individualized response was observed in cells from patients with GD2-3 that varied with GBA mutations. EGT and AMB enhanced the formation of lysosomal/ late endosomal compartments and autophagy, and this effect was independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of the mitochondrial function by activating the mitochondrial membrane potential. These results suggest that EGT and ABX may have different molecular mechanisms of action, but both enhance GCase activity, improve autophagy-lysosome dynamics and mitochondrial functions.

molecular biology↗