Modèles animaux de troubles bipolaires : vers de nouvelles perspectives

Animal models of psychiatric disorder are unlikely to be possible either conceptually or practically. Specifically for Bipolar Disorders (BD), the cyclic nature of the disease, characterized by a recurrence of manic and depressive states, creates an additional level of complexity. Moreover, animal models should ideally have construct (share the mechanism of the disease), face (mimic the symptoms) and predictive validity (share the same treatment response). To date, no such animal model for BD exists and current models mimic only mania. In this review, we first describe classical animal models of BD based on pharmacological, behavioral or strain selection manipulations and, more recently, on genetic modifications. However, all these models are based on a partial and stable phenotype of one polarity and do not allow the assessment of the neurobiology of the switch process. In this context, we discuss the interest of optogenetics, a technique that allows optical manipulation of a specific neuronal type and/or neuronal circuit in freely-moving animals, as a new tool to explore mood switches. We review recent studies using this relatively novel technique to identify potential brain circuits involved in mood swings. Recent work has shown that activation or inhibition of neurons projecting from the basolateral nucleus of the amygdala (BLA) to the ventral hippocampus induces an increase or respective decrease in anxiety and depression-like states. Moreover, it has been shown that two genetically distinct types of neurons in the BLA play a pivotal antagonistic role in valence attribution of positive and negative stimuli. These results give a glimpse into the interest to explore behavioral changes induced by activation or inhibition of specific neural circuits to better understand complex diseases. This approach is perfectly in line with the research advocated by the Rdoc program by working on preclinical models of isolated behaviors and domains involved in psychiatric disorders to go toward a nosology supported by physiopathology.