Effects of Lateral Habenula 2-Arachidonoylglycerol Manipulation on Dorsal Raphe Nucleus Immediate Early Gene Expression

Rafael Urrutia-Camargo

doi:10.7273/000003781

It is yet unknown how manipulation of endocannabinoid signaling in the lateral habenula alters coping strategies. Given the strong inhibitory influence of the lateral habenula over dorsal raphe serotonin neurons and the ability of stress to recruit endocannabinoids to increase lateral habenula activity, we hypothesize that stress increases 2-AG in the lateral habenula, thereby leading to a reduction in the activity serotonin neurons in the dorsal raphe nucleus. To test this hypothesis, we locally inhibited the synthesis of 2-AG in the lateral habenula in male rats on the final day of a 7-day social defeat stressed paradigm. We then measured the amount of serotonin neuron activation within the dorsal raphe nucleus by co-labeling for tryptophan hydroxylase, which is the enzyme responsible for serotonin synthesis, and the immediate early gene c-fos, which is expressed in recently activated cells. We predicted that inhibition of 2-AG synthesis in the lateral habenula of social defeat stressed rats, will cause an increase in serotonin neuronal activation within the dorsal raphe nucleus, as indicated by a greater density of c-fos protein labeling in these neurons compared to vehicle-treated control rats. Contrary to our hypothesis, we discovered that inhibition of 2-AG synthesis within the lateral habenula dose-dependently decreases activation of dorsal raphe nucleus serotonin neurons under conditions of stress. These results did not support our hypothesis, meaning there has to be a greater influence of 2-AG over excitatory inputs on to lateral habenula neurons under these experimental conditions which might decrease the ability of lateral habenula neurons to dampen serotonin activity under conditions of chronic stress. Altogether, these data indicate that recruitment of endocannabinoid signaling in the lateral habenula may protect against stress-induced reductions in serotonin activity. Future studies will examine whether endocannabinoid signaling predominantly alters excitatory vs. inhibitory inputs on to lateral habenula neurons that project to the dorsal raphe nucleus using a slice electrophysiology approach. Additionally, we can examine whether increasing 2-AG within the lateral habenula exerts antidepressant-like effects in stressed rats by increasing the activity of dorsal raphe serotonin neurons.

Effects of Lateral Habenula 2-Arachidonoylglycerol Manipulation on Dorsal Raphe Nucleus Immediate Early Gene Expression

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