Elucidating actions of DRN 5HT neurons on behavior and circuits with DREADDS

Elucidating how the brain’s serotonergic network mediates diverse behavioral actions over both relatively short (minutes-hours) and long period of time (days-weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility and spatio-temporal control. Recently we have demonstrated that our chemogenetic approach (eg, Designer ReceptorsExclusively Activated by Designer Drugs, DREADDs) provides a reliable and robust tool for controlling genetically defined neural populations. Here we show how short- and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short- and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network activity via a recently developed non-invasive imaging technology DREAMM (DREADD Associated Metabolic Mapping). Our findings reveal a previously unappreciated brain network elicited by selective activation of DRN serotonin neurons and illuminate potential therapeutic and adverse effects of drugs targeting DRN neurons.

Major technical issues addressed:

  1. How to dose CNO chronically via drinking water
  2. Chronic CNO does not lead to desensitization of DREADDs expressed in DRN 5HT neurons
  3. DREAMM is useful to elucidate brain networks
  4. Acute vs chronic driving of DRN 5HT neurons has differential effects on behavior


  1. Hi,
    1. I see that here CNO was provided in the drinking water at a concentration of 40 mg/l but in your protocol it's only 5mg/200ml(=25mg/l), what would you recommend using?
    2. Is it possible to prepare the mix in advance and freeze until use?
    Thank you!

  2. 1. 25 or 40 makes very little difference in experimental design
    2. Do not freeze nor prepare in advance


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