The different forms of depression – animal models and role of sleep – DEPSOM

We first plan to use two genetic mouse lines, namely the H-TST (anxious) and H-FST (non anxious) mice, modeling forms of depression comorbidly expressed or not with anxiety traits. In addition, we plan to compare results obtained with these genetic models with an environmental model (learned helplessness or LH) of induced depression in normal mice. We plan to study in these three models 1) their response to classical and novel antidepressants, 2) their sleep/wake cycle as well as the quality of their sleep, and to identify, in these models and during this sleep/wake cycle, the brain structures involved in depression (amygdalar-hippocampal-prefrontal network). We are particularly interested in the expression of synaptic plasticity biomarkers as well as the rate of adult hippocampal neurogenesis. We plan to use well-described and classical procedures such as in vivo electrophysiology, neuro-imaging, in situ hybrization and immunohistochemistry.

These past 18 months, we have determined that, beside their difference in anxiety, our two genetic models had very distinct phenotypes. H-TST (depressive/anxious) mice spend more time in paradoxical sleep than H-FST (depressive/non-anxious) mice. They also display a more pronounced anhedonia (inability to experience pleasure from activities usually found enjoyable) than H-FST mice. Anhedonia, anxiety and paradoxical sleep increase being often (but not always) reported in depressive patients, these results strongly suggest that our two mice lines model different types of depression, the H-TST line modeling the most common form of depression. We are now trying to characterize neurobiological differences existing between our two genetic models. We have already found that they do not respond to the same class of antidepressants. This result could help predict what antidepressant is more suited to cure depression depending on the form of depression to treat.

In the next 18 months, we will try to ascertain the differences in term of brain functions in our two genetic models of depression. These new results should help determine new ways of action to treat depression based on the form of depression involved.
Besides genetic factors, depression can be caused by environmental factors such as traumatic events leading to major stress. To take this into account, we will compare the results obtained with our genetic models with a study of an environmental model of induced depression in which normal mice are exposed to chronic stress.

Since the start of our project, we have published an article related to the characterization of our first historical (genetic) model of depression that we did not mention in these pages but that will be helpful as a standard for genetic analyses (transcriptome) of H-TST and H-FST mice. A second research article describing these two genetic models is now in preparation. We believe this second article can have a strong impact for research on depressive disorders due to the originality of our results concerning the modeling of different forms of depression.

Depressive disorders represent a major health problem worldwide as the treatments available today are not always efficient to treat depression. On the other hand, the discovery of new ways and drugs to treat this disease is prevented by the fact that the physiopathology of depression remains poorly understood. This is probably because there is not one but several forms of depression. Depression may thus be induced by traumatic or painful experience and/or by genetic factors, and can be expressed, or not, comorbidly with other disorder such as anxiety.

Sleep, and in particular REM sleep, is very often altered in patients suffering from depressive disorders. But the question whether sleep alterations are associated to all forms of depression, and if they are a cause or a consequence of depression remains unsolved. Answering these questions, and understanding the molecular substrates of the sleep alterations in depressed patients could be crucial to find new ways to treat depression. In the future, we could plan to give new drugs that positively modulate sleep, and REM sleep in particular, in order to cure some forms of depression.

As a preclinical study to find such cure, our project deals with the study of different animal models developed by our team and representing various aspects and different forms of depression. We first plan to use two genetic mouse lines, namely the H/TST (anxious) and H/FST (non anxious) mice, modelling forms of depression comorbidly expressed or not with anxiety traits. In addition, we plan to compare results obtained with these genetic models with an environmental model (learned helplessness or LH) of induced depression in normal mice. We plan to study in these three models 1) their response to classical and novel antidepressants, 2) their sleep/wake cycle as well as the quality of their sleep, 3) the effect of REM sleep deprivation on depressive symptoms expressed in these models and on brain structures known to be involved in both depression and REM sleep (Amygdalar-Hippocampal-Cortical network). We are particularly interested in the expression of markers of synaptic plasticity such as BDNF and Zif268 in these regions, as well as the rate of hippocampal neurogenesis. To do so, we plan to use well-described procedures of neuro-imagery (in situ hybridization – Immunohistochemistry) or in vivo electrophysiology, but also innovative techniques such as optogenetics allowing a rapid and transient modulation of neuronal activity in targeted brain regions. This project describes all the experiments planned to solve the fore-mentioned questions with these techniques.