a-dual-color-fiber-photometry-method-for-recording-astrocyte-neuron

A Dual-Color Fiber Photometry Method for Recording Astrocyte-Neuron Activity Across Multiple Brain Regions During Learning and Memory Behaviors

Learning and memory depend critically on the coordination between neurons and astrocytes across distributed brain regions. Astrocytes modulate synaptic ...

Guangxi University

Third Military Medical University

Histamine H receptor (HR) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although HR is elevated in Alzheimer's disease (AD) patients, whether HR antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved HR antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.

Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease.

 Alzheimer's disease (AD) is the most common dementia, characterized by significant cognitive impairments and neural network dysfunction. Currently, multiple therapeutic strategies are being developed to design effective anti-AD drugs. Among them, Withaferin A (WA), a natural steroidal lactone extracted from Withania somnifera leaves, has been shown to reduce amyloid-β (Aβ) peptide levels in vitro. However, its potential to improve cognitive function in AD remains unclear.  In this study, 5xFAD mice were administered WA (2 mg/kg intraperitoneally every 2 days) for 14 days, and its neuroprotective effects were evaluated through behavioral tests, wide-field imaging, immunohistochemistry, and ELISA.  WA significantly improved short-term memory, as evidenced by enhanced performance in the Novel Object Recognition Test (NORT) ( < 0.001,  = 10), Novel Location Recognition Test (NLRT) ( < 0.01,  = 14), and Three-Chamber Social Test (TCST) ( < 0.001,  = 8). WA also ameliorated long-term memory deficits in the Morris Water Maze Test (MWMT) ( < 0.05,  = 7). Furthermore, cortical wide-field Ca imaging revealed that WA treatment rescued slow-wave impairments by enhancing long-range coherence (0.8363 ± 0.0185,  < 0.01,  = 8) and reducing the frequency of slow-wave activity (0.6578 ± 0.0512 Hz,  < 0.01,  = 8). Additionally, WA treatment significantly reduced Aβ plaque deposition in both cortical and hippocampal regions.  These findings suggest that WA may be a promising therapeutic agent for AD, exerting neuroprotective effects.

Withaferin A Rescues Brain Network Dysfunction and Cognitive Deficits in a Mouse Model of Alzheimer's Disease.

Spatial exploration is fundamental to the construction of internal cognitive maps, yet the mechanisms underlying its fine-scale microstructural disruption in Alzheimer's disease (AD) remain elusive. The medial entorhinal cortex layer II (MECII) serves as a critical hub for spatial navigation, where norepinephrine (NE) signaling modulates astrocyte activity to shape neuronal network dynamics. In this study, we combined fine-grained behavioral quantification with simultaneous in vivo dual-color fiber photometry to investigate astrocyte-neuronal coupling in the MECII of APP/PS1 transgenic mice. We report that AD mice exhibit a distinct fragmented exploration phenotype, characterized by frequent but transient sniffing and rearing bouts, which coincides with a profound loss of temporal synchronization between MECII astrocytes and neurons. Notably, pharmacological activation of the noradrenergic axis using the highly selective α-adrenergic receptor (αAR) agonist A61603 successfully re-established astrocyte-neuronal network coupling across behavioral states. This intervention significantly ameliorated the fragmented exploration phenotype without altering general locomotor activity. These findings identify disrupted astrocyte-neuronal temporal coordination in the MECII as a pivotal physiological mechanism driving spatial exploration deficits in AD, suggesting that restoring αAR signaling represents a promising therapeutic strategy for early AD-related cognitive dysfunction.

α-adrenergic receptor activation ameliorates fragmented spatial exploration by improving astrocyte-neuronal coupling in the medial entorhinal cortex of Alzheimer's disease mice.

Article	Year
Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease. Translational psychiatry\| PubMed ID: 40185739	2025
Withaferin A Rescues Brain Network Dysfunction and Cognitive Deficits in a Mouse Model of Alzheimer's Disease. Pharmaceuticals (Basel, Switzerland)\| PubMed ID: 40573212	2025
α-adrenergic receptor activation ameliorates fragmented spatial exploration by improving astrocyte-neuronal coupling in the medial entorhinal cortex of Alzheimer's disease mice. Neurobiology of disease\| PubMed ID: 41997460	2026

Jihua Fan

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