The impact of stress in mice lacking molecular breaks of critical periods of plasticity

• Grant number: 22/06330-1
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: October 10, 2022
• End date: April 09, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Felipe Villela Gomes
• Grantee: Debora Akemi Endo Colodete
• Supervisor: Hirofumi Morishita
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Icahn School of Medicine at Mount Sinai, United States
• Associated to the scholarship: 21/03391-7 - Reopening the sensitive period of susceptibility to stress through perineuronal nets degradation, BP.MS

Abstract

The onset of some psychiatric disorders, such as schizophrenia, anxiety disorders, and depression, often occurs in late adolescence/early adulthood, which is a period of greater vulnerability to adverse socioenvironmental factors. Evidence suggests that socioenvironmental factors, such as trauma, psychosocial stress, along with genetic predisposition, may increase the individual's susceptibility to developing psychiatric disorders. The impact of these factors seems to be more pronounced during critical periods of development, such as childhood and adolescence, when parvalbumin-containing GABAergic interneurons (PVI) have not reached their "mature" state. It is thought that stress during these periods, contrary to stress during adulthood, causes functional loss of PVI in the ventral hippocampus (vHip) and prefrontal cortex (PFC), as observed in some psychiatric disorders. The period of greater vulnerability of PVI occurs until the end of critical periods of development, which is marked by the appearance of perineuronal nets (PNNs), an extracellular matrix, around PVI. PNNs act as a molecular "brake" by promoting PVI maturation and limiting its plasticity, and protect PVI from metabolic and oxidative damage. PNN degradation in adulthood is thought to recreate an adolescent-like phenotype of stress vulnerability. Other molecular "breaks" also limit PVI plasticity, such as Lynx1, a factor which influences cholinergic signaling. Lynx1 plays a key role in modulating attentional behavior in adulthood. This process appears to be impaired in a mouse model of fragile X syndrome (Fmr1) due to reduced Lynx1 expression. Here, we aim at investigating the impact of stress on Lynx1 KO and Fmr1 KO mice, which are mouse models of juvenile-like elevated plasticity. We hypothesize that the lack or reduced expression of Lynx1, a molecular "brake" that limits PVI plasticity, would lead to an abnormal PNN formation and PVI maturation, which in turn increases PVI susceptibility to stress. (AU)