Levinstein, M. R. | Search bioRxiv

bioRxiv2020

Stress induces divergent gene expression among lateral habenula efferent pathways

The lateral habenula (LHb) integrates critical information regarding aversive stimuli that shapes decision making and behavioral responses. The three major LHb outputs innervate dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). LHb neurons that project to these targets are segregated and nonoverlapping, and this led us to consider whether they have distinct molecular phenotypes and adaptations to stress exposure. In order to capture a time-locked profile of gene expression after repeated forced swim stress, we used intersectional expression of RiboTag in rat LHb neurons and next-gen RNA sequencing to interrogate the RNAs actively undergoing translation from each of these pathways. The "translatome" in the neurons comprising these pathways was similar at baseline, but diverged after stress, especially in the neurons projecting to the RMTg. Using weighted gene co-expression network analysis, we found one module comprising genes downregulated after stress in the RMTg-projecting LHb neurons; there was an overrepresentation of genes associated with phosphoinositide 3 kinase (PI3K) signaling in this module. Reduced PI3K signaling in RMTg-projecting LHb neurons may be a compensatory adaptation that alters the functional balance of LHb outputs to GABAergic vs. monoaminergic neurons following repeated stress exposure.

neuroscience↗

bioRxiv2018

Dentate Gyrus Activin Signaling Mediates the Antidepressant Treatment Response

Antidepressants that target monoaminergic systems, such as selective serotonin reuptake inhibitors (SSRIs), are widely used to treat neuropsychiatric disorders including major depressive disorder, several different anxiety disorders, and obsessive-compulsive disorder. However, these treatments are not ideal because only a subset of patients achieve remission. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Here, we developed a paradigm to assess antidepressant treatment resistance in mice. Treatment of mice with either chronic corticosterone or chronic social defeat stress effectively induces increased negative valence behaviors. Subsequent chronic treatment with the SSRI fluoxetine reverses these behavioral changes in some, but not all, of the mice, permitting stratification into persistent responders and non-responders to fluoxetine. We found several significant differences in expression of Activin signaling-related genes between responders and non-responders to fluoxetine in the dentate gyrus, a region that we recently reported is critical for the beneficial behavioral effects of fluoxetine. Furthermore, enhancement of Activin signaling in the dentate gyrus converted behavioral non-responders into responders to fluoxetine treatment more effectively than commonly used adjunctive antidepressant treatments, while inhibition of Activin signaling in the dentate gyrus converted responders into non-responders. Taken together, these results demonstrate that the behavioral response to FLX can be bidirectionally modified via targeted manipulations of the dentate gyrus and suggest that molecular- and neural circuit-based modulations of dentate gyrus may provide a new therapeutic avenue for more effective antidepressant treatments or adjunctive therapies.

neuroscience↗