The Limbic System and Higher Mental Functions

The Limbic System

The Limbic System is a complex set of structures found just beneath
the cerebrum and on both sides of the thalamus. It combines higher
mental functions, and primitive emotion, into one system. It is often
referred to as the emotional nervous system. It is not only responsible
for our emotional lives, but also our higher mental functions, such as
learning and formation of memories. The Limbic system explains why
some things seem so pleasurable to us, such as eating and why some
medical conditions are caused by mental stress, such as high blood
pressure. There are two significant structures within the limbic system
and several smaller structures that are important as well. They are:

1. The Hippocampus
2. The Amygdala
3. The Thalamus
4. The Hypothalamus
5. The Fornix and Parahippocampus
6. The Cingulate Gyrus

Structures of the Limbic System

Hippocampus

The Hippocampus is found deep in the temporal lobe, shaped like a seahorse. It consists of two horns that
curve back from the amygdala. It is situated in the brain so as to make the prefrontal area aware of our past
experiences stored in that area. The prefrontal area of the brain consults this structure to use memories to
modify our behavior. The hippocampus is responsible for memory.

Amygdala

The Amygdala is a little almond shaped structure, deep inside the anteroinferior region of the temporal lobe,
connects with the hippocampus, the septi nuclei, the prefrontal area and the medial dorsal nucleus of the
thalamus. These connections make it possible for the amygdala to play its important role on the mediation and
control of such activities and feelings as love, friendship, affection, and expression of mood. The amygdala is
the center for identification of danger and is fundamental for self preservation. The amygdala is the nucleus
responsible for fear.

Thalamus

Lesions or stimulation of the medial, dorsal, and anterior nuclei of the thalamus are associated with changes in
emotional reactivity. However, the importance of these nuclei on the regulation of emotional behavior is not
due to the thalamus itself, but to the connections of these nuclei with other limbic system structures. The
medial dorsal nucleus makes connections with cortical zones of the prefrontal area and with the hypothalamus.
The anterior nuclei connect with the mamillary bodies and through them, via fornix, with the hippocampus and
the cingulated gyrus, thus taking part in what is known as the Papez's circuit.


Hypothalamus

The Hypothalamus is a small part of the brain located just below
the thalamus on both sides of the third ventricle. Lesions of the
hypothalamus interfere with several vegetative functions and
some so called motivated behaviors like sexuality,
combativeness, and hunger. The hypothalamus also plays a role
in emotion. Specifically, the lateral parts seem to be involved
with pleasure and rage, while the medial part is linked to
aversion, displeasure, and a tendency to uncontrollable and loud
laughing. However, in general the hypothalamus has more to do
with the expression of emotions. When the physical symptoms
of emotion appear, the threat they pose returns, via the
hypothalamus, to the limbic centers and then the prefrontal
nuclei, increasing anxiety.

The Fornix and Parahippocampal

These small structures are important connecting pathways for the limbic system.

The Cingulate Gyrus

The Cingulate Gyrus is located in the medial side of the brain between the cingulated sulcus and the corpus
callosum. There is still much to be learned about this gyrus, but it is already known that its frontal part
coordinates smells and sights, with pleasant memories of previous emotions. The region participates in the
emotional reaction to pain and in the regulation of aggressive behavior.

Memory and Learning

Memory is defined as : The mental faculty of retaining and recalling past experiences, the act or instance of
remembering recollection. Learning takes place when we retain and utilize past memories.
Overall, the mechanisms of memory are not completely understood. Brain areas such as the hippocampus, the
amygdala, the striatum, or the mammillary bodies are thought to be involved in specific types of memory. For
example, the hippocampus is believed to be involved in spatial learning and declarative learning (learning
information such as what you're reading now), while the amygdala is thought to be involved in emotional memory.
Damage to certain areas in patients and animal models and subsequent memory deficits is a primary source of
information. However, rather than implicating a specific area, it could be that damage to adjacent areas, or to a
pathway traveling through the area is actually responsible for the observed deficit. Further, it is not sufficient to
describe memory, and its counterpart, learning, as solely dependent on specific brain regions. Learning and memory
are attributed to changes in neuronal synapses, thought to be mediated by long-term potentiation and long-term
depression.

There are three basic types of memory:

1. Sensory Memory
2. Short Term Memory
3. Long Term Memory

Sensory Memory

The sensory memories act as a buffer for stimuli through senses. A sensory memory retains an exact copy of
what is seen or heard:  iconic memory for visual, echoic memory for aural and haptic memory for touch.
Information is passed from sensory memory into short term memory. Some believe it lasts only 300
milliseconds, it has unlimited capacity. Selective attention determines what information moves from sensory
memory to short term memory.

Short Term Memory

Short Term Memory acts as a scratch pad for temporary recall of the information under process. For instance,
in order to understand this sentence you need to hold in your mind the beginning of the sentence as you read
the rest. Short term memory decays rapidly and also has a limited capacity. Chunking of information can lead
to an increase in the short term memory capacity, this is the reason why a hyphenated phone number is easier
to remember than a single long number. The successful formation of a chunk is known as closure. Interference
often causes disturbance in short term memory retention. This accounts for the desire to complete a task held
in short term memory as soon as possible.

Within short term memory there are three basic operations:

1. Iconic memory - the ability to hold visual images
2. Acoustic memory - the ability to hold sounds. Can be held longer than iconic.
3. Working memory - an active process to keep it until it is put to use. Note that the goal is not really to move the
information from short term memory to long term memory, but merely to put it to immediate use.

The process of transferring information from short term to long term memory involves the encoding or consolidation
of information. This is not a function of time, that is, the longer the memory stays in the short term the more likely it
is to be placed in the long term memory. On organizing complex information in short term before it can be encoded
into the long term memory, in this process the meaningfulness or emotional content of an item may play a greater
role in its retention in the long term memory. The limbic system sets up local reverberating circuits such as the
Papez's Circuit.

Long Term Memory

Long Term Memory is used for storage of information over a long time. Information from short to long term
memory is transferred after a short period. Unlike short term memory, long term memory has little decay.
Long term potential is an enhanced response at the synapse within the hippocampus. It is essential to memory
storage. The limbic system isn't directly involved in long term memory necessarily but it selects them from
short term memory, consolidates these memories by playing them like a continuous tape, and involves the
hippocampus and amygdala.
There are two types of long term memory:

1. Episodic Memory
2. Semantic Memory

Episodic memory represents our memory of events and experiences in a serial form. It is from this memory that we
can reconstruct the actual events that took place at a given point in our lives. Semantic memory, on the other hand, is
a structured record of facts, concepts, and skills that we have acquired. The information in the semantic memory is
derived from our own episode memory, such as that we can learn new facts or concepts from experiences.
There are three main activities that are related to long term memory:

1. Storage
2. Deletion
3. Retrieval

Information for short term memory is stored in long term memory by rehearsal. The repeated exposure to a stimulus
or the rehearsal of a piece of information transfers it into long term memory. Experiments also suggest that learning
is most effective if it is distributed over time. Deletion is mainly caused by decay and interference. Emotional factors
also affect long term memory. However, it is debatable whether we actually ever forget anything or whether it just
sometimes becomes increasingly difficult to retrieve it. Information may not be recalled sometimes but may be
recognized, or may be recalled only with prompting. This leads us to the third operation of memory, information
retrieval.
There are two types of information retrieval:

1. Recall
2. Recognition

In recall, the information is reproduced from memory. In recognition the presentation of the information provides the
knowledge that the information has been seen before. Recognition is of lesser complexity, as the information is
provided as a cue. However, the recall may be assisted by the provision of retrieval cues which enable the subject to
quickly access the information in memory.

Long-term Potentiation

. Long-term potentiation (LTP) is the lasting enhancement of connections between two neurons that results from
stimulating them simutaneously. Since neurons communicate via chemical synapses, and because memories are
believed to be stored within these synapses, LTP and it's opposing process, long-term depression, are widely
considered the major cellular mechanisms that underlie learning and memory. This has been proven by lab
experiments. When one of the chemicals involved (PKMzeta, it will be discussed later) is inhibited in rats, it causes
retrograde amnesia with short term memory left intact (meaning they can't recall events from before the inhibitor was
given).
By enhancing synaptic transmission, LTP improves the ability of two neuron, one presynaptic and the other
postsynaptic, to communicate with one another across a synapse. The precise mechanism for this enhancement isn't
known, but it varies based on things like brain region, age and species. This will focus on LTP in the CA1 section of
the hippocampus, because that's what is well known.
The end result of LTP is a well established neural circuit that can be called upon later for memory.
LTP in the CA1 hippocampus is called NMDA receptor-dependent LTP. It has four main properties.
• Rapid induction
LTP can be rapidly induced by applying one or more brief, high-frequency, stimulus to a presynaptic cell.
• Input specificity
Once induced, LTP at one synapse does not spread to other synapses; rather LTP is input specific. LTP is only
propagated to those synapses according to the rules of associativity and cooperativity.
• Associativity
Associativity refers to the observation that when weak stimulation of a single pathway is insufficient for the
induction of LTP, simultaneous strong stimulation of another pathway will induce LTP at both pathways.
• Cooperativity
LTP can be induced either by strong tetanic stimulation of a single pathway to a synapse, or cooperatively via
the weaker stimulation of many. When one pathway into a synapse is stimulated weakly, it produces
insufficient postsynaptic depolarization to induce LTP. In contrast, when weak stimuli are applied to many
pathways that converge on a single patch of postsynaptic membrane, the individual postsynaptic
depolarizations generated may collectively depolarize the postsynaptic cell enough to induce LTP
cooperatively. Synaptic tagging, discussed later, may be a common mechanism underlying associativity and
cooperativity.
LTP is generally divided into three parts that occur sequentially: Short-term potentiation, early LTP (E-LTP) and late
LTP (L-LTP). Short-term potentiation isn't well understood and will not be discussed.
E-LTP and L-LTP phases of LTP are each characterized by a series of three events: induction, maintenance and
expression. Induction happens when a short-lived signal triggers that phase to begin. Maintenance corresponds to the
persistent biochemical changes that occur in response to the induction of that phase. Expression entails the
long-lasting cellular changes that result from activation of the maintenance signal.
Each phase of LTP has a set of mediator molecules that dictate the events of that phase. These molecules include
protein receptors, enzymes, and signaling molecules that allow progression from one phase to the next. In addition to
mediators, there are modulator molecules that interact with mediators to fine tune the LTP. Modulators are a bit
beyond the scope of this introductory book, and won't be discussed here.

Early Phase

Induction
E-LTP induction begins when the calcium inside the postsynaptic cell exceeds a threshold. In many types of LTP,
the flow of calcium into the cell requires the NMDA receptor, which is why these types of LTP are considered
NMDA receptor-dependent.
When a stimulus is applied to the presynaptic neuron, it releases a neurotransmitter, typically glutamate, onto the
postsynaptic cell membrane where it binds to AMPA receptors, or AMPARs. This causes an influx of sodium ions
into the postsynaptic cell, this short lived depolarization is called the excitatory postsynaptic potential (EPSP) and
makes it easier for the neuron to fire an action potential.
A single stimulus doesn't cause a big enough depolarization to trigger an E-LTP, instead it relies on EPSP
summation. If EPSPs are reaching the cell before the others decay, they will add up. When the depolarization reaches
a critical level, NMDA receptors lose the magnesium molecule they were originally plugged with and let calcium in.
The rapid rise in calcium within the postsynaptic neuron trigger the short lasting activation of several enzymes that
mediate E-LTP induction. Of particular importance are some protein kinase enzymes, including CaMKII and PKC.
To a lesser extent, PKA and MAPK activation also contribute.
Maintenance
During the maintenance stage of E-LTP, CaMKII and PKC lose their dependence on calcium and become
autonomously active. They then carry out phosphorylation that underlies E-LTP expression.
Expression
CaMKII and PKC phosphorylate existing AMPA receptors to increase their activity, and mediate the insertion of
additional AMPA receptors onto the postsynaptic cell membrane. This is achieved by having a pool of nonsynaptic
AMPA receptors adjacent to the postsynaptic membrane. When the appropriate stimulus arrives, the nonsynaptic
AMPA receptors are brought into the postsynaptic membrane under the influence of protein kinases.
AMPA receptors are one of the most common type of receptors in the brain. Their effect is excitatory. By adding
more AMPA receptors, and increasing their activity, future stimuli will generate larger postsynaptic responses.

Late Phase

Late LTP is the natural extension of E-LTP. L-LTP requires gene transcription and protein synthesis in the
postsynaptic cell, unlike E-LTP. Late LTP is also associated with the presynaptic synthesis of synaptotagmin and an
increase in synaptic vesicle number, suggesting that L-LTP induces protein synthesis not only in postsynaptic cells,
but in presynaptic cells as well. This is discussed under "retrograde messenger" below.
Induction
Late LTP is induced by changes in gene expression and protein synthesis brought about by persistent activation of
protein kinases activated during E-LTP, such as MAPK. In fact, MAPK--Specifically the ERK subfamily of
MAPKs--may be the molecular link between E-LTP and L-LTP, since many signaling cascades involved in E-LTP,
including CaMKII and PKC, can converge on ERK.
Maintenance
Upon activation, ERK may phosphorylate a number of cytoplasmic and nuclear molecules that ultimately result in
the protein synthesis and morphological changes associated with L-LTP. These chemicals may include transcription
factors such as CREB. ERK-mediated changes in transcription factor activity may trigger the synthesis of proteins
that underlie the maintenance of L-LTP. PKMzeta is one such molecule. When this molecule is inhibited in rats, they
experience retrograde amnesia (where you can't recall previous events but short term memory works fine).
Expression
Aside from PKMzeta, many of the proteins synthesized during L-LTP are unknown. They are though to increase
postsynaptic dendritic spine number, surface area and sensitivity to the neurotransmitter associated with L-LTP
expression.

Retrograde Signaling

Retrograde signaling is a hypothesis that attempts to explain that, while LTP is induced and expressed
postsynaptically, some evidence suggests that it is expressed presynaptically as well. The hypothesis gets its name
because normal synaptic transmission is directional and proceeds from the presynaptic to the postsynaptic cell. For
induction to occur postsynaptically and be partially expressed presynaptically, a message must travel from the
postsynaptic cell to the presynaptic cell in a retrograde (reverse) direction. Once there, the message presumably
initiates a cascade of events that leads to a presynaptic component of expression, such as the increased probability of
neurotransmitter vesicle release.
Retrograde signaling is currently a contentious subject as some investigators do not believe the presynaptic cell
contributes at all to the expression of LTP. Even among proponents of the hypothesis there is controversy over the
identity of the messenger.
Language and Speech
Language depends on semantic memory so some of the same areas in the brain are involved in both memory and
language. Articulation, the forming of speech, is represented bilaterally in the motor areas. However, for most
individuals, language analysis and speech formation take place in regions of the left hemisphere only. The two
regions involved are:

1. Broca's Area
2. Wernicke's Area

Broca's area is located just in front of the voice control area of the left motor cortex. This region assembles the motor
of speech and writing. For example, patients with lesions in this area:

1. Understand language perfectly
2. May be able to write perfectly
3. Seldom speak spontaneously

Wernicke's area is part of the auditory and visual associations cortex. This region is responsible for the analysis and
formation of language content. For example, patients with lesions in this area:

1. Are unable to name objects
2. Are unable to understand the meaning of words
3. Articulate speech readily but usually nonsensically
Diseases of the Limbic System

There are several well known diseases that are disorders of the limbic system. Several are discussed here.
Schizophrenia
An increased dopamine (DA) response in the limbic system results in schizophrenia. DA may be synthesized or
secreted in excess, DA receptors may be supersensitive, and DA regulatory mechanism may be defective. Symptoms
are decreased by drugs which block DA receptors. Symptoms of schizophrenia are:

1. Loss of touch with reality
2. Decreased ability to think and reason
3. Decreased ability to concentrate
4. Decreased memory
5. Regress in child-like behavior
6. Altered mood and impulsive behavior
7. Auditory hallucinations

Symptoms may be so severe that the individual cannot function.

Depression

Depression is the most common major mental illness and is characterized by both emotional and physical symptoms.
Symptoms of depression are:

1. Intense sadness and despair
2. Anxiety
3. Loss of ability to concentrate
4. Pessimism
5. Feelings of low self esteem
6. Insomnia or hypersomnia
7. Increased or decreased appetite
8. Changes in body temperature and endocrine gland function

10 to 15% of depressed individuals display suicidal behavior during their lifetime.
The cause of depression and its symptoms are a mystery but we do understand that it is an illness associated with
biochemical changes in the brain. A lot of research goes on to explain that it is associated with a lack of amines
serotonin and norephinephrine. Therefore pharmacological treatment strategies often try to increase amine
concentrations in the brain.
One class of antidepressants is monoamine oxidase inhibitors. Mono amine oxidase is a enzyme that breaks down
your amines like norephinephrine and serotonin. Because the antidepressants inhibit their degradation they will
remain in the synaptic cleft for a longer period of time making the effect just as if you had increased theses types of
neurotransmitters.
A newer class of antidepressants is selective serotonin reuptake inhibitors (SSRI's). With SSRI's decreasing the
uptake of serotonin back into the cell that will increase the amount of serotonin present in the synaptic cleft. SSRI's
are more specific than the monoamine oxidase inhibitors because they only affect serotonergic synapses. You might
recognize these SSRI's by name as Prozac and Paxil.

Bipolar Disorder

Another common form of depression is manic depression. Manic is an acute state characterized by:

1. Excessive elation and impaired judgment
2. Insomnia and irritability
3. Hyperactivity
4. Uncontrolled speech

Manic depression, also known as bipolar disorder, displays mood swings between manic and depression. The limbic
system receptors are unregulated. Drugs used are unique mood stabilizers.
The hippocampus is particularly vulnerable to several disease processes, including ischemia, which is any
obstruction of blood flow or oxygen deprivation, Alzheimer’s disease, and epilepsy. These diseases selectively attack
CA1, which effectively cuts through the hippocampal circuit.
An Autism Link
A connection between autism and the limbic system has also been noted as well. URL: http:/  / www. autism. org/
limbic. html

Case Study

Central Pain Syndrome

I was 42 years old when my life changed forever. I had a stroke. As an avid viewer of medical programs on
television I assumed that I would have physical therapy for my paralyzed left side and get on with my life. No one
ever mentioned pain or the possibility of pain, as a result of the stroke. I did experience unusual sensitivity to touch
while still in the hospital, but nothing to prepare me for what was to come.
The part of my brain that is damaged is the Thalamus. This turns out to be the pain center and what I have now is an
out of control Thalamus, resulting in Thalamic Pain syndrome, also called Central Pain Syndrome. This means that
24 hours a day, seven days a week, my brain sends messages of pain and it never goes away. I am under the care of
physicians, who not only understand chronic pain, but are also willing to treat it with whatever medications offer
some help. None of the medications, not even narcotic medications, take the pain away. They just allow me to
manage it so I can function.

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