The neuromodulator serotonin has been implicated in a variety of functions that involve patience or impulse control. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, the team studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next. Critically, mice were required to actively nose-poke in order to exploit a given site. The team show that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increases the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function.
In order to optically stimulate ChR2-expressing 5-HT neurons, the team used blue light from a 473 nm laser that was controlled by an acousto-optical modulator (AOM; MTS110-A1-VIS or MTS110-A3- VIS, AA optoelectronic, Orsay, France). Light exiting the AOM was focused into an optical fiber patchcord connected to a second fiber patchcord through a rotary joint (FRJ 1 × 1, Doric lenses), which was then connected to the chronically implanted optic fiber cannula.
In order to confirm the effectiveness of our photostimulation protocol, the team recorded electrophysiological responses in ChR2-eYFP-expressing anesthetized mice (Supplementary Fig. 5). An optrode consisting of an optical fiber (200 µm diameter) coupled to a 470 nm laser (Laserglow Technologies) and a microelectrode (1–3 MΩ; FHC) was lowered into the DRN at a 32° angle. Multi-units were acquired digitally using the Spike2 software (Cambridge Electronic Design). Data were stored on a personal computer for offline analysis. Each recording session consisted of 10 15 s long photostimulation sweeps (10 ms pulse width, 25 Hz) and a 60 s interval was inserted between sweeps to allow for activity to return to baseline. In total, the team recorded seven multi-units from two ChR2-expressing SERT-Cre mice.
The team found that optogenetic activation of DRN 5-HT neurons increases the number of active nose-pokes a mouse would carry out in an attempt to gain water before giving up. These results contradict the behavioral inhibition hypothesis and support the notion that 5-HT promotes waiting by enhancing persistence in the face of uncertainty and delay.
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