By densely innervating multiple forebrain targets, serotonin-producing neurons affect complex physiological and behavioral responses, an effect that may involve cross-talk with additional neurotransmitter systems. To selectively manipulate endogenous serotonergic activity in the living brain and identify the brainwide substrates modulated by serotonin (5-HT) neurotransmission, we generated two novel DREADD (Designed Receptors Exclusively Activated by Designed Drugs) conditional knock-in mouse models (hMD3q and hM4Di) that, crossed with Pet1-Cre transgenic mice, allowed us to activate (hM3Dq) or inhibit (hM4Di) 5-HT neurons firing in a time-controlled manner by systemic administration of Clozapine-N-Oxide (CNO). By using functional magnetic resonance imaging (fMRI) and c-Fos immunostaining, we demonstrate that chemogenetically evoked 5-HT results in region-specific activation of cortical and subcortical brain substrates involved in emotional responses, plus a specific and robust activation of focal terminals of the dopamine (DA) reward-systems, suggesting a possible 5-HT-mediated modulation of reward processing. To probe this hypothesis, we chemogenetically inhibited 5-HT raphe neurons during a sucrose preference test and show that serotonergic neurons exerts a permissive role for the expression of this hedonic behavior. We also demonstrate that the same inhibition does not induce depressive-like behaviors, arguing against contribution of confounding hypo-hedonic states. Collectively, our results document a previously unreported permissive role of 5-HT neurons on hedonic behavior and corroborate the emerging view of a central role of 5-HT neurotransmission in reward processing
A permissive role of serotonergic neurons on hedonic behavior
GIORGI, ANDREA;MADDALONI, GIACOMO;MIGLIARINI, SARA;PASQUALETTI, MASSIMO
2016-01-01
Abstract
By densely innervating multiple forebrain targets, serotonin-producing neurons affect complex physiological and behavioral responses, an effect that may involve cross-talk with additional neurotransmitter systems. To selectively manipulate endogenous serotonergic activity in the living brain and identify the brainwide substrates modulated by serotonin (5-HT) neurotransmission, we generated two novel DREADD (Designed Receptors Exclusively Activated by Designed Drugs) conditional knock-in mouse models (hMD3q and hM4Di) that, crossed with Pet1-Cre transgenic mice, allowed us to activate (hM3Dq) or inhibit (hM4Di) 5-HT neurons firing in a time-controlled manner by systemic administration of Clozapine-N-Oxide (CNO). By using functional magnetic resonance imaging (fMRI) and c-Fos immunostaining, we demonstrate that chemogenetically evoked 5-HT results in region-specific activation of cortical and subcortical brain substrates involved in emotional responses, plus a specific and robust activation of focal terminals of the dopamine (DA) reward-systems, suggesting a possible 5-HT-mediated modulation of reward processing. To probe this hypothesis, we chemogenetically inhibited 5-HT raphe neurons during a sucrose preference test and show that serotonergic neurons exerts a permissive role for the expression of this hedonic behavior. We also demonstrate that the same inhibition does not induce depressive-like behaviors, arguing against contribution of confounding hypo-hedonic states. Collectively, our results document a previously unreported permissive role of 5-HT neurons on hedonic behavior and corroborate the emerging view of a central role of 5-HT neurotransmission in reward processingI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
