Defence of the PhD Thesis of Luka CULIG

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on the November 13, 2017


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salle des thèses, Bat L

Effets de l’augmentation de la neurogenèse adulte dans un modèle murin écologique de dépression

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Major depressive disorder (MDD) is a complex and heterogeneous disorder hypothesized to be associated with alterations in brain circuitry, dysregulations of the hypothalamic–pituitary–adrenal (HPA) axis and impairments in adult hippocampal neurogenesis (AHN). AHN is the process of generation and development of new neurons in the hippocampus of the adult brain, and these adult-born neurons are implicated in roles such as hippocampus-dependent learning, pattern separation, anxiety-like behavior, cognitive flexibility and in the therapeutic action of antidepressants. Multiple lines of evidence point to the involvement of AHN in mood and anxiety disorders, leading to the formation of the “neurogenesis hypothesis”, which postulates that adult-born hippocampal neurons are involved in the etiology and treatment efficacy of MDD. While there have been advances in elucidating the role of adult-born neurons in depression, along with progress in determining the mechanism through which these neurons might exert their effects, the picture is still incomplete and there are still important questions left unanswered. The interaction between exposure to stress (a major risk factor for depression), AHN and depression itself is underexplored. It is an open question if increasing AHN after stress has already started having deleterious effects would be able to rescue behavioral deficits and, if it would, which mechanisms and brain areas would be involved in remission.

In order to explore this question and attempt to determine the role of adult-born neurons after the onset of stress exposure, we combined (1) the unpredictable chronic mild stress (UCMS) in mice, which is a naturalistic animal model of depression that uses socio-environmental stressors to induce depression-like alterations in mice, with (2) iBax mice, which belong to a bi-transgenic line that enables us to inducibly delete the pro-apoptotic gene Bax in neural stem cells and their progeny via tamoxifen injections and therefore increase AHN by preventing apoptosis in those adult-born neurons. This combination of a novel and specific gain of function approach to increase AHN with the currently most validated animal model of depression enabled us to more precisely examine the role of adult-born neurons after exposure to stress.

In the first set of experiments, we focused on the effects that increasing AHN might produce, ranging from various behavioral outputs, endocrine measures and activity in certain brain areas. To achieve this, we exposed the animals to UCMS from the beginning of the protocol and treated them with tamoxifen in week 3 to induce an increase in neurogenesis. In week 8, we submitted the animals to a battery of behavioral tests to assess depressive- and anxiety-like behavior, while in week 9 the animals were stereotaxically implanted with bilateral guide cannulas in order to assess corticosterone levels and activity in the the bed nucleus of the stria terminalis (BNST) after intra-hippocampal dexamethasone infusions in week 10. Results indicate that increasing neurogenesis is sufficient to buffer against the effects of chronic stress on certain behavioral and endocrine levels and thus to display antidepressant-like effects, both behaviorally and physiologically.

In the second set of experiments, the focus has shifted to the mechanism underlying the observed results, and thus we attempted to examine the influence of adult-born neurons on other brain regions that the hippocampus might influence, by analyzing the whole-brain network properties. We hypothesized that local changes in the hippocampal network (addition of new neurons in the dentate gyrus) might change the activity of neural circuitry in the areas to which the hippocampus projects, or even perhaps the whole brain network. Our target protein for the “stressome” construction was ΔFosB, an unusually stable transcription factor which belongs to the Fos family of proteins, but unlike other members of the family, accumulates over time after repeated stress exposure. This accumulation has been observed in many animal models of depression, including UCMS, and it could be the basis of certain behavioral consequences of exposure to chronic stress. We utilized a similar experimental design to the first set of experiments, exposing iBax mice to UCMS for 9 weeks and treating them with tamoxifen 3 weeks after the beginning of the UCMS. In week 8, they were submitted to a battery of behavioral tests to assess depressive- and anxiety-like behavior. In week 9, blood was collected to assess basal corticosterone levels, and the animals were sacrificed and their brain collected for ΔFosB immunohistochemistry. Brain-wide maps of ΔFosB expression were constructed and graph theoretical analyses were used to study the changes in brain networks after stress.

Keywords: depression, neurogenesis, chronic stress, animal model, remission, ΔFosB, connectome