Download 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