Nucleus accumbens

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Nucleus accumbens
Medial surface, person facing to the left. Nucleus accumbens is very roughly in Brodmann area 34
Nucleus accumbens of the mouse brain
Details
Part of	Mesolimbic pathway Basal ganglia (Ventral striatum)
Parts	Nucleus accumbens shell Nucleus accumbens core
Identifiers
Latin	nucleus accumbens septi
Acronym(s)	NAc or NAcc
MeSH	D009714
NeuroNames	277
NeuroLex ID	birnlex_727
TA	A14.1.09.440
FMA	61889
Anatomical terms of neuroanatomy

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 A_2A 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 GABA_A receptors in the NAc shell have inhibitory control on turning behavior influenced by dopamine, and GABA_B 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 A_2A 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]
 

Summary of addiction-related plasticity

Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment
ΔFosB expression in nucleus accumbens D1-type MSNs	↑	↑	↑	↑	↑	↑	[44]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				[44]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	[44]
Psychostimulant self-administration	↑	↑	↓		↓	↓	[44]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	[44]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	[44]
Neurochemical plasticity
CREB phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	[44]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			[44]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	[44]
Altered striatal opioid signaling	No change or ↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change	[44]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	[44]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			[44]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			[44]

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

• 

  Dopamine and serotonin
  
• 

  MRI coronal slice showing nucleus accumbens outlined in red
  
• 

  Sagittal MRI slice with highlighting (red) indicating the nucleus accumbens.
  

The Web Within Us: Minds and Machines Become One.

February 21, 2001 by Ray Kurzweil
Original link:  http://www.kurzweilai.net/the-web-within-us-minds-and-machines-become-one

By the second half of the next century, there will be no clear distinction between human and machine intelligence. Two things will allow this to happen. First, our biological brains will be enhanced by neural implants. This has already begun. Doctors use neural implants to counteract symptoms of Parkinson’s disease, for instance, and neuroscientists from Emory University School of Medicine in Atlanta recently placed an electrode into the brain of a paralyzed stroke victim who now communicates using a PC. In the 2020s, these neural implants will not be just for people with disabilities, but will be used to improve our perception, memory, and logical thinking, and even create virtual sensory experiences. These implants will plug us directly into the Web. By 2030, “going to a Website” will mean entering a virtual reality environment. Our implants will generate streams of sensory input that would otherwise come from our real senses, creating an all-encompassing virtual environment that responds to our behavior. This virtual reality will be as realistic, detailed, and subtle as the reality we know today.

Also, we will have created nonbiological brains, which will extend vastly our own human brains. While our biological intelligence is, for all practical purposes, at a standstill, our nonbiological intelligence is growing at a double-exponential rate. Computing devices have been consistently multiplying in power from the electromechanical calculating devices used in the 1890 U.S. Census through today. Along the way there’s been exponential growth in the rate of exponential growth. Computer speed (per unit cost) doubled every three years between 1910 and 1950, doubled every two years between 1950 and 1966, and is now doubling every year. By the end of the 21st century, nonbiological thinking will be trillions of times more powerful than that of its human progenitors.

There are many new technologies waiting in the wings that will allow this to happen. Nanotube circuits, for example, are capable of forming extremely dense three-dimensional arrays of computing elements. A 1 inch cube of nanotube circuitry would be at least a million times more powerful than the human brain. Other experimental technologies include three-dimensional chips, optical computing, crystalline computing, DNA, and quantum computing. By 2019, a $1,000 computer will match the processing power of the human brain–about 20 million billion calculations per second. By 2029, your average PC will be equivalent to 1,000 human brains.

Reverse-engineering the Human Brain

This level of processing power is a necessary but not sufficient condition for achieving human-level intelligence in a machine. The organization and content of these resources–the software of intelligence–is also critical. The most compelling scenario for mastering the software of intelligence is to reverse-engineer the human brain–to essentially copy its design–so these machines will seem very human. And through nanotechnology, they will have human-like–but greatly enhanced–bodies as well. Having human origins, they will claim to be human, and to have human feelings. And being immensely intelligent, they’ll be very convincing when they tell us these things.

Human brain scanning has already started. A condemned killer donated his brain and body to be scanned, and you can access all 10 billion bytes of him on the Web. We also have noninvasive scanning techniques today, including high-resolution magnetic resonance imaging (MRI) scans, optical imaging, and near-infrared scanning. Future generations of scanning technology will enable us to show the connections between neurons. Ultimately we will be able to peer inside the synapses themselves.  

The most viable approach to scanning the brain will be to scan it from inside. By 2030, nanobot technology will be feasible, and brain scanning will be a prominent application. Billions of bots could travel through every capillary of a human brain, and scan every detail. The billions of nanobots would all be on a high-speed wireless Intranet allowing them to communicate with each other, and with computers compiling the brain-scan database. From this data, we will learn how the brain works, and we’ll be able to copy the information into a neural computer.

The Web as Virtual Reality Arena

The nanobots will do more than scan the brain. They will also extend it. One vital application will be full-immersion virtual reality–a VR induced by the interaction of nanobots with the brain. We already have electronic devices that can detect and even control the firing of neurons–essentially creating two-way communication between electronic and neural circuits (such as the “neuron transistors” demonstrated at Germany’s Max-Planck Institute for Biochemistry. Scientists have also demonstrated that biological and nonbiological neurons can work together on pattern recognition tasks just like an all-biological network.  

When we want to experience real reality, the nanobots do nothing. If we want to enter virtual reality, they suppress all of the inputs coming from the real senses, and replace them with signals appropriate for the virtual environment. Your brain would then send signals intended to cause your muscles and limbs to move as you normally would, but the nanobots again intercept these interneuronal signals, suppress your real limbs from moving, and instead cause your virtual limbs to “move” while providing the appropriate movement and reorientation (as well as sounds and tactile sensations) in the virtual environment.  

The Web will provide a panoply of virtual environments to explore, and “going” to these Web environments will not require any equipment not already in our heads. Some will be recreations of earthly places; others will be fanciful environments that have no “real” counterpart. Some would be virtual worlds that seem to violate laws of physics. Want to fly? Walk on walls like a spider? You can, in this virtual world. We’ll be able to visit these virtual Web environments alone, or we’ll meet others there, people both real and simulated. Ultimately, there won’t be a clear distinction between the two.

Nanobot technology will expand our minds in virtually any way imaginable. Our brains today are relatively fixed in design. Although we do add patterns of interneuronal connections and neurotransmitter concentrations as a normal part of the learning process, the overall capacity of the human brain is highly constrained (to a mere hundred trillion connections). Brain implants based on massively distributed intelligent nanobots will ultimately expand our memories a trillionfold, and vastly improve all of our sensory, pattern recognition and cognitive abilities.  

Of course, there will be great concern regarding who’s controlling the nanobots, and over who the nanobots may be talking to. Organizations such as governments or extremist groups or just clever individuals could put trillions of undetectable nanobots in the water or food supply. These “spy” nanobots could then monitor, influence, and even control our thoughts and actions. We won’t be defenseless, however. Just as we have virus scanning software today, we will make use of patrol nanobots that search for (and destroy) unauthorized nanobots in our brains and bodies.

Beyond the 21st Century

Can the pace of technological progress continue to speed up indefinitely? Will we not reach a point where humans are unable to think fast enough to keep up with it? With regard to unenhanced humans, clearly so. But what would a million scientists, each a thousand times more intelligent than human scientists today, and each operating a thousand times faster than contemporary humans (because the information processing in their nonbiological, Web-based brains is faster) accomplish?  

For one thing, they would come up with technology to become even more intelligent (because intelligence is no longer of fixed capacity). They would change their own thought processes to think even faster. When the scientists evolve to be a million times more intelligent and operate a million times faster, then an hour could result in a century of progress.  

Once a species develops computing technology, it’s only a matter of a few centuries before the nonbiological form of their intelligence permeates the matter and energy in its vicinity, and then expands outward. Ultimately, it becomes capable of maneuvering and controlling cosmological forces through its exquisite and vast technology, and creates the world it wants.  

What kind of world will that be? Wait and see.

Limbic system

From Wikipedia, the free encyclopedia

 

Limbic system
Cross section of the human brain showing parts of the limbic system from below. Traité d'Anatomie et de Physiologie (1786)
The limbic system largely consists of what was previously known as the limbic lobe.
Details
Identifiers
Latin	Systema limbicum
MeSH	D008032
NeuroNames	2055
FMA	242000
Anatomical terms of neuroanatomy

The limbic system is a set of brain structures located on both sides of the thalamus, immediately beneath the cerebrum. It has also been referred to as the paleomammalian cortex. It is not a separate system but a collection of structures from the telencephalon, diencephalon, and mesencephalon. It includes the olfactory bulbs, hippocampus, hypothalamus, amygdala, anterior thalamic nuclei, fornix, columns of fornix, mammillary body, septum pellucidum, habenular commissure, cingulate gyrus, parahippocampal gyrus, entorhinal cortex, and limbic midbrain areas.

The limbic system supports a variety of functions including emotion, behavior, motivation, long-term memory, and olfaction.^[4] Emotional life is largely housed in the limbic system, and it has a great deal to do with the formation of memories.

Although the term only originated in the 1940s, some neuroscientists, including Joseph LeDoux, have suggested that the concept of a functionally unified limbic system should be abandoned as obsolete because it is grounded mainly in historical concepts of brain anatomy that are no longer accepted as accurate.^[5]

Structure

Anatomical components of the limbic system

The limbic system was originally defined by Paul D, MacLean as a series of cortical structures surrounding the limit between the cerebral hemispheres and the brainstem: the border, or limbus, of the brain. These structures were known together as the limbic lobe.^[6] Further studies began to associate these areas with emotional and motivational processes and linked them to subcortical components that were grouped into the limbic system.^[7] The existence of such a system as an isolated entity responsible for the neurological regulation of emotion has gone into disuse and currently it is considered as one of the many parts of the brain that regulate visceral, autonomic processes.^[8]

Therefore, the definition of anatomical structures considered part of the limbic system is a controversial subject. The following structures are, or have been considered, part of the limbic system:^[9][10]

• Cortical areas:
  • Limbic lobe
  • Orbitofrontal cortex, a region in the frontal lobe involved in the process of decision-making.
  • Piriform cortex, part of the olfactory system.
  • Entorhinal cortex, related with memory and associative components.
  • Hippocampus and associated structures, which play a central role in the consolidation of new memories.
  • Fornix, a white matter structure connecting the hippocampus with other brain structures, particularly the mammillary bodies and septal nuclei
• Subcortical areas:
  • Septal nuclei, a set of structures that lie in front of the lamina terminalis, considered a pleasure zone.
  • Amygdala, located deep within the temporal lobes and related with a number of emotional processes.
  • Nucleus accumbens: involved in reward, pleasure, and addiction.
• Diencephalic structures:
  • Hypothalamus: a center for the limbic system, connected with the frontal lobes, septal nuclei and the brain stem reticular formation via the medial forebrain bundle, with the hippocampus via the fornix, and with the thalamus via the mammillothalamic fasciculus. It regulates a great number of autonomic processes.
  • Mammillary bodies, part of the hypothalamus that receives signals from the hippocampus via the fornix and projects them to the thalamus.
  • Anterior nuclei of thalamus receive input from the mammillary bodies. Involved in memory processing.

Function

The structures of the limbic system are involved in motivation, emotion, learning, and memory. The limbic system is where the subcortical structures meet the cerebral cortex.^[1] The limbic system operates by influencing the endocrine system and the autonomic nervous system. It is highly interconnected with the nucleus accumbens, which plays a role in sexual arousal and the "high" derived from certain recreational drugs. These responses are heavily modulated by dopaminergic projections from the limbic system. In 1954, Olds and Milner found that rats with metal electrodes implanted into their nucleus accumbens, as well as their septal nuclei, repeatedly pressed a lever activating this region, and did so in preference to eating and drinking, eventually dying of exhaustion.^[11] The limbic system also includes the basal ganglia. The basal ganglia are a set of subcortical structures that direct intentional movements. The basal ganglia are located near the thalamus and hypothalamus. They receive input from the cerebral cortex, which sends outputs to the motor centers in the brain stem. A part of the basal ganglia called the striatum controls posture and movement. Recent studies indicate that, if there is an inadequate supply of dopamine, the striatum is affected, which can lead to visible behavioral symptoms of Parkinson's disease.^[1]

The limbic system is also tightly connected to the prefrontal cortex. Some scientists contend that this connection is related to the pleasure obtained from solving problems. To cure severe emotional disorders, this connection was sometimes surgically severed, a procedure of psychosurgery, called a prefrontal lobotomy (this is actually a misnomer). Patients having undergone this procedure often became passive and lacked all motivation.

The limbic system is often classified as a “cerebral structure”. This structure is closely linked to olfaction, emotions, drives, autonomic regulation, memory, and pathologically to encephalopathy, epilepsy, psychotic symptoms, cognitive defects.^[12] The functional relevance of the limbic system has proven to serve many different functions such as affects/emotions, memory, sensory processing, time perception, attention, consciousness, instincts, autonomic/vegetative control, and actions/motor behavior. Some of the disorders associated with the limbic system are epilepsy and schizophrenia.^[13]

Hippocampus

Various processes of cognition involve the hippocampus.

Spatial memory

The first and most widely researched area concerns memory, spatial memory in particular. Spatial memory was found to have many sub-regions in the hippocampus, such as the dentate gyrus (DG) in the dorsal hippocampus, the left hippocampus, and the parahippocampal region. The dorsal hippocampus was found to be an important component for the generation of new neurons, called adult-born granules (GC), in adolescence and adulthood.^[14] These new neurons contribute to pattern separation in spatial memory, increasing the firing in cell networks, and overall causing stronger memory formations.

While the dorsal hippocampus is involved in spatial memory formation, the left hippocampus is a participant in the recall of these spatial memories. Eichenbaum^[15] and his team found, when studying the hippocampal lesions in rats, that the left hippocampus is “critical for effectively combining the ‘what, ‘when,’ and ‘where’ qualities of each experience to compose the retrieved memory.” This makes the left hippocampus a key component in the retrieval of spatial memory. However, Spreng^[16] found that the left hippocampus is, in fact, a general concentrated region for binding together bits and pieces of memory composed not only by the hippocampus, but also by other areas of the brain to be recalled at a later time. Eichenbaum’s research in 2007 also demonstrates that the parahippocampal area of the hippocampus is another specialized region for the retrieval of memories just like the left hippocampus.

Learning

The hippocampus, over the decades, has also been found to have a huge impact in learning. Curlik and Shors^[17] examined the effects of neurogenesis in the hippocampus and its effects on learning. This researcher and his team employed many different types of mental and physical training on their subjects, and found that the hippocampus is highly responsive to these latter tasks. Thus, they discovered an upsurge of new neurons and neural circuits in the hippocampus as a result of the training, causing an overall improvement in the learning of the task. This neurogenesis contributes to the creation of adult-born granules cells (GC), cells also described by Eichenbaum^[15] in his own research on neurogenesis and its contributions to learning. The creation of these cells exhibited "enhanced excitability" in the dentate gyrus (DG) of the dorsal hippocampus, impacting the hippocampus and its contribution to the learning process.^[15]

Hippocampus damage

Damage related to the hippocampal region of the brain has reported vast effects on overall cognitive functioning, particularly memory such as spatial memory. As previously mentioned, spatial memory is a cognitive function greatly intertwined with the hippocampus. While damage to the hippocampus may be a result of a brain injury or other injuries of that sort, researchers particularly investigated the effects that high emotional arousal and certain types of drugs had on the recall ability in this specific memory type. In particular, in a study performed by Parkard,^[18] rats were given the task of correctly making their way through a maze. In the first condition, rats were stressed by shock or restraint which caused a high emotional arousal. When completing the maze task, these rats had an impaired effect on their hippocampal-dependent memory when compared to the control group. Then, in a second condition, a group of rats were injected with anxiogenic drugs. Like the former these results reported similar outcomes, in that hippocampal-memory was also impaired. Studies such as these reinforce the impact that the hippocampus has on memory processing, in particular the recall function of spatial memory. Furthermore, impairment to the hippocampus can occur from prolonged exposure to stress hormones such as Glucocorticoids (GCs), which target the hippocampus and cause disruption in explicit memory.^[19]

In an attempt to curtail life-threatening epileptic seizures, 27-year-old Henry Gustav Molaison underwent bilateral removal of almost all of his hippocampus in 1953. Over the course of fifty years he participated in thousands of tests and research projects that provided specific information on exactly what he had lost. Semantic and episodic events faded within minutes, having never reached his long term memory, yet emotions, unconnected from the details of causation, were often retained. Dr. Suzanne Corkin, who worked with him for 46 years until his death, described the contribution of this tragic "experiment" in her 2013 book.^[20]

Amygdala

Episodic-autobiographical memory (EAM) networks

Another integrative part of the limbic system, the amygdala is involved in many cognitive processes. Like the hippocampus, processes in the amygdala seem to impact memory; however, it is not spatial memory as in the hippocampus but episodic-autobiographical memory (EAM) networks. Markowitsch's^[21] amygdala research shows it encodes, stores, and retrieves EAM memories. To delve deeper into these types of processes by the amygdala, Markowitsch^[21] and his team provided extensive evidence through investigations that the "amygdala's main function is to charge cues so that mnemonic events of a specific emotional significance can be successfully searched within the appropriate neural nets and re-activated." These cues for emotional events created by the amygdala encompass the EAM networks previously mentioned.

Attentional and emotional processes

Besides memory, the amygdala also seems to be an important brain region involved in attentional and emotional processes. First, to define attention in cognitive terms, attention is the ability to home in on some stimuli while ignoring others. Thus, the amygdala seems to be an important structure in this ability. Foremost, however, this structure was historically thought to be linked to fear, allowing the individual to take action in response to that fear. However, as time has gone by, researchers such as Pessoa,^[22] generalized this concept with help from evidence of EEG recordings, and concluded that the amygdala helps an organism to define a stimulus and therefore respond accordingly. However, when the amygdala was initially thought to be linked to fear, this gave way for research in the amygdala for emotional processes. Kheirbek^[14] demonstrated research that the amygdala is involved in emotional processes, in particular the ventral hippocampus. He described the ventral hippocampus as having a role in neurogenesis and the creation of adult-born granule cells (GC). These cells not only were a crucial part of neurogenesis and the strengthening of spatial memory and learning in the hippocampus but also appear to be an essential component in the amygdala. A deficit of these cells, as Pessoa (2009) predicted in his studies, would result in low emotional functioning, leading to high retention rate of mental diseases, such as anxiety disorders.

Social processing

Social processing, specifically the evaluation of faces in social processing, is an area of cognition specific to the amygdala. In a study done by Todorov,^[23] fMRI tasks were performed with participants to evaluate whether the amygdala was involved in the general evaluation of faces. After the study, Todorov concluded from his fMRI results that the amygdala did indeed play a key role in the general evaluation of faces. However, in a study performed by researchers Koscik^[24] and his team, the trait of trustworthiness was particularly examined in the evaluation of faces. Koscik and his team demonstrated that the amygdala was involved in evaluating the trustworthiness of an individual. They investigated how brain damage to the amygdala played a role in trustworthiness, and found that individuals that suffered damage tended to confuse trust and betrayal, and thus placed trust in those having done them wrong. Furthermore, Rule,^[25] along with his colleagues, expanded on the idea of the amygdala in its critique of trustworthiness in others by performing a study in 2009 in which he examined the amygdala's role in evaluating general first impressions and relating them to real-world outcomes. Their study involved first impressions of CEOs. Rule demonstrated that while the amygdala did play a role in the evaluation of trustworthiness, as observed by Koscik in his own research two years later in 2011, the amygdala also played a generalized role in the overall evaluation of first impression of faces. This latter conclusion, along with Todorov's study on the amygdala’s role in general evaluations of faces and Koscik’s research on trustworthiness and the amygdala, further solidified evidence that the amygdala plays a role in overall social processing.

Evolution

Paul D. MacLean, as part of his triune brain theory, hypothesized that the limbic system is older than other parts of the forebrain, and that it developed to manage circuitry attributed to the fight or flight first identified by Hans Selye ^[26] in his report of the General Adaptation Syndrome in 1936. It may be considered a part of survival adaptation in reptiles as well as mammals (including humans). MacLean postulated that the human brain has evolved three components, that evolved successively, with more recent components developing at the top/front. These components are, respectively:

1. The archipallium or primitive ("reptilian") brain, comprising the structures of the brain stem – medulla, pons, cerebellum, mesencephalon, the oldest basal nuclei – the globus pallidus and the olfactory bulbs.
2. The paleopallium or intermediate ("old mammalian") brain, comprising the structures of the limbic system.
3. The neopallium, also known as the superior or rational ("new mammalian") brain, comprises almost the whole of the hemispheres (made up of a more recent type of cortex, called neocortex) and some subcortical neuronal groups. It corresponds to the brain of the superior mammals, thus including the primates and, as a consequence, the human species. Similar development of the neocortex in mammalian species unrelated to humans and primates has also occurred, for example in cetaceans and elephants; thus the designation of "superior mammals" is not an evolutionary one, as it has occurred independently in different species. The evolution of higher degrees of intelligence is an example of convergent evolution, and is also seen in non-mammals such as birds.

According to Maclean, each of the components, although connected with the others, retained "their peculiar types of intelligence, subjectivity, sense of time and space, memory, mobility and other less specific functions".

However, while the categorization into structures is reasonable, the recent studies of the limbic system of tetrapods, both living and extinct, have challenged several aspects of this hypothesis, notably the accuracy of the terms "reptilian" and "old mammalian". The common ancestors of reptiles and mammals had a well-developed limbic system in which the basic subdivisions and connections of the amygdalar nuclei were established.^[27] Further, birds, which evolved from the dinosaurs, which in turn evolved separately but around the same time as the mammals, have a well-developed limbic system. While the anatomic structures of the limbic system are different in birds and mammals, there are functional equivalents.

Clinical significance

Damage to the structures of limbic system results in conditions like Alzheimer's disease, anterograde amnesia, retrograde amnesia, and Klüver-Bucy syndrome.

Society and culture

Etymology and history

The term limbic comes from the Latin limbus, for "border" or "edge", or, particularly in medical terminology, a border of an anatomical component. Paul Broca coined the term based on its physical location in the brain, sandwiched between two functionally different components.

The limbic system is a term that was introduced in 1949 by the American physician and neuroscientist, Paul D. MacLean.^[28][29] The French physician Paul Broca first called this part of the brain le grand lobe limbique in 1878.^[6] He examined the differentiation between deeply recessed cortical tissue and underlying, subcortical nuclei.^[30] However, most of its putative role in emotion was developed only in 1937 when the American physician James Papez described his anatomical model of emotion, the Papez circuit.^[31]

The first evidence that the limbic system was responsible for the cortical representation of emotions was discovered in 1939, by Heinrich Kluver and Paul Bucy. Kluver and Bucy, after much research, demonstrated that the bilateral removal of the temporal lobes in monkeys created an extreme behavioral syndrome. After performing a temporal lobectomy, the monkeys showed a decrease in aggression. The animals revealed a reduced threshold to visual stimuli, and were thus unable to recognize objects that were once familiar.^[32] MacLean expanded these ideas to include additional structures in a more dispersed "limbic system", more on the lines of the system described above.^[29] MacLean developed the intriguing theory of the "triune brain" to explain its evolution and to try to reconcile rational human behavior with its more primal and violent side. He became interested in the brain's control of emotion and behavior. After initial studies of brain activity in epileptic patients, he turned to cats, monkeys, and other models, using electrodes to stimulate different parts of the brain in conscious animals recording their responses.^[33] In the 1950s, he began to trace individual behaviors like aggression and sexual arousal to their physiological sources. He analyzed the brain's center of emotions, the limbic system, and described an area that includes structures called the hippocampus and amygdala. Developing observations made by Papez, he determined that the limbic system had evolved in early mammals to control fight-or-flight responses and react to both emotionally pleasurable and painful sensations. The concept is now broadly accepted in neuroscience.^[34] Additionally, MacLean said that the idea of the limbic system leads to a recognition that its presence "represents the history of the evolution of mammals and their distinctive family way of life." In the 1960s, Dr. MacLean enlarged his theory to address the human brain's overall structure and divided its evolution into three parts, an idea that he termed the triune brain. In addition to identifying the limbic system, he pointed to a more primitive brain called the R-complex, related to reptiles, which controls basic functions like muscle movement and breathing. The third part, the neocortex, controls speech and reasoning and is the most recent evolutionary arrival.^[35] The concept of the limbic system has since been further expanded and developed by Walle Nauta, Lennart Heimer and others.

Academic dispute

There is controversy over the use of the term limbic system, with scientists such as LeDoux arguing that the term be considered obsolete and abandoned.^[36] Originally, the limbic system was believed to be the emotional center of the brain, with cognition being the business of the neocortex. However, cognition depends on acquisition and retention of memories, in which the hippocampus, a primary limbic structure, is involved: hippocampus damage causes severe cognitive (memory) deficits. More important, the "boundaries" of the limbic system have been repeatedly redefined because of advances in neuroscience. Therefore, while it is true that limbic structures are more closely related to emotion, the brain can be thought of as an integrated whole.