Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice

Clara Bueno-Fernandez; Marta Perez-Rando; Julia Alcaide; Simona Coviello; Carmen Sandi; Esther Castillo-Gómez; Juan Nacher

doi:10.1016/j.ynstr.2021.100322

Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice

Neurobiol Stress. 2021 Apr 1:14:100322. doi: 10.1016/j.ynstr.2021.100322. eCollection 2021 May.

Authors

Clara Bueno-Fernandez¹, Marta Perez-Rando¹, Julia Alcaide¹, Simona Coviello¹, Carmen Sandi², Esther Castillo-Gómez^{3

4}, Juan Nacher^{1

4

5}

Affiliations

¹ Neurobiology Unit, Institute for Biotechnology and Biomedicine (BIOTECMED), Universitat de València, 46100, Spain.
² Department of Life Sciences, Laboratory of Behavioral Genetics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
³ Department of Medicine, School of Medical Sciences, Universitat Jaume I, Valencia, Spain.
⁴ Spanish National Network for Research in Mental Health CIBERSAM, 28029, Spain.
⁵ Fundación Investigación Hospital Clínico de Valencia, INCLIVA, 46010, Valencia, Spain.

Abstract

The impact of stressful events is especially important during early life, because certain cortical regions, especially the prefrontal cortex (PFC), are still developing. Consequently, aversive experiences that occur during the peripubertal period can cause long-term alterations in neural connectivity, physiology and related behaviors. Although sex influences the stress response and women are more likely to develop stress-related psychiatric disorders, knowledge about the effects of stress on females is still limited. In order to analyze the long-term effects of peripubertal stress (PPS) on the excitatory and inhibitory circuitry of the adult PFC, and whether these effects are sex-dependent, we applied an unpredictable chronic PPS protocol based on psychogenic stressors. Using two strains of transgenic mice with specific fluorescent cell reporters, we studied male and diestrus females to know how PPS affects the structure and connectivity of parvalbumin expressing (PV+) interneurons and pyramidal neurons. We also studied the expression of molecules related to excitatory and inhibitory neurotransmission, as well as alterations in the expression of plasticity-related molecules. The structure of pyramidal neurons was differentially affected by PPS in male and female mice: while the former had a decreased dendritic spine density, the latter displayed an increase in this parameter. PPS affected the density of puncta expressing excitatory and inhibitory synaptic markers exclusively in the female mPFC. Similarly, only in female mice we observed an increased complexity of the dendritic tree of PV+ neurons. Regarding the perisomatic innervation on pyramidal and PV + neurons by basket cells, we found a significant increase in the density of puncta in stressed animals, with interesting differences between the sexes and the type of basket cell analyzed. Finally, the PPS protocol also altered the total number of somata expressing the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) when we analyzed both sexes together. These results highlight the strong programming effects of aversive experiences during early life for the establishment of cortical circuitry and the special impact of these stressful events on females.