Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Abstract

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 Receptors Exclusively 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.

DREADDs for Neuroscientists

“…More modest life-long expression of the Gs-DREADD (GsD) also was attained without any detectible electrophysiological, behavioral, or anatomical phenotype (Farrell et al, 2013). High levels of virally mediated expression of various DREADDs have yet not been reported to yield any significant basal phenotypes (Urban et al, 2015; Vardy et al, 2015; Denis et al, 2015; Isosaka et al, 2015; Hayashi et al, 2015). Of course, the absence of reports of basal activity does not imply the absence of basal activity.…”

“…Based on many reports, CNO appears to be pharmacologically and behaviorally inert in mice (Alexander et al, 2009; Krashes et al, 2011; Farrell et al, 2013; Guettier et al, 2009; Urban et al, 2015; Zhu et al, 2014) and rats (Ferguson et al, 2011, 2013) when administered at the recommended doses (generally 0.1–3 mg/kg). CNO may be metabolized via back-transformation to clozapine—especially in guinea pigs, humans (Jann et al, 1994), and nonhuman primates (unpublished obsrevations).…”

“…Many therapeutic applications of DREADD-based therapeutics have been suggested, including diabetes (Jain et al, 2013), metabolic disorders (Li et al, 2013), Parkinson’s Disease (Dell’Anno et al, 2014), psychostimulant (Ferguson et al, 2011) and ethanol (Pleil et al, 2015) abuse, depression (Urban et al, 2015), post-traumatic stress disorder (Zhu et al, 2014), intractable seizures (Kätzel et al, 2014), inflammatory disorders (Park et al, 2014), autism (Peñagarikano et al, 2015), and many other disorders (English and Roth, 2015). DREADDs have been successfully expressed in nonhuman primates without apparent toxicity, and an exciting new report demonstrates that CNO-DREADDs can modulate circuitry, electrophysiology, and behavior in nonhuman primates (Eldridge et al, 2016).…”

DREADDS: Use and application in behavioral neuroscience.

“…PAC dynorphin neuron inhibition increased blood corticosterone levels, decreased voluntary sucrose intake, increased freezing behavior, and increased metabolic activity in extended amygdala structures including medial and central amygdala, accumbens shell, and BNST. This group has since used the same DREAMM technique to examine circuit effects of manipulating D1/D2 nucleus accumbens neurons, and dorsal raphe serotonin neurons (Michaelides et al, 2013; Urban et al, 2015). These findings highlight the usefulness of DREADDs to non-invasively perturb nodes in behavior-related brain circuits while simultaneously examining wider neuronal circuit activity in vivo.…”

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels

“…The most frequently prescribed medications for depression and anxiety disorders target the serotonin (5-HT) producing neurons (Blier et al, 1990; Nutt, 2005), the majority of which are located in the dorsal raphe nucleus (DRN) (Descarries et al, 1982). The activity of 5-HT neurons is highly vulnerable to stress (Lira et al, 2003; Bambico et al, 2009; Espallergues et al, 2012; Challis et al, 2013) and is critical for depressive-like, anxiogenic, and reward-associated behaviors (Liu et al, 2014; Teissier et al, 2015; Urban et al, 2016). Interestingly, social isolation in rodents has been shown to affect endogenous 5-HT release and 5-HT turnover in postsynaptic areas (Heidbreder et al, 2000; Muchimapura et al, 2002, 2003).…”