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

Abstract

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.

Unravelling the Role of Habenula Subnuclei on Avoidance Response: Focus on Activation and Neuroinflammation

“…Notably, animals were evaluated after eight sessions in the shuttle box, suggesting that LHbMPc may be sensitive to stress even after consecutive sessions. Supporting our data, it has been shown that a variety of stressor could increase FOS expression in the lateral habenula, emphasizing the close interaction with the medial prefrontal cortex, lateral septum, extended amygdala, hypothalamus and dorsal raphe [50][51][52][53][54]. In a similar way, both groups showed a decrease in astroglial immunoreactivity in the LHbLB.…”

Cerebellar contributions to a brainwide network for reversal learning

“…To examine functional connectivity using our c-Fos data, we calculated the Spearman's rank coefficient ρ among the mice within any one experimental group [40,41]. For crus I, to attain a large sample size we combined left, right, and bilateral inhibition groups.…”

Acute restraint stress regulates brain DNMT3a and promotes defensive behaviors in male rats

“…Exposure to stress is an unavoidable life event. When an organism is confronted with a stressful situation, the hypothalamic–pituitary–adrenal (HPA) axis is activated and, subsequently, glucocorticoids are released into the bloodstream by the adrenal glands where they circulate, cross the blood-brain barrier, and ultimately influence the brain by binding to mineralocorticoid and glucocorticoid receptors located in the amygdala, hippocampus, and prefrontal cortex [ 1 – 3 ].…”