Multiscale imaging informs translational mouse modeling of neurological disease

Wang, Yundi; LeDue, Jeffrey; Murphy, Timothy H.

doi:10.1016/j.neuron.2022.09.006

Cited by 4 publications

(2 citation statements)

References 236 publications

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“…Live brain imaging of the PNN structural and functional dynamics has remained absent until very recently, although longitudinal in vivo imaging techniques for brain cells and some ECM components have been around for a while [175,182,183]. To that end, a highly promising methodology-oriented study has reported longitudinal in vivo imaging of the PNN using live brain two-photon microscopy on a mouse barrel cortex [89].…”

Section: Future Methodological Perspective For Pnn Microscopy 81 Mult...mentioning

confidence: 99%

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

Paveliev,

Egorchev,

Musin

et al. 2024

IJMS

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Perineuronal nets (PNN) are a special highly structured type of extracellular matrix encapsulating synapses on large populations of CNS neurons. PNN undergo structural changes in schizophrenia, epilepsy, Alzheimer’s disease, stroke, post-traumatic conditions, and some other brain disorders. The functional role of the PNN microstructure in brain pathologies has remained largely unstudied until recently. Here, we review recent research implicating PNN microstructural changes in schizophrenia and other disorders. We further concentrate on high-resolution studies of the PNN mesh units surrounding synaptic boutons to elucidate fine structural details behind the mutual functional regulation between the ECM and the synaptic terminal. We also review some updates regarding PNN as a potential pharmacological target. Artificial intelligence (AI)-based methods are now arriving as a new tool that may have the potential to grasp the brain’s complexity through a wide range of organization levels—from synaptic molecular events to large scale tissue rearrangements and the whole-brain connectome function. This scope matches exactly the complex role of PNN in brain physiology and pathology processes, and the first AI-assisted PNN microscopy studies have been reported. To that end, we report here on a machine learning-assisted tool for PNN mesh contour tracing.

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Section: Future Methodological Perspective For Pnn Microscopy 81 Mult...mentioning

confidence: 99%

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

Paveliev,

Egorchev,

Musin

et al. 2024

IJMS

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“…The disruption of neural connectivity networks, widespread structural changes in the brain, and abnormal neurotransmitter transmission have been widely recognized as playing an important role in the onset of MDD [ 32 ]. With the remarkable advancements in biological imaging and microscopy techniques, the scope of depression research has transcended from the macro- to the microscale and even delved into the nanoscale [ 15 , 33 ].…”

Section: Challenges In Mdd: Cross-scale Abnormalitiesmentioning

confidence: 99%

Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures

Yao,

Wang,

Chi

et al. 2024

Molecules

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Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs.

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