Getting to the Core of the issue between the Nucleus Accumbens and ImpulsivityJustin Achua
Impulsive Choice Induced in Rats by Lesions of the Nucleus Accumbens CoreRudolf N. Cardinal, David R. Pennicott, C. Lakmali Sugathapala, Trevor W. Robbins, and Barry J. Everitt
Why?
Impulsive choice – “Choosing a small or poor reward that is available immediately, in preference to a larger but delayed reward”
Yet the neural mechanisms underlying impulsivity and delayed reinforcement is not understood
Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder (ADHD), mania, and personality disorders
Why the Nucleus Accumbens?
Several studies suggest the Nucleus Accumbens (NAc) and afferents are involved in regulating choice between alternative reinforcers
Anterior cingulate cortex (ACC) and medial prefontal cortex (mPFC)
Why the Nucleus Accumbens?
1.A key site for reinforced learning and motivational impact of impending reinforcers
2.Regulated by Dopamine (DA) and Serotonin (5-HT)
- Manipulation of these systems affect impulsive choice
3.Abnormalities of limbic systems have been observed in impulsive individuals
- Animal models of ADHD have shown abnormal DA release in the NAc and mPFC
- Humans have shown abnormalities in the mPFC and ACC associated with ADHD
How to test this?
Lesions to the nucleus accumbens core (NAcC), ACC, or mPFC in rats testing impulsivity
Rats would select between a smaller immediate appetitive reinforcer and delayed larger reinforcer
The delay to reinforcement would be increase
Materials and Methods
Lister-hooded rats were trained on the task
Ranked into pairs according to sensitivity to delay
Randomly assigned one rat from each pair to recieve excitotoxic lesions and one to recieve sham surgeries
Lesion rats were separated into NAcC, ACC, and mPFC lesioned groups
Delayed Reinforcement Choice Task
Results
Prior to surgery rats shifted preference from the large to small reinforcer as the delay increased
Lesions to NAcC caused a deficit in rats’ ability to choose the delayed reinforcer
Rats became more impulsive
Not due to pre-testing bias
NAcC rats chose larger reinforcer at zero second delay
Lesioned rats were hypersensitive to delays when reintroduced
Results
NAaC lesioned rats were hyperactive, ~10% lighter than controls, and took longer to habituate to novel testing apparatus
Ate slower than control rats, but did not differ in total amount consumed
Unlikely that differences in motivation affected impulsive choice
Results
NAaC lesioned rats displayed two signs of ADHD
Locomotor hyperactivity
Impulsive choice
Attention deficts can not be seen in rats
NAaC lesions can represent hyperactive/impulsive subtype of ADHD
Results
Lesions to the ACC did not affect impulsivity
No change in rats’ ability to choose a delayed reinforcer
Lesions to the mPFC showed an insignificant shift from large to small reinforcer
Lesions to the NAaC induced impulsive choice
Basolateral amygdala and orbitofrontal cortex may promote delayed reinforcers in the NAaC
Effect of NAaC, ACC, and mPFC lesions
Closing Notes
Found that NAc is involved in impulsive choice
NAc could contribute to ADHD, addiction, and other impulse control disorders
Double dissociation of the effects of selective nucleus accumbens core and shell lesions on impulsive-choice behaviour and salience learning in ratsHelen H. J. Pothuizen, Ana L. Jongen-Relo, Joram Feldon, and Benjamin K. Yee
The Nucleus Accumbens
Consists of two subregions
Dorsolateral Core
Ventromedial Shell
The regions are distinguished by:
Locomotion
Explorative behavior
Latent inhibition
Spatial working memory
Prepulse inhibition of the acoustic startle reflex
The Nucleus Accumbens
Also involved in the control of choice behavior
Excitotoxic lesions of the Core result in impulsive behavior
Eg. Choosing a small immediate reward over a larger delayed reward (Cardinal et al., 2001)
Introduction
Compared core and shell lesions of the NAc using:
An initial evaluation of latent inhibition
Similar delayed reward choice paradigm
Differential reinforcement for low rates of responding (DRL) operant task
Materials and Methods
Male Winstar rats were used for all experiments
Animals were separated into core lesion, shell lesion, sham operation, and no operation groups
All test conducted during dark phase
Stereotaxic bilateral lesions were made by injecting N-methyl-D-aspartate (NMDA)
All animals were tested for latent inhibition (LI) then separated into two groups
Delayed reward choice experiment
DRL experiment
Figure 1. Extent of NAcC and NAcS in a coronal plane
Figure 2. Selective NAcC and NAcS lesions
Experiment 1 : Latent inhibition
Rats from the four surgical groups were subdivided into two groups
Pre-exposure (PE)
Nonpre-exposure (NPE)
During pre-exposure PE rats were placed into the testing chamber with the tone stimulus playing
NPE rats were placed into the chamber without tone
The number of crossings was measured as basal locomotor activity
Experiment 1 : Latent inhibition
During conditioning rats were placed into testing chamber for 100 trials
Trials consist of:
10s tone
Followed by 2s foot shock
If subject crosses barrier during first 10s of tone, no foot shock, avoidance response is recorded
If subject crosses barrier during foot shock, foot shock and tone are terminated, escape response is recorded
If subject fails to cross barrier after 2s foot shock, escape failure is recorded
Experiment 1 : Latent inhibition
The number of avoidance response over successive 10-trial blocks were recorded
Measurement of conditioned avoidance learning
LI effect present – lower avoidance response in PE when compared to NPE
LI was reduced in the shell lesioned group when compared to core and sham groups
Selective core lesion did not affect integrity of the shell lesion
Experiment 1 : Latent inhibition
Experiment 2 : Delayed reward choice paradigm
Testing was conducted in phases 3-9 days of forced-trial training
2-10 days of choice-trial testing
No-delay conditioning occurred before every choice-trial
Inside the test chamber there is a CRF lever and PRF lever Continuously reinforced (CRF) lever dispense a food pellet
after a set delay 0, 20, 0, 10, 0, 15, 0, 20s delay respective to each phase
Partially reinforced (PRF) lever has a probability of 25% of dispensing a food pellet
Experiment 2 : Delayed reward choice paradigm Forced-trial training consisted of giving the subject 12
forced CRF trials followed by 12 forced PRF trials
Only one lever was given in testing chamber
Choice-trial training consisted of the presence of both levers
The nonselected lever was immediately removed
The selected lever as removed after 5 presses
If CRF lever selected, light switched on, nose-poke initiates deliver of food pellet
If PRF lever selected, an immediate food pellet or nothing is delivered
Experiment 2 : Delayed reward choice paradigm
20s (1) delayed CRF lever dropped to near chance levels
Shifting of CRF lever towards PRF lever was observed over 5 days of testing for shell lesion and sham groups
Core lesion group remained at chance levels
Experiment 2 : Delayed reward choice paradigm
10s delayed CRF lever shifted away from CRF, but CRF bias remained over 5 days of testing
Experiment 2 : Delayed reward choice paradigm
15s delayed CRF lever comparable to 10s delayed CRF lever with lower CRF bias
Experiment 2 : Delayed reward choice paradigm
20s (2) delayed CRF lever showed a shift of preference away from CRF
Initial shift maintained above chance levels for shell lesion and sham groups
Most pronounced shift in core lesion group
Experiment 3 : Differential reinforcement for low rates of response task
After the first lever press only responses made after a specific delay are reinforced with a food pellet
Premature responses are not rewarded and reset the time to zero
The ration of mean lever-presses per reward is used to analyze DRL performance
Experiment 3 : Differential reinforcement for low rates of response task
DRL-4s – performance improved over the three 2-day blocks
Experiment 3 : Differential reinforcement for low rates of response task
DRL-8s – increase in delay resulted in decreased performance
Performance improved over the three 2-day blocks
Improvement to a lesser degree for the core lesion group
Experiment 3 : Differential reinforcement for low rates of response task
DRL-12s – initial reduction in performance followed by improvement
Continued trend of poor improvement in core lesion group
Experiment 3 : Differential reinforcement for low rates of response task
DRL-18s – initial reduction in performance followed by improvement
Shell lesion and sham groups performance at similar levels
Continued trend of inferior performance in core lesion group
Discussion
Expands upon finding of Cardinal et al., 2001 using a similar delayed reward choice test
Utilizes contrast between reward probability and reward size
Impulsive-like behavior was associated with NAc core damage
DRL performance was impaired by core lesion
Core lesion lead to impulsive-like behavior in delayed reward choice test
NAc shell lesions did not show similar results
Conclusion
LI is not associated with enhanced impulsive behavior
Lesions of the NAc shell abolished LI
Dysfunction of the NAc core, not shell, may be associated with the appearance of impulsive-like behaviors
Evidence by a pronounced shift from choosing the CRF lever to PRF lever
Impaired performance on DRL task
Gamma Aminobutyric Acidergic and Neuronal Structural Markers in the Nucleus Accumbens Core Underlie Trait-like Impulsive BehaviorDaniele Caprioli, Stephen J. Sawiak, Emiliano Merlo, David E.H. Theobald, Marcia Spoelder, Bianca Jupp, Valerie Voon, T. Adrian Carpenter, Barry J. Everitt, Trevor W. Robbins, and Jeffrey W. Dalley
Introduction
Impulsivity – defined as a wide variety of behaviors, including, “A failure of motor inhibition to individual predisposition to choose small, immediate rewards as opposed to large but delayed rewards”
Motor impulsivity – motor response inhibition
Decisional impulsivity – delay discounting and reflection impulsivity
High levels of impulsivity have been associated with:
ADHD
Conduct disorders
Antisocial behaviors
Substance use disorders
Introduction
Mechanisms of impulsivity are not well understood
Deficiencies in norepinephrine (NE) and dopamine (DA)
Abnormalities in PFC and striatum’
Previous research points towards nucleus accumbens
Behavior output in the NAc is governed by GABA-ergic medium-spiny neurons (MSN)
May play a critical role in synaptic transmission in the NAc and impulsivity
Materials and Methods
Lister-hooded rats
Assessed impulsivity using a five-choice serial reaction time task (5-CSRTT)
Subjects were trained on the task and separated into high impulsivity (HI), medium impulsivity (MI), and low impulsivity (LI) groups
Conversion of LI group to HI behavior using IC injection of glutamate decarboxylase (GAD)
Materials and Methods
5-CSRTT – rats were trained to locate a brief visual stimuli in one of 5 apertures
Correct response was rewarded with a food pellet
Incorrect responses, no responses, and premature responses resulted in a 5s time out and no food pellet
HI rats – over 50% of trials with premature responses
LI rats – lowest premature responses
MI rats – intermediate levels of premature responses
MRI was given after the 5-CSRTT
Materials and Methods
LI rats’ NAcC was intracerebrally cannulated
Received bilateral injections of GAD antisense scramble sequence (ASO) or scramble pairs (Scr)
Unilateral injections of ASO and Scr
Cannulated rats were then ran on the 5-CSRTT
Western blot analysis was performed on LI and HI rats
Results
When delay to 5-CSRTT visual stimuli was increased from 5s to 7s
Greatest increase in impulsivity observed in HI rats
MRI revealed a significant reduction of gray matter in the left NAcC of HI rats
Correlated inversely with impulsivity on 5-CSRTT
Western blot analysis of the left NAcC in HI rats showed significantly lower levels of:
GAD
Marker microtubule associated protein (MAP2)
Dendritic spine marker spinophilin
Figure 1
Figure 2
Results
GAD ASO caused a significant increase in impulsivity in LI rats
No effect on locomotor activity, speed, or accuracy on 5-CSRTT
Bilateral injections of GAD ASO resulted in observed increase in impulsivity
Unilateral injections to left or right NAcC showed no significant effect
Confirmed localization of GAD ASO to NAcC core
No presence in NAcS
Figure 3
Discussion
Relationship between nucleus accumbens core and impulsivity on the 5-CSRTT
Reduction of grey matter density in NAcC of HI rats corresponds with impulsivity
Reduction in GAD
Reduction in dendritic spine and microtubule markers
Discussion
Experimentally reducing NAcC GAD in LI rats increased impulsivity
May be caused by impaired DA-ergic and Glu-ergic afferents on dendritic spines of GABA-ergic MSNs
Impulsive functions modulated by GABA-ergic neurons in NAcC
No difference in NeuN
# of neurons in left NAcC of HI rats similar to LI rats
Suggests structural integrity and density of dendritic spines affected by impulsivity of 5-CSRTT
Discussion
Inverse relationship between GAD and impulsivity in left NAcC
Lower levels of GAD present in right NAcC in HI compared to LI
Partial asymmetry may be responsible for the need of bilateral injections of GAD ASO to increase impulsivity in LI
Depletion of GAD in both NAcCs needed for an increase in impulsivity
Conclusion
GABA MSNs play a part in the regulation of impulsivity
Reduction of grey matter in the left NAcC was observed with a decrease in GAD and dendritic spines and microtubules
Reduction in levels of GAD in right NAcC may be critical in the development of HI rats
Dendritic spines on MSNs in the NAcC may be critical in HI rats’ predisposition to escalate nicotine and cocaine self-administration, and relapse after abstinence
Take Home Notes
The nucleus accumbens core, not shell, is involved in hyperactivity impulsivity
Lesions of the NAcC gave similar results to disinhibition of the NAcC
An inability to delay gratification
Impulsivity can be increased in low impulsivity subjects through reduction of GABA
GAD reduction must occur in the left NAcC
Similar reduction may be necessary in right NAcC as well