Zhang Yufeng - USD Biology

Serotonin and Impulsivity Yufeng Zhang

Serotonin • Originate from the median and dorsal raphe nuclei. • Serotonin has been implicated in a variety of motor, cognitive, and affective functions such as locomotion, sleep–wake cycles, mood disorders, stress (Li et al., in review) and aggressive behaviors (Bubak et al., 2014) • Reduced levels of 5-HT in the central nervous system promote impulsive behaviors

Serotonin • 5-HT in the central nervous system promote impulsive action and impulsive choice • 5-HT manipulations are more effective on impulsive action than on impulsive choice.

5-CSRTT Impulsive action

Delay discounting task Impulsive choice

Stop-signal task response inhibition

Impulsivity task • Go/No-go task – assesses the ability of subjects to withhold a prepotent response on a small subset of discrete ‘nogo’ trials, which are signalled by a discriminative sensory cue

• 5-CSRTT has no trials with an explicit signal to inhibit responding, nor any feedback that a trial has been successfully inhibited

Serotonin systems • Depletion of 5-HT was accompanied by a selective increase in premature responding on the 5-CSRTT • Administration of SSRIs → increase extracellular serotonin concentrations → increased the selection rate of a large, delayed reward → a decrease in impulsive choice

Agonist and Antagonist • 5-HT agonist – + impulsivity on both reaction time and delay discounting tasks – another agonist - reaction time task but + delay discounting impulsivity – 5-HT reuptake inhibitors - on both the 5-CSRTT and the delay discounting task

• 5-HT antagonist had no effect on 5-CSRTT impulsivity but decreased impulsive responding on the delay discounting task – Nacb, Prefrontal cortex

Direct measurement of 5-HT • premature responses were positively correlated with extracellular levels of 5-HT in the medial PFC – sub-cortical sites may be responsible for the effects of global 5-HT depletion on impulsivity, possibly through interactions with the mesolimbic DA system

• 5-HT levels increased significantly in the medial PFC, but not the OFC on a delay discounting task

Serotonin for delayed reward • 5-HT controls the time scale of reward prediction, with increased 5-HT activity promoting the consideration of further delayed rewards in action choice • in vivo microdialysis, compare 5-HT levels in the DRN were working for immediate or delayed rewards • Food water navigation task

Serotonin for delayed reward • 5-HT neurons exhibited an increase in tonic activity during the period in which the rat waited for forthcoming rewards • Waiting behavior for delayed rewards was the crucial behavioral event for activating 5-HT neurons in the DRN

Serotonin for delayed reward • When the reward and tone delays were independently extended, tonic firing persisted until the delivery of the reward or tone, and the rats waited longer for primary rewards than for the conditioned reinforcer tone

Tone delay was fixed at 1.5s and the reward delay at both sites was increased gradually every 300 s (2, 4, 6, 8, 12 s)

Serotonin for delayed reward • Rewards wait error gradually increased, and 5HT neural activity ceased before the rats ceased waiting for possible future rewards

Serotonin for delayed reward • Rewards wait error gradually increased, and 5HT neural activity ceased before the rats ceased waiting for possible future rewards • When an expected water reward was suddenly omitted for several continuous trials, 5-HT neural activity also dropped

Obtain reward and avoid punishment • 5-HT system is involved in the decrease of behavioral activity both to avoid aversive events with a prediction of punishment as well as to achieve rewards with a prediction of reward • Go/no-go task: action restraint • Stop-signal reaction time task: action cancellation

Obtain reward and avoid punishment • 5-HT depletion impairs waiting but not the stop-signal reaction time, which supports a role of 5-HT in the “waiting to obtain reward” • correct no-go response reward: “waiting to obtain reward” • Incorrect no-go response is punished: “waiting to avoid punishment”

5-HT and neural circuits • The integrity of the NAcc is necessary for the prevention of premature responses • DRN 5-HT neurons project to the NAcc, mPFC, and OFC

In the SDR condition, the rats obtained a reward after 2 s of nose poking. In the LDR condition, the rats were required to poke their nose for 7–11 s.

Results

• The number of total trials was largest during the second 10 min period in the water trials in the SDR condition, although there was no significant difference in the food trials. • Decrease over time in the number of total trials shown by the significant main effect of Time in both food and water trials in the LDR condition

in the long delayed reward condition, the numbers of food and water wait errors significantly increased during the inhibition of 5-HT neural activity while the numbers of total food and water trials were not significantly influenced.

Conclusion • Several different dimensions of impulsivity • Simple monotonic influence of 5-HT on any given aspect of impulsivity is unlikely • A return to 5-HT seems warranted – Interactions between DA and 5-HT in influencing different types of impulsivity