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Wojtek KREZEL"Role of retinoid signalling in affective behavior in mice."

Abstract :

Role of retinoid signalling in brain development

Developmental and postnatal brain expression of a number of retinoid receptors and retinoic acid metabolizing enzymes suggests an important role of retinoid signalling in brain development and functions. Using genetically modified mouse models, we showed previously that RARβ and RXRγ are implicated in control of locomotor behaviors related to abnormal functions of the dopaminergic signalling in the striatum. We currently investigate developmental functions of these retinoid receptors and the role of endogenous retinoic acid in control of their transcriptional activities and functions. For these studies we carry out pre- and post-natal gene inactivation of retinoid receptors and retinoic acid metabolising enzymes in the whole brain or selected brain regions or circuits. Behavioral and pharmacological analyses are our functional readout of such manipulations, whereas analysis of the expression of genes implicated in cell differentiation, migration and homeostasis are used to reveal molecular and cellular mechanisms controlled by retinoid signalling.

Role of retinoid receptor signalling in the central nervous system

An environmental experience such as sensory stimulation or chemical composition of a meal, leads to short term modifications of brain functions. Long term exposure to such stimuli leads to adaptive changes, which involve transcriptional modifications and which contribute to the final make-up and activities of the central nervous system. The involvement of retinoid signalling in brain development and its implication in fine tuning of neurotransmission systems in the adult, is potential determinant of responses and adaptation to environmental stimuli. These functions of retinoid signalling, might be of particular relevance for etiology and/or treatment of anxiety, depression or schizophrenia, some of the neuropsychiatric disorders resulting from abnormal interactions between genetic and environmental factors. In addition, retinoid receptors as well as other nuclear receptors are particularly well suited to form a dynamic interface between environment and genome in the adult since they act as ligand-regulated transcription factors and can sense nutrients, hormones (including stress hormones) and xenobiotics and translate such signals into transcriptional, adaptive responses. The possibility of pharmacological modulation of retinoid and other nuclear receptors has therefore an immediate medical relevance and we are keen to investigate the potential biomedical application of our research.

We have recently focused our studies on the mechanisms of cognitive functions and emotional processes and found that RXRγ is a positive modulator of spatial and recognition working memory. We are currently studying the functions of RXRs and associated nuclear receptors in the context of adaptive processes. We investigate neuroanatomical and neurochemical substrates of these processes, employing technologies such as virus-based gene therapy and gene expression profiling with DNA microarrays. The electrophysiological and behavioral analyses are used as functional readout of genetic and pharmacological manipulations, but also as tools to identify the potential mechanisms of nuclear receptor functions in the brain.

Selected publications

Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice.Krzyzosiak A, Szyszka-Niagolov M, Wietrzych M, Gobaille S, Muramatsu S, Krezel W.
Neuron. 2010 Jun 24;66(6):908-20.

Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice.Mingaud F, Mormede C, Etchamendy N, Mons N, Niedergang B, Wietrzych M, Pallet V, Jaffard R, Krezel W, Higueret P, Marighetto A. J Neurosci. 2008 Jan 2;28(1):279-91.

Marie Pierre Moisan