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The
nucleus accumbens (
NAc or
NAcc), also known as the
accumbens nucleus, or formerly as the
nucleus accumbens septi (Latin for
nucleus adjacent to the septum) is a region in the
basal forebrain rostral to the
preoptic area of the
hypothalamus. The nucleus accumbens and the
olfactory tubercle collectively form the
ventral striatum. The ventral striatum and
dorsal striatum collectively form the
striatum, which is the main component of the
basal ganglia. The
dopaminergic neurons of the
mesolimbic pathway project onto the
GABAergic medium spiny neurons of the nucleus accumbens and
olfactory tubercle. Each
cerebral hemisphere
has its own nucleus accumbens, which can be divided into two
structures: the nucleus accumbens core and the nucleus accumbens shell.
These substructures have different morphology and functions.
Different NAcc subregions (core vs shell) and neuron subpopulations within each region (
D1-type vs.
D2-type medium spiny neurons) are responsible for different
cognitive functions.
[5][6] As a whole, the nucleus accumbens has a significant role in the cognitive processing of
motivation,
aversion,
reward (i.e.,
incentive salience,
pleasure, and
positive reinforcement), and
reinforcement learning (e.g.,
Pavlovian-instrumental transfer);
[4][7][8][9][10] hence, it has a significant role in
addiction.
[4][8] In addition, part of the nucleus accumbens core is centrally involved in the induction of
slow-wave sleep.
[11][12][13][14] The nucleus accumbens plays a lesser role in processing
fear (a form of aversion),
impulsivity, and the
placebo effect.
[15][16][17] It is involved in the encoding of new
motor programs as well.
[4]
Structure
The nucleus accumbens is an aggregate of neurons which is described as having an outer shell and an inner core.
[4]
Input
Major glutamatergic inputs to the nucleus accumbens include the
prefrontal cortex (particularly the
prelimbic cortex and
infralimbic cortex),
basolateral amygdala, ventral
hippocampus,
thalamic nuclei (specifically the
midline thalamic nuclei and
intralaminar nuclei of the thalamus), and glutamatergic projections from the
ventral tegmental area.
[18] The nucleus accumbens receives
dopaminergic inputs from the
ventral tegmental area (VTA), which connect via the
mesolimbic pathway. The nucleus accumbens is often described as one part of a
cortico-basal ganglia-thalamo-cortical loop.
[19]
Dopaminergic inputs from the VTA modulate the activity of
GABAergic neurons within the nucleus accumbens. These neurons are activated directly or indirectly by
euphoriant drugs (e.g.,
amphetamine,
opiates, etc.) and by participating in rewarding experiences (e.g., sex, music, exercise, etc.).
[20][21]
Another major source of input comes from the CA1 and ventral
subiculum of the
hippocampus to the
dorsomedial
area of the nucleus accumbens. Slight depolarizations of cells in the
nucleus accumbens correlates with positivity of the neurons of the
hippocampus, making them more excitable. The correlated cells of these
excited states of the medium spiny neurons in the nucleus accumbens are
shared equally between the subiculum and CA1. The subiculum neurons are
found to hyperpolarize (increase negativity) while the CA1 neurons
"ripple" (fire > 50 Hz) in order to accomplish this priming.
[22]
The nucleus accumbens is one of the few regions that receive histaminergic projections from the
tuberomammillary nucleus (the sole source of
histamine neurons in the brain).
[23]
Output
The output neurons of the nucleus accumbens send
axonal projections to the
basal ganglia and the ventral analog of the
globus pallidus, known as the
ventral pallidum (VP). The VP, in turn, projects to the
medial dorsal nucleus of the dorsal
thalamus, which projects to the
prefrontal cortex as well as the
striatum. Other efferents from the nucleus accumbens include connections with the
tail of the ventral tegmental area,
[24] substantia nigra, and the
reticular formation of the
pons.
[1]
Shell
The
nucleus accumbens shell (
NAcc shell) is a substructure of the nucleus accumbens. The shell and core together form the entire nucleus accumbens.
Location: The shell is the outer region of the nucleus accumbens, and – unlike the core – is considered to be part of the
extended amygdala, located at its rostral pole.
Cell types: Neurons in the nucleus accumbens are mostly
medium spiny neurons (MSNs) containing mainly
D1-type (i.e.,
DRD1 and
DRD5) or
D2-type (i.e.,
DRD2,
DRD3, and
DRD4)
dopamine receptors. A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both
DRD1 and
DRD2 mRNA.
[19][25][26] These mixed-type NAcc MSNs with both D1-type and D2-type receptors are mostly confined to the NAcc shell.
[19] The neurons in the shell, as compared to the core, have a lower density of
dendritic spines,
less terminal segments, and less branch segments than those in the
core. The shell neurons project to the subcommissural part of the
ventral pallidum as well as the ventral tegmental area and to extensive areas in the
hypothalamus and
extended amygdala.
[27][28][29]
Function: The shell of the nucleus accumbens is involved in the cognitive processing of
reward, including subjective "liking" reactions to certain
pleasurable stimuli,
motivational salience, and
positive reinforcement.
[4][5][30][31] That NAcc shell has also been shown to mediate
specific Pavlovian-instrumental transfer, a phenomenon in which a
classically conditioned stimulus modifies
operant behavior.
[32][9][10]
A "hedonic hotspot" or pleasure center which is responsible for the
pleasurable or "liking" component of some intrinsic rewards is also
located in a small compartment within the medial NAcc shell.
[30][33][34] The D1-type medium spiny neurons in the Nacc shell mediate reward-related cognitive processes,
[5][35][36] whereas the D2-type medium spiny neurons in the NAcc shell mediate aversion-related cognition.
[6] Addictive drugs have a larger effect on dopamine release in the shell than in the core.
[4]
Core
The
nucleus accumbens core (
NAcc core) is the inner substructure of the nucleus accumbens.
Location: The nucleus accumbens core is part of the
ventral striatum, located within the
basal ganglia.
Cell types: The core of the NAcc is made up mainly of
medium spiny neurons
containing mainly D1-type or D2-type dopamine receptors. The neurons in
the core, as compared to the neurons in the shell, have an increased
density of
dendritic spines, branch segments, and terminal segments. From the core, the neurons project to other sub-cortical areas such as the
globus pallidus and the
substantia nigra.
GABA is one of the main neurotransmitters in the NAcc, and
GABA receptors are also abundant.
[27][29]
Function: The nucleus accumbens core is involved in the cognitive processing of
motor function related to reward and reinforcement and the regulation of
slow-wave sleep.
[4][11][12][13] Specifically, the core encodes new motor programs which facilitate the acquisition of a given reward in the future.
[4] The indirect pathway (i.e., D2-type) neurons in the NAcc core which co-express
adenosine A2A receptors activation-dependently promote slow-wave sleep.
[11][12][13] The NAcc core has also been shown to mediate
general Pavlovian-instrumental transfer, a phenomenon in which a
classically conditioned stimulus modifies
operant behavior.
[32][9][10]
Cell types
Approximately 95% of neurons in the NAcc are GABAergic
medium spiny neurons (MSNs) which primarily express either
D1-type or
D2-type receptors;
[20] about 1–2% of the remaining neuronal types are large aspiny
cholinergic interneurons and another 1–2% are GABAergic interneurons.
[20] Compared to the GABAergic MSNs in the shell, those in the core have an increased density of
dendritic spines, branch segments, and terminal segments. From the core, the neurons project to other sub-cortical areas such as the
globus pallidus and the
substantia nigra.
GABA is one of the main neurotransmitters in the NAcc, and
GABA receptors are also abundant.
[27][29] These neurons are also the main projection or output neurons of the nucleus accumbens.
Neurochemistry
Some of the neurotransmitters, neuromodulators, and hormones that signal through receptors within the nucleus accumbens include:
Dopamine: Dopamine is released into the nucleus accumbens following exposure to
rewarding stimuli, including
recreational drugs like
substituted amphetamines,
cocaine, and
morphine.
[37][38]
Phenethylamine and
tyramine:
Phenethylamine and
tyramine are
trace amines which are synthesized in neurons that express the
aromatic amino acid hydroxylase (AADC)
enzyme, which includes all dopaminergic neurons.
[39] Both compounds function as dopaminergic
neuromodulators which regulate the reuptake and release of dopamine into the Nacc via interactions with
VMAT2 and
TAAR1 in the axon terminal of mesolimbic dopamine neurons.
Glucocorticoids and dopamine: Glucocorticoid receptors are the only
corticosteroid receptors in the nucleus accumbens shell.
L-DOPA,
steroids,
and specifically glucocorticoids are currently known to be the only
known endogenous compounds that can induce psychotic problems, so
understanding the hormonal control over dopaminergic projections with
regards to glucocorticoid receptors could lead to new treatments for
psychotic symptoms. A recent study demonstrated that suppression of the
glucocorticoid receptors led to a decrease in the release of dopamine,
which may lead to future research involving anti-glucocorticoid drugs to
potentially relieve psychotic symptoms.
[40]
GABA: A recent study on rats that used
GABA agonists and antagonists indicated that
GABAA receptors in the NAc shell have inhibitory control on turning behavior influenced by dopamine, and
GABAB receptors have inhibitory control over turning behavior mediated by
acetylcholine.
[27][41]
Glutamate: Studies have shown that local blockade of
glutamatergic NMDA receptors in the NAcc core impaired spatial learning.
[42] Another study demonstrated that both NMDA and AMPA (both
glutamate receptors) play important roles in regulating instrumental learning.
[43]
Serotonin (5-HT): Overall,
5-HT
synapses are more abundant and have a greater number of synaptic
contacts in the NAc shell than in the core. They are also larger and
thicker, and contain more large dense core vesicles than their
counterparts in the core.
Function
Reward and reinforcement
The nucleus accumbens, being one part of the
reward system,
plays an important role in processing rewarding stimuli, reinforcing
stimuli (e.g., food and water), and those which are both rewarding and
reinforcing (addictive drugs, sex, and exercise).
[4][44] The predominant response of neurons in the nucleus accumbens to the reward
sucrose is inhibition; the opposite is true in response to the administration of aversive
quinine.
[45]
Substantial evidence from pharmacological manipulation also suggests
that reducing the excitability of neurons in the nucleus accumbens is
rewarding, as, for example, would be true in the case of
μ-opioid receptor stimulation.
[46] The
blood oxygen level dependent signal (BOLD)
in the nucleus accumbens is selectively increased during the perception
of pleasant, emotionally arousing pictures and during mental imagery of
pleasant, emotional scenes. However, as BOLD is thought to be an
indirect measure of regional net excitation to inhibition, the extent to
which BOLD measures valence dependent processing is unknown.
[47][48]
Because of the abundance of NAcc inputs from limbic regions and strong
NAcc outputs to motor regions, the nucleus accumbens has been described
by Gordon Mogensen as the interface between the limbic and motor system.
[49][50]
Tuning
of appetitive and defensive reactions in the nucleus accumbens shell.
(Above) AMPA blockade requires D1 function in order to produce motivated
behaviors, regardless of valence, and D2 function to produce defensive
behaviors. GABA agonism, on the other hand, does not requires dopamine
receptor function.(Below)The expansion of the anatomical regions that
produce defensive behaviors under stress, and appetitive behaviors in
the home environment produced by AMPA antagonism. This flexibility is
less evident with GABA agonism.
[51]
The nucleus accumbens is causally related to the experience of pleasure. Microinjections of
μ-opioid agonists,
δ-opioid agonists or
κ-opioid agonists
in the rostrodorsal quadrant of the medial shell enhance "liking",
while more caudal injections can inhibit disgust reactions, liking
reactions, or both.
[30]
The regions of the nucleus accumbens that can be ascribed a causal
role in the production of pleasure are limited both anatomically and
chemically, as besides opioid agonists only
endocannabinoids can enhance liking. In the nucleus accumbens as a whole, dopamine,
GABA receptor agonist or
AMPA antagonists solely modify
motivation,
while the same is true for opioid and endocannabinoids outside of the
hotspot in the medial shell. A rostro-caudal gradient exists for the
enhancement of appetitive versus fearful responses, the later of which
is traditionally thought to require only D1 receptor function, and the
former of which requires both D1 and D2 function. One interpretation of
this finding, the disinhibition hypothesis, posits that inhibition of
accumbens MSNs(which are GABAergic) disinhibits downstream structures,
enabling the expression of appetitive or consummatory behaviors.
[52]
The motivational effects of AMPA antagonists, and to a lesser extent
GABA agonists, is anatomically flexible. Stressful conditions can
expand the fear inducing regions, while a familiar environment can
reduce the size of the fear inducing region. Furthermore, cortical
input from the
orbitofrontal cortex (OFC) biases the response towards that of appetitive behavior, and
infralimbic input, equivalent to the human subgenual cingulate cortex, suppresses the response regardless of valence.
[30]
The nucleus accumbens is neither necessary nor sufficient for
instrumental learning, although manipulations can affect performance on
instrumental learning tasks. One task where the effect of NAc lesions
is evident is
Pavlovian-instrumental transfer (PIT),
where a cue paired with a specific or general reward can enhance
instrumental responding. Lesions to the core of the NAc impair
performance after devaluation and inhibit the effect of general PIT. On
the other hand, lesions to the shell only impair the effect of specific
PIT. This distinction is thought to reflect consummatory and
appetitive conditioned responses in the NAc shell and the NAc core,
respectively.
[53]
In the dorsal striatum, a dichotomy has been observed between
D1-MSNs and D2-MSNs, with the former being reinforcing and enhancing
locomotion, and the latter being aversive and reducing locomotion. Such
a distinction has been traditionally assumed to apply to the nucleus
accumbens as well, but evidence from pharmacological and optogenetics
studies is conflicting. Furthermore, a subset of NAc MSNs express both
D1 and D2 MSNs, and pharmacological activation of D1 versus D2 receptors
need not necessarily activate the neural populations exactly. While
most studies show no effect of selective optogenetic stimulation of D1
or D2 MSNs on locomotor activity, one study has reported a decrease in
basal locomotion with D2-MSN stimulation. While two studies have
reported reduced reinforcing effects of cocaine with D2-MSN activation,
one study has reported no effect. NAc D2-MSN activation has also been
reported to enhance motivation, as assessed by PIT, and D2 receptor
activity is necessary for the reinforcing effects of VTA stimulation.
[54]
A 2018 study reported that D2 MSN activation enhanced motivation via
inhibiting the ventral pallidum, thereby disinhibiting the VTA.
[55]
Maternal behavior
An
fMRI
study conducted in 2005 found that when mother rats were in the
presence of their pups the regions of the brain involved in
reinforcement, including the nucleus accumbens, were highly active.
[56]
Levels of dopamine increase in the nucleus accumbens during maternal
behavior, while lesions in this area upset maternal behavior.
[57]
When women are presented pictures of unrelated infants, fMRIs show
increased brain activity in the nucleus accumbens and adjacent caudate
nucleus, proportionate to the degree to which the women find these
infants "cute".
[58]
Aversion
Activation of D1-type MSNs in the nucleus accumbens is involved in
reward, whereas the activation of D2-type MSNs in the nucleus accumbens promotes
aversion.
[6]
Slow-wave sleep
In late 2017, studies on rodents which utilized
optogenetic and
chemogenetic methods found that the indirect pathway (i.e., D2-type)
medium spiny neurons in the nucleus accumbens core which co-express
adenosine A2A receptors and project to the
ventral pallidum are involved in the regulation of
slow-wave sleep.
[11][12][13][14]
In particular, optogenetic activation of these indirect pathway NAcc
core neurons induces slow-wave sleep and chemogenetic activation of the
same neurons increases the number and duration of slow-wave sleep
episodes.
[12][13][14] Chemogenetic inhibition of these NAcc core neurons suppresses sleep.
[12][13] In contrast, the D2-type medium spiny neurons in the NAcc shell which express adenosine A
2A receptors have no role in regulating slow-wave sleep.
[12][13]
Clinical significance
Addiction
Current models of addiction from chronic drug use involve alterations in
gene expression in the
mesocorticolimbic projection.
[20][59][60] The most important
transcription factors that produce these alterations are
ΔFosB, cyclic adenosine monophosphate (
cAMP) response element binding protein (
CREB), and nuclear factor kappa B (
NFκB).
[20] ΔFosB is the most significant gene transcription factor in addiction since its
viral or genetic overexpression in the nucleus accumbens is
necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in
self-administration and
reward sensitization) seen in drug addiction.
[20][35][61] ΔFosB overexpression has been implicated in addictions to
alcohol (ethanol),
cannabinoids,
cocaine,
methylphenidate,
nicotine,
opioids,
phencyclidine,
propofol, and
substituted amphetamines, among others.
[20][59][61][62][63]
Increases in nucleus accumbens ΔJunD expression can reduce or, with a
large increase, even block most of the neural alterations seen in
chronic drug abuse (i.e., the alterations mediated by ΔFosB).
[20]
ΔFosB also plays an important role in regulating behavioral
responses to natural rewards, such as palatable food, sex, and exercise.
[20][21]
Natural rewards, like drugs of abuse, induce ΔFosB in the nucleus
accumbens, and chronic acquisition of these rewards can result in a
similar pathological addictive state through ΔFosB overexpression.
[20][21][44] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards as well;
[20][21][44] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.
[21]
Research on the interaction between natural and drug rewards suggests
that psychostimulants and sexual behavior act on similar biomolecular
mechanisms to induce ΔFosB in the nucleus accumbens and possess
cross-sensitization effects that are mediated through ΔFosB.
[44][64]
Similar to drug rewards, non-drug rewards also increase the level
of extracellular dopamine in the NAcc shell. Drug-induced dopamine
release in the NAcc shell and NAcc core is usually not prone to
habituation (i.e., the development of
drug tolerance:
a decrease in dopamine release from future drug exposure as a result of
repeated drug exposure); on the contrary, repeated exposure to drugs
that induce dopamine release in the NAcc shell and core typically
results in
sensitization
(i.e., the amount of dopamine that is released in the NAcc from future
drug exposure increases as a result of repeated drug exposure).
Sensitization of dopamine release in the NAcc shell following repeated
drug exposure serves to strengthen stimulus-drug associations (i.e.,
classical conditioning that occurs when drug use is repeatedly paired with environmental stimuli) and these associations become less prone to
extinction
(i.e., "unlearning" these classically conditioned associations between
drug use and environmental stimuli becomes more difficult). After
repeated pairing, these classically conditioned environmental stimuli
(e.g., contexts and objects that are frequently paired with drug use)
often become
drug cues which function as
secondary reinforcers of drug use (i.e., once these associations are established, exposure to a paired environmental stimulus triggers
a craving or desire to use the drug which they've become associated with).
[27][38]
In contrast to drugs, the release of dopamine in the NAcc shell
by many types of rewarding non-drug stimuli typically undergoes
habituation following repeated exposure (i.e., the amount of dopamine
that is released from future exposure to a rewarding non-drug stimulus
normally decreases as a result of repeated exposure to that stimulus).
[27][38]
Depression
In April 2007, two research teams reported on having inserted electrodes into the nucleus accumbens in order to use
deep brain stimulation to treat severe
depression.
[65]
In 2010, experiments reported that deep brain stimulation of the
nucleus accumbens was successful in decreasing depression symptoms in
50% of patients who did not respond to other treatments such as
electroconvulsive therapy.
[66]
Nucleus accumbens has also been used as a target to treat small groups
of patients with therapy-refractory obsessive-compulsive disorder.
[67]
Ablation
To treat addiction and in an attempt to treat mental illness
radiofrequency ablation of the nucleus accumbens has been performed. The results are inconclusive and controversial.
[68][69]
Placebo effect
Activation of the NAcc has been shown to occur in the anticipation of effectiveness of a drug when a user is given a
placebo, indicating a contributing role of the nucleus accumbens in the
placebo effect.
[16][70]
Additional images
-
MRI coronal slice showing nucleus accumbens outlined in red
Sagittal MRI slice with highlighting (red) indicating the nucleus accumbens.
.jpg)
