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

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.

Rodent models of stress and dendritic plasticity – Implications for psychopathology

“…While CUS in males affected HPC and NAc dendrites similarly to what was described above, neither of these effects were observed in females ( Gaspar et al, 2021 ). In female mice, peripubertal CUS increased PFC spine density in females mice, while the previously reported decrease was observed in males ( Bueno-Fernandez et al, 2021 ). Restraint stress also has opposing effects on male and female PFC neurons: in females, dendritic length was increased while in males it was decreased ( Garrett and Wellman, 2009 ).…”

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

“…Luo et al ., 2020). However, it is noteworthy that several environmental, pharmacological and genetic perturbation models of neurodevelopmental disorders are reported to impact PV-positive interneuron structure and function across multiple networks (Smith-Hicks, 2013; Goodwill et al ., 2018; Todorović et al ., 2019; Soares et al ., 2020; Aksic et al ., 2021; Bueno-Fernandez et al ., 2021; Klimczak et al ., 2021; Mukhopadhyay et al ., 2021; Woodward and Coutellier, 2021). In this regard, our approach to chemogenetically manipulate PV-positive interneurons during postnatal development across diverse circuits bears relevance to both models of early adversity and neurodevelopmental disorders, which impact PV-positive interneurons across several limbic brain regions (Ruden et al ., 2021).…”

Non-Cell-Autonomous Factors Implicated in Parvalbumin Interneuron Maturation and Critical Periods

“…Thus, while NCAM is not strictly a non-cell-autonomous factor, its various forms and fragments can impact the ECM and FS-PV cell plasticity, thereby influencing juvenile CPs and adult functions. Indeed, its misexpression is linked with chronic stress and psychiatric disorders (Bueno-Fernandez et al, 2021 ).…”

“…Exposure during CPs may result in maladaptation of the HPA-axis that will affect basal and stress-induced activity in adulthood (Van Bodegom et al, 2017 ). The effects of early-life stress are also manifested by changes in FS-PV cell development and maturation (Chen et al, 2018 ; Page et al, 2019 ; Nawreen et al, 2020 ; Vasistha et al, 2020 ), typically within the mPFC (Bueno-Fernandez et al, 2021 ), which has a negative feedback function on the HPA-axis (Van Bodegom et al, 2017 ). Implicated in behavioral and psychiatric disorders, the maturation of mPFC connectivity occurs in multiple CP windows from childhood through to adolescence enabling complex brain functions such as memory, cognition, decision making, social behaviors, and mood (for review, see Klune et al, 2021 ).…”