The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'',
Latin
Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...
for "
nucleus adjacent to the
septum") is a region in the
basal forebrain
Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal b ...
rostral to the
preoptic area
The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular).
Functions
The preoptic area is responsible for ther ...
of the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
.
[ ] The nucleus accumbens and the
olfactory tubercle collectively form the
ventral striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutam ...
. The ventral striatum and
dorsal striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutama ...
collectively form the
striatum, which is the main component of the
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
. The
dopaminergic neurons of the
mesolimbic pathway
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmentum, ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the for ...
project onto the
GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle.
Figure 3: The ventral striatum and self-administration of amphetamine
/ref> Each cerebral hemisphere
The vertebrate cerebrum (brain) is formed by two cerebral hemispheres that are separated by a groove, the longitudinal fissure. The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres ...
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
The D2-like receptors are a subfamily of dopamine receptors that bind the endogenous neurotransmitter dopamine. The D2-like subfamily consists of three G-protein coupled receptors that are coupled to Gi/Go and mediate inhibitory neurotransmissio ...
medium spiny neurons) are responsible for different cognitive functions
Cognitive skills, also called cognitive functions, cognitive abilities or cognitive capacities, are brain-based skills which are needed in acquisition of knowledge, manipulation of information and reasoning. They have more to do with the mechanisms ...
. 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
In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher fr ...
), and reinforcement
In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher fr ...
learning (e.g., Pavlovian-instrumental transfer
Pavlovian-instrumental transfer (PIT) is a psychological phenomenon that occurs when a conditioned stimulus (CS, also known as a "cue") that has been associated with rewarding or aversive stimuli via classical conditioning alters motivational sal ...
); hence, it has a significant role in addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
. In addition, part of the nucleus accumbens core is centrally involved in the induction of slow-wave sleep. The nucleus accumbens plays a lesser role in processing fear
Fear is an intensely unpleasant emotion in response to perceiving or recognizing a danger or threat. Fear causes physiological changes that may produce behavioral reactions such as mounting an aggressive response or fleeing the threat. Fear ...
(a form of aversion), impulsivity, and the placebo effect
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
. It is involved in the encoding of new motor programs as well.
Structure
The nucleus accumbens is an aggregate of neurons which is described as having an outer shell and an inner core.
Input
Major glutamatergic
Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonis ...
inputs to the nucleus accumbens include the prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46 ...
(particularly the prelimbic cortex
The dorsomedial prefrontal cortex (dmPFC or DMPFC is a section of the prefrontal cortex in some species' brain anatomy. It includes portions of Brodmann areas BA8, BA9, BA10, BA24 and BA32, although some authors identify it specifically wi ...
and infralimbic cortex
The infralimbic cortex (IL) is a cortical region in the ventromedial prefrontal cortex which is important in tonic inhibition of subcortical structures and emotional responses, such as fear.
Structure
Connectivity
Primates
GABAergic neurons wi ...
), basolateral amygdala, ventral hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
, thalamic nuclei (specifically the midline thalamic nuclei and intralaminar nuclei of the thalamus), and glutamatergic projections from the ventral tegmental area (VTA).
Figure 1: Glutamatergic afferents to the nucleus accumbens involved in addictive behavior
/ref> The nucleus accumbens receives dopaminergic inputs from the ventral tegmental area, which connect via the mesolimbic pathway
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmentum, ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the for ...
. The nucleus accumbens is often described as one part of a cortico-basal ganglia-thalamo-cortical loop
The cortico-basal ganglia-thalamo-cortical loop (CBGTC loop) is a system of neural circuits in the brain. The loop involves connections between the cortex, the basal ganglia, the thalamus, and back to the cortex. It is of particular relevance t ...
.
Dopaminergic inputs from the VTA modulate the activity of GABAergic neurons within the nucleus accumbens. These neurons are activated directly or indirectly by euphoriant
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...
drugs (e.g., amphetamine, opiates, etc.) and by participating in rewarding experiences (e.g., sex, music, exercise, etc.).
Another major source of input comes from the CA1 and ventral subiculum
The subiculum (Latin for "support") is the most inferior component of the hippocampal formation. It lies between the entorhinal cortex and the CA1 subfield of the hippocampus proper.
The subicular complex comprises a set of related structures ...
of the hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
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.
The nucleus accumbens is one of the few regions that receives a high density of histaminergic projections from the tuberomammillary nucleus
The tuberomammillary nucleus (TMN) is a histaminergic nucleus located within the posterior third of the hypothalamus. It consists of, largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, l ...
(the sole source of histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...
neurons in the brain).
Output
The output neurons of the nucleus accumbens send axonal projections to the basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
and the ventral analog of the globus pallidus, known as the ventral pallidum
The ventral pallidum (VP) is a structure within the basal ganglia of the brain. It is an output nucleus whose fibres project to thalamic nuclei, such as the ventral anterior nucleus, the ventral lateral nucleus, and the medial dorsal nucleus.
The ...
(VP). The VP, in turn, projects to the medial dorsal nucleus
The medial dorsal nucleus (or dorsomedial nucleus of thalamus) is a large nucleus in the thalamus.
It is believed to play a role in memory.
Structure
It relays inputs from the amygdala and olfactory cortex and projects to the prefrontal cortex ...
of the dorsal thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
, which projects to the prefrontal cortex as well as back to the ventral and to dorsal striatum. Other efferents from the nucleus accumbens include connections with the tail of the ventral tegmental area, substantia nigra, and the reticular formation of the pons
The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum.
The pons is also called the pons Varolii ("bridge of Va ...
.
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 The extended amygdala is a macrostructure in the brain that is involved in reward cognition and defined by connectivity and neurochemical staining. It includes the central medial amygdala, sublenticular substantia innominata, and the bed nucleus o ...
, 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
The D2-like receptors are a subfamily of dopamine receptors that bind the endogenous neurotransmitter dopamine. The D2-like subfamily consists of three G-protein coupled receptors that are coupled to Gi/Go and mediate inhibitory neurotransmissio ...
(i.e., DRD2, DRD3
Dopamine receptor D3 is a protein that in humans is encoded by the ''DRD3'' gene.
This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in ph ...
, and DRD4
The dopamine receptor D4 is a dopamine D2-like G protein-coupled receptor encoded by the gene on chromosome 11 at 11p15.5.
The structure of DRD4 was recently reported in complex with the antipsychotic drug nemonapride.
As with other dopamine ...
) dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
s. A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both DRD1 and DRD2 mRNA. These mixed-type NAcc MSNs with both D1-type and D2-type receptors are mostly confined to the NAcc shell. 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
The ventral pallidum (VP) is a structure within the basal ganglia of the brain. It is an output nucleus whose fibres project to thalamic nuclei, such as the ventral anterior nucleus, the ventral lateral nucleus, and the medial dorsal nucleus.
The ...
as well as the ventral tegmental area and to extensive areas in the hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
and extended amygdala.
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
In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher fr ...
. That NAcc shell has also been shown to mediate specific Pavlovian-instrumental transfer, a phenomenon in which a classically conditioned stimulus modifies operant behavior. 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.
Figure 3: Neural circuits underlying motivated 'wanting' and hedonic 'liking'.
/ref> Addictive drug
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use of ...
s have a larger effect on dopamine release in the shell than in the core.
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
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutam ...
, 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 D1-type medium spiny neurons mediate reward-related cognitive processes, whereas the D2-type medium spiny neurons mediate aversion-related cognition. 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
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
are also abundant.[
Function: The nucleus accumbens core is involved in the cognitive processing of ]motor function
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both ...
related to reward and reinforcement and the regulation of slow-wave sleep. Specifically, the core encodes new motor programs which facilitate the acquisition of a given reward in the future. The indirect pathway (i.e., D2-type) neurons in the NAcc core which co-express adenosine A2A receptors activation-dependently promote slow-wave sleep. The NAcc core has also been shown to mediate general Pavlovian-instrumental transfer, a phenomenon in which a classically conditioned stimulus modifies operant behavior.
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; about 1–2% of the remaining neuronal types are large aspiny cholinergic
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...
interneurons and another 1–2% are GABAergic interneurons.
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.[ 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
The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and clas ...
, including recreational drugs like substituted amphetamines
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...
, cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...
, nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
and morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...
.
Phenethylamine and tyramine
Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood ...
: Phenethylamine and tyramine are trace amine
Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to th ...
s which are synthesized in neurons that express the aromatic amino acid hydroxylase (AADC) enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
, which includes all dopaminergic neurons. Both compounds function as dopaminergic neuromodulator
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...
s which regulate the reuptake and release of dopamine into the Nacc via interactions with VMAT2
The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—partic ...
and TAAR1
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...
in the axon terminal of mesolimbic dopamine neurons.
Glucocorticoids and dopamine: Glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...
receptors are the only corticosteroid receptors in the nucleus accumbens shell. L-DOPA
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -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 regard 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.
GABA: A recent study on rats that used GABA agonists and antagonists indicated that GABAA receptors in the NAcc shell have inhibitory control on turning behavior influenced by dopamine, and GABAB receptors have inhibitory control over turning behavior mediated by acetylcholine.[
Glutamate: Studies have shown that local blockade of glutamatergic NMDA receptors in the NAcc core impaired spatial learning.] Another study demonstrated that both NMDA and AMPA (both glutamate receptor
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...
s) play important roles in regulating instrumental learning.
Serotonin (5-HT): Overall, 5-HT synapses are more abundant and have a greater number of synaptic contacts in the NAcc 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). 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
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal le ...
. 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. 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. 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.
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. 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 endocannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
s 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 latter 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. 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.
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 NAcc 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 NAcc 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 NAcc shell and the NAcc core, respectively.
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 NAcc 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. NAcc 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. A 2018 study reported that D2 MSN activation enhanced motivation via inhibiting the ventral pallidum, thereby disinhibiting the VTA.
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. Levels of dopamine increase in the nucleus accumbens during maternal behavior, while lesions in this area upset maternal behavior. 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".
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.
Slow-wave sleep
In late 2017, studies on rodents which utilized optogenetic and chemogenetic
Chemogenetics is the process by which macromolecules can be engineered to interact with previously unrecognized small molecules. Chemogenetics as a term was originally coined to describe the observed effects of mutations on chalcone isomerase activ ...
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
The ventral pallidum (VP) is a structure within the basal ganglia of the brain. It is an output nucleus whose fibres project to thalamic nuclei, such as the ventral anterior nucleus, the ventral lateral nucleus, and the medial dorsal nucleus.
The ...
are involved in the regulation of slow-wave sleep. 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. Chemogenetic inhibition of these NAcc core neurons suppresses sleep. In contrast, the D2-type medium spiny neurons in the NAcc shell which express adenosine A2A receptors have no role in regulating slow-wave sleep.
Clinical significance
Addiction
Current models of addiction from chronic drug use involve alterations in gene expression in the mesocorticolimbic projection. The most important transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s that produce these alterations are ΔFosB, cyclic adenosine monophosphate ( cAMP) response element binding protein (CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first de ...
), and nuclear factor kappa B ( NFκB). 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
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
) seen in drug addiction. ΔFosB overexpression has been implicated in addictions to alcohol (ethanol), cannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
s, cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...
, methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser exten ...
, nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
, opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
s, phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted percept ...
, propofol, and substituted amphetamines
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...
, among others. 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).
ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. 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. Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. 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.
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
Habituation is a form of non-associative learning in which an innate (non-reinforced) response to a stimulus decreases after repeated or prolonged presentations of that stimulus. Responses that habituate include those that involve the intact org ...
(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
Sensitization is a non-associative learning process in which repeated administration of a stimulus results in the progressive amplification of a response. Sensitization often is characterized by an enhancement of response to a whole class of sti ...
(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
Classical conditioning (also known as Pavlovian or respondent conditioning) is a behavioral procedure in which a biologically potent stimulus (e.g. food) is paired with a previously neutral stimulus (e.g. a triangle). It also refers to the learni ...
that occurs when drug use is repeatedly paired with environmental stimuli) and these associations become less prone to extinction
Extinction is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed and ...
(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).
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).
Depression
In April 2007, two research teams reported on having inserted electrodes into the nucleus accumbens in order to use deep brain stimulation
Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleus ...
to treat severe depression. 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
Electroconvulsive therapy (ECT) is a psychiatric treatment where a generalized seizure (without muscular convulsions) is electrically induced to manage refractory mental disorders.Rudorfer, MV, Henry, ME, Sackeim, HA (2003)"Electroconvulsive th ...
. Nucleus accumbens has also been used as a target to treat small groups of patients with therapy-refractory obsessive-compulsive disorder.
Ablation
To treat addiction and in an attempt to treat mental illness radiofrequency ablation
Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternati ...
of the nucleus accumbens has been performed. The results are inconclusive and controversial.
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
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
, indicating a contributing role of the nucleus accumbens in the placebo effect
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
.[
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Additional images
Image:Dopamine_and_serotonin_pathways.png, Dopamine and serotonin
Image:Nucleus_accumbens_MRI.PNG, MRI coronal slice showing nucleus accumbens outlined in red
Image:Nucleus accumbens sag.jpg, Sagittal MRI slice with highlighting (red) indicating the nucleus accumbens.
File:Nucleus accumbens coronal sections.gif, Nucleus accumbens highlighted in green on coronal T1 MRI images
File:Nucleus accumbens sagittal sections.gif, Nucleus accumbens highlighted in green on sagittal T1 MRI images
File:Nucleus accumbens transversal sections.gif, Nucleus accumbens highlighted in green on transversal T1 MRI images
See also
*Septal nuclei
The septal area (medial olfactory area), consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum.
The septal nuclei are loca ...
References
External links
The role of the nucleus accumbens in the reward circuit.
Part of "The Brain From Top to Bottom." at thebrain.mcgill.ca
Nucleus Accumbens – Cell Centered Database
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{{Authority control
Limbic system
Addiction
Basal ganglia