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

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

• What is the problem/issue being addressed? Cognitive deficits are hallmarks of most psychiatric illnesses causing severe and persistent functional decline and are so far resistant to current treatments. The prefrontal cortex (PFC), as indicated by clinical and preclinical research, plays a central role in cognition. Imaging studies in patients have associated abnormal PFC function with cognitive impairment in several pathologies such as schizophrenia, unipolar depression, and bipolar disorder. Requirement of the PFC for cognitive capabilities such as working memory, behavioral flexibility, and decision-making, has also been clearly established by lesion studies. Due to the apparent role of the PFC and its related networks in cognitive deficits related to psychiatric diseases, it is important to understand the factors that can disrupt PFC microcircuits and thereby alter cognition. Stress exposure is an environmental factor that modulates cognitive function. It causes the release of glucocorticoids (GCs), enabling the organism to produce adaptive behavioural responses to environmental changes. However, chronic stress exposure can lead to persistent cognitive and mood dysregulation, facilitating the development of psychiatric diseases. Prolonged stress has been reported to affect decision-making in human and cognitive impairment in patients with major depression has been correlated with high GC levels. In animal studies, chronic stress has been shown to have deleterious effects on PFC-dependent cognitive functions such as spatial working memory, behavioural flexibility and decision-making. Morphological abnormalities in the PFC, altered synaptic transmission, misbalance between excitation and inhibition, and reduced myelination in the PFC due to chronic stress have been reported. These data collectively suggest that stress exposure may induce cognitive deficits through the action of GCs within the PFC. However, the local impact of GCs and on prefrontal microcircuit function and cognition has only been sparsely examined. • Why is it important for society? From a therapeutic perspective it is crucial to investigate links between stress posed by the environment and events happening at a molecular level which lead to behavioural alterations. This is because chronic stress exposure has been linked to most major psychopathological disorders like depression, anxiety, schizophrenia, Alzheimer’s Disease, Parkinson’s disease etc. which plague our society in present days. In fact, the global cost of mental health conditions was estimated at US$ 2.5 trillion in 2010, with an estimated increase to over US$6 trillion in 2030. In Europe, the cost of all brain disorders was estimated at €798 billion in 2010 posing a major concern. In this project investigating the events at molecular level induced by stress, a factor which is increasingly being associated with mental health in modern societies and which is a risk factor for the development of many psychopathological disorders. • What were the overall objectives? The overall objective of this proposal was to understand the local impact of stress on prefrontal microcircuit function and cognition. For the same, two strategies were adopted in parallel. First, wild-type mice were subjected to different chronic stress paradigms which resulted in reduced glucocorticoid receptor (GR) expression in the medial PFC. This was followed by genetic inactivation of GR in the PFC, as well as, its excitatory microcircuit using viral vectors expressing a transgene. All the above models generated were systematically analysed using behavioural, molecular and physiological means leading to a deeper understanding of the role of PFC in mediating stress induced changes.

Data: CORDIS, © European Union