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

Periodic Reporting for period 1 - StressPFCog (Mechanisms of stress-induced cognitive deficits : Role of the glucocorticoid receptor and its partners in the regulation of PFC function.)

Período documentado: 2018-01-04 hasta 2020-01-03

• 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.
In this study, the affects of different types of chronic stress exposure with regards to mPFC dependent cognitive tasks was analysed and followed up by examining the affects on PV and CR immunoreactive interneurons in the mPFC. Furthermore, the physiological correlates in the mouse models which displayed working memory deficits was examined. Finally, the role of GR in the mPFC was investigated by employing a viral approach using a neuron specific promoter followed by a promoter specific for excitatory neurons.

• Main results and conclusions:

We dissociated the behavioural outcomes of different kinds of stress manipulations, both environmental and genetic, in mice. We demonstrated, using several frequently used stress inducing paradigms, namely, early-life maternal separation, adult-life social defeat and chronic unpredictable stress, as well as, a systemic treatment with corticosterone, that different kinds of chronic stressors evoke different and specific outcomes in terms of PFC-dependent behavior.

In addition, the observed specific alterations in cognitive flexibility, working memory, and novel object recognition capabilities were found to be accompanied by certain specific alterations at the molecular level, as exemplified by the immunohistochemical analyses of parvalbumin-expressing interneurons in the prelimbic and infralimbic cortices. We also observed electrophysiological alterations in the mPFC and its related circuits in the models displaying working memory deficits.

Furthermore, we observed that a viral vector-mediated inactivation of the glucocorticoid receptor gene in the mPFC specifically impaired reversal learning while sparing certain other forms of behavioural capabilities. Additionally, it affected the parvalbumin and calretinin immunoreactive interneurons in specific areas of the mPFC. Interestingly, these effects were not observed in mice with GR-deletion exclusively in the pyramidal neurons of the mPFC suggesting a role played by the GR in the interneuronal subpopulations of the mPFC.

To conclude, this study facilitated mechanistic dissociation of stress-induced molecular and physiological pathways in the mPFC. This project helped us understand in a systematic manner the deleterious effects of stress on medial prefrontal cortex based cognitive abilities. It is therefore a step further in understanding how stress affects behaviour, a pertinent topic in present societies.
The results obtained through this project are very relatable in the current socio-economical context in which stress-related mental and physical disorders are becoming more and more common. This project strengthened current collaborations of the host team and increased the scientific maturity and expertise of the researchers involved. Such collaborative projects are necessary for pan-European competitiveness. 5 students were trained during the project from European and non-European countries, a very important impact of the grant. Also, the various scientific and public meetings in which the results were presented guaranteed a societal impact.