INSIGHT of medicine(phase 25, 2024)

1.The ventromedial prefrontal cortex in response to threat omission is associated with subsequent explicit safety memory

DOI: 10.1038/s41598-024-57432-0

https://www.nature.com/articles/s41598-024-57432-0

In a study using fMRI, researchers investigated how the brain processes threat and safety cues. Participants viewed faces paired with either aversive stimuli or safety. When they later remembered associations, the hippocampus was more active. The ventromedial prefrontal cortex was linked to remembering safe associations, while the dorsolateral prefrontal cortex related to outcome processing. Notably, when no threat occurred, the medial prefrontal cortex showed extended activity, suggesting it helps integrate sensory information with memory. Visual and somatosensory cortex activity, along with the inferior frontal gyrus, predicted memory performance a week later. These findings highlight the collaboration between prefrontal and sensory areas in forming declarative safety memory, emphasizing the brain's intricate processing of threatening and safe stimuli.

2.Kir4.1 channels contribute to astrocyte CO2/H+-sensitivity and the drive to breathe

DOI: 10.1038/s42003-024-06065-0

https://www.nature.com/articles/s42003-024-06065-0

Astrocytes in the retrotrapezoid nucleus (RTN) play a role in breathing regulation in response to CO2/H⁺, but it's unclear how they sense these changes. Kir4.1/5.1 channels are CO2/H⁺-sensitive and vital for astrocyte functions. In RTN astrocytes, we found expression of Kir4.1 and Kir5.1 transcripts. Studying astrocyte-specific Kir4.1 knockout mice (Kir4.1 cKO), we observed normal breathing under normal air but reduced response to high CO2 levels, partially restored by Kir4.1 re-expression. At the cellular level, knockout astrocytes were less responsive to CO2/H+ and less effective in modulating respiratory neurons. This suggests Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory regulation, shedding light on mechanisms behind breathing control in response to CO2/H⁺.

3.Altered excitatory and inhibitory ionotropic receptor subunit expression in the cortical visuospatial working memory network in schizophrenia

DOI: 10.1038/s41386-024-01854-x

https://www.nature.com/articles/s41386-024-01854-x

In individuals with schizophrenia (SZ), dysfunction in the cortical dorsal visual stream and visuospatial working memory (vsWM) network may result from alterations in excitatory and inhibitory neurotransmission in key brain regions like V1, V2, PPC, and DLPFC. However, the expression patterns of glutamatergic and GABAergic receptor subunits in these regions and their alterations in SZ remain unexplored. We examined receptor subunit transcript levels in postmortem brain tissue from SZ and unaffected individuals. In unaffected individuals, distinct rostral-to-caudal gradients were observed for AMPAR and NMDAR subunits, with GABAAR subunits showing different expression patterns. In SZ, most transcript levels were lower, particularly in sensory regions, suggesting early abnormalities in the vsWM pathway contributing to altered processing in higher-order regions.

4.TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models

DOI: 10.1038/s41593-024-01610-w

https://www.nature.com/articles/s41593-024-01610-w

Genetic studies link faulty myeloid responses to late-onset Alzheimer's disease (AD). Aging involves decreased myeloid metabolism, leading to immune dysregulation. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases remains unclear. Trem1-deficient mice exhibit preserved myeloid metabolism, reduced inflammation, and improved memory with aging. In vitro, Trem1-deficient microglia resist amyloid-β42 oligomer-induced metabolic changes, implicating TREM1 in microglial dysfunction. In AD mouse models, Trem1 deficiency prevents memory loss, maintains microglial health, and preserves synaptic function. Postmortem AD brains show TREM1 colocalization with amyloid plaques, correlating with disease severity. TREM1 appears to exacerbate cognitive decline in aging and amyloid pathology, suggesting it as a potential therapeutic target for AD.

5.Coumarin linked to 2-phenylbenzimidazole derivatives as potent α-glucosidase inhibitors

DOI: 10.1038/s41598-024-57673-z

https://www.nature.com/articles/s41598-024-57673-z

A new series of coumarin-linked 2-phenylbenzimidazole derivatives were synthesized and evaluated for their anti-α-glucosidase activity. Compound 5k showed significant inhibition (IC50 = 10.8 µM) compared to acarbose (IC50 = 750.0 µM). Kinetic analysis revealed competitive inhibition by 5k against α-glucosidase. Molecular docking elucidated key interactions contributing to the inhibitory effects. These findings suggest the potential of these derivatives as promising candidates for developing α-glucosidase inhibitors, offering insights into their mechanism of action and paving the way for further drug development in managing type 2 diabetes mellitus.