Reopening the sensitive period of susceptibility to stress through perineuronal nets degradation

Author(s)

Débora Akemi Endo Colodete

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-11-21

Examining board members

Felipe Villela Gomes; Vanessa Costhek Abilio; Fernando Eduardo Padovan Neto

• Advisor: Felipe Villela Gomes

Abstract

The onset of some psychiatric disorders, such as schizophrenia, anxiety disorders, and depression, often occurs in late adolescence and/or early adulthood, a period of greater vulnerability to socioenvironmental factors. The impact of these factors seems to be more pronounced during sensitive developmental periods, such as childhood and adolescence, when parvalbumin-positive GABAergic interneurons have not reached their \"mature\" state. Stress during these periods can lead to the functional loss of PV interneurons in the ventral hippocampus (vHip), as evidenced in these disorders. This period of vulnerability of PV interneurons occurs until the end of the sensitive period of development, which is completed with the appearance of the perineuronal nets (PNNs) around these interneurons. Therefore, during adolescence, when the PNNs are not yet fully formed, stress can damage PV interneurons. If this hypothesis is correct, it could be predicted that reopening the sensitive period in adulthood may recreate an adolescent-like phenotype of susceptibility to stress. Thus, this project aimed to investigate whether the degradation of PNNs in the vHip of adult animals through the local infusion of the enzyme chondroitinase ABC would increase the impact of stress on PV interneurons, reinforcing the idea that they are more susceptible in periods of higher plasticity. Adolescent (postnatal day 31-40) and adult (postnatal day 61-70) male Sprague-Dawley rats were exposed to a combination of stressors (foot shocks for 10 days and three sessions of restraint stress for 1 hour on days 1, 2, and 10). Between 3-4 weeks after stress exposure, the animals underwent behavioral tests to assess anxiety-related behaviors (elevated plus maze and light-dark box), sociability (social interaction test), cognitive function (object recognition test), and MK-801 responsiveness (MK-801-induced hyperlocomotion). In vivo electrophysiological activity of dopaminergic neurons in the Ventral Tegmental Area (VTA) was also recorded. To degrade PNNs, adult rats received a bilateral infusion of Chondroitinase ABC (ChABC) in the vHip (PD56-58). After one week of recovery, they underwent the same protocol of stress exposure, behavioral tests, and electrophysiological recordings. In contrast to adulthood, adolescent stress induced anxiety-like behaviors, cognitive and sociability impairments, and a hyperdopaminergic state in the VTA, similar to what is observed in schizophrenia. ChABC infusion reduced the number of PNN+ cells and PV+/PNN+ cells in the vHip. Adult animals that received intra-vHip ChABC infusion and were exposed to stress exhibited the same long-lasting impairments found after adolescent stress exposure. Our findings suggest that the degradation of PNNs in the adult vHip recreates an adolescent-like phenotype of stress susceptibility. Understanding the role of PNNs in protecting PV interneurons against stress can help develop strategies to improve the dysfunction of these interneurons and prevent the development of psychiatric disorders. (AU)

• FAPESP's process: 21/03391-7 - Reopening the sensitive period of susceptibility to stress through perineuronal nets degradation
• Grantee: Debora Akemi Endo Colodete
• Support Opportunities: Scholarships in Brazil - Master