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Mechanisms of stress-induced cognitive deficits : Role of the glucocorticoid receptor and its partners in the regulation of PFC function.

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Could stress be a cause of mental health problems?

Cognitive impairment is associated with mental disorders, but our understanding about the underlying mechanisms is limited. A European study provides evidence on how physical and emotional stress can have an impact on cognition, triggering the release of hormones that act on a specific part of the brain.

Health

Under stressful conditions, our body releases glucocorticoid hormones (GCs) such as cortisol from the adrenal gland, allowing the regulation of essential processes such as energy production, water balance and body temperature. GCs act through specialised glucocorticoid receptors (GRs), present on practically all cells of the body, to modulate the expression of a large set of genes. Emerging evidence indicates that GCs also impact the prefrontal cortex, PFC, the area of the brain responsible for higher-order cognition and executive control.

Investigating the role of stress on behaviour

The StressPFCog project was undertaken with the support of the Marie Skłodowska-Curie (MSC) programme and worked under the hypothesis that GCs modify brain circuit physiology with changes in behaviour. “Our overall objective was to understand the impact of stress on cognition and the function of the PFC,” explain François Tronche and Sébastien Parnaudeau from the CNRS, Inserm and Sorbonne University team Institute of Biology Paris-Seine, which hosted the project. To delineate the impact of stress on behaviour, the MSC fellow Soumee Bhattacharya subjected experimental animals to three different standard chronic stress conditions: separation from the mother, repeated social defeat, and random unpredictable stress. All animals underwent PFC-dependent cognitive tasks and their behaviour was monitored. Results showed that different types of chronic stress decrease GR expression in the PFC but evoke very specific and distinctive effects on cognitive performance. Maternal separation profoundly impairs working memory, social defeat affects the ability to shift attentional focus, while unpredictable stress causes severe deficits in reversal learning. “Our data clearly indicate that the stress circuitry is intricately tuned and does not always respond uniformly to different types of stressors,” outlines Bhattacharya.

GR action on the brain

StressPFCog researchers also investigated the role of the GR in the PFC. GR acts as a transcription factor upon activation, triggering gene expression and facilitating adaptive behavioural responses to environmental changes. Scientists genetically inactivated the GR gene in the PFC neurons in experimental animals and performed a detailed behavioural analysis. They observed a loss of a specific type of cognitive flexibility, with experimental animals failing to reverse what they have learned earlier. This indicated that GRs in the PFC play a crucial role in overruling prior knowledge and adapting to a new situation.

Project significance and future directions

Understanding the mechanisms that drive cognitive impairment is fundamental for treating psychiatric illnesses. PFC has long been recognised as a functionally important cerebral structure that acts as a network hub for cognitive processes. It is also extremely vulnerable to chronic stress known to aggravate most major psychiatric, neurological and neurodegenerative disorders. However, the underlying molecular and physiological mechanisms of this effect remain poorly understood. StressPFCog provided compelling evidence on how different types of chronic stressors affect the PFC and impact cognitive behaviour. “Compared to other studies that employ pharmacological manipulations, our project allowed the neuron-specific deletion of GRs in the PFC using genetic means, offering a precise analysis,” emphasises Bhattacharya. Future plans include investigation of the fine-tuning of stress circuits in the brain, alongside study of the unique gene expression and physiological consequences of different stressors.

Keywords

StressPFCog, stress, PFC, brain, cognition, glucocorticoid hormones, prefrontal cortex, mental health, psychiatric illness

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