Functional brain-wide network mapping during acute stress exposure in rats: Interaction between the lateral habenula and cortical, amygdalar, hypothalamic and monoaminergic regions.

Upon stress exposure, a broad network of structures comes into play in order to provide adequate responses and restore homeostasis. It has been known for decades that the main structures engaged during the stress response are the medial prefrontal cortex, the amygdala, the hippocampus, the hypothalamus, the monoaminergic systems (noradrenaline, dopamine and serotonin) and the periaqueductal gray. The lateral habenula (LHb) is an epithalamic structure directly connected to prefrontal cortical areas and to the amygdala, whereas it functionally interacts with the hippocampus. Also, it is a main modulator of monoaminergic systems. The LHb is activated upon exposure to basically all types of stressors, suggesting it is also involved in the stress response. However, it remains unknown if and how the LHb functionally interacts with the broad stress response network. In the current study we performed in rats a restraint stress procedure followed by immunohistochemical staining of the c-Fos protein throughout the brain. Using graph theory-based functional connectivity analyses, we confirm the principal hubs of the stress network (e.g., prefrontal cortex, amygdala and periventricular hypothalamus) and show that the LHb is engaged during stress exposure in close interaction with the medial prefrontal cortex, the lateral septum and the medial habenula. In addition, we performed DREADD-induced LHb inactivation during the same restraint paradigm in order to explore its consequences on the stress response network. This last experiment gave contrasting results as the DREADD ligand alone, clozapine-N-oxide, was able to modify the network.