Getting to the Core of the issue between the Nucleus Accumbens and Impulsivity

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


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


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


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 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


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


10s delayed CRF lever shifted away from CRF, but CRF bias remained over 5 days of testing


15s delayed CRF lever comparable to 10s delayed CRF lever with lower CRF bias


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


DRL-4s – performance improved over the three 2-day blocks


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


DRL-12s – initial reduction in performance followed by improvement

Continued trend of poor improvement in core lesion group


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


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)


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


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

Documents

Getting to the Core of the issue between the Nucleus Accumbens and Impulsivity