Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

Short- and Long-Term Effects of Subchronic Stress Exposure in Male and Female Brain-Derived Neurotrophic Factor Knock-In Val66Met Mice.

Stress is an important risk factor for the onset of anxiety and depression. The ability to cope with stressful events varies among different subjects, probably depending on different genetic variants, sex and previous life experiences. The Val66Met variant of Brain-Derived Neurotrophic Factor (BDNF), which impairs the activity-dependent secretion of BDNF, has been associated with increased susceptibility to the development of various neuropsychiatric disorders. Adult male and female wild-type Val/Val (BDNFV/V) and heterozygous Val/Met (BDNFV/M) mice were exposed to two sessions of forced swimming stress (FSS) per day for two consecutive days. The mice were behaviorally tested 1 day (short-term effect) or 11 days (long-term effect) after the last stress session. Protein and mRNA levels were measured in the hippocampus 16 days after the end of stress exposure. Stressed mice showed a higher anxiety-like phenotype compared to non-stressed mice, regardless of the sex and genotype, when analyzed following the short period of stress. In the prolonged period, anxiety-like behavior persisted only in male BDNFV/M mice (p < 0.0001). Interestingly, recovery in male BDNFV/V mice was accompanied by an increase in pCREB (p < 0.001) and Bdnf4 (p < 0.01) transcript and a decrease in HDAC1 (p < 0.05) and Dnmt3a (p = 0.01) in the hippocampus. Overall, our results show that male and female BDNF Val66Met knock-in mice can recover from subchronic stress in different ways.