1

Assignment No 1

Topic: Neurochemistry

Subject: Psychophysiology and Psychopharmacology

Submitted by

Asia Amir

Reg: FUI/FUSST/S-24-MSPY-001

Maimoona Noor

Reg: FUI/FUSST/S-24-MSPY-002

Saima Said Wali

Reg: FUI/FUSST/S-24-MSPY-015

Submitted to

Muhammad Aqeel

Department of psychology

Foundation University School of Science and Technology

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Synapse

A synapse is a small gap at the end of a neuron that allows a signal to pass from one
neuron to the next. Synapses are found where neurons connect with other neurons.

Synapses connect neurons and help transmit information from one neuron to the next.
When a nerve signal reaches the end of the neuron, it cannot simply continue to the next cell.
Instead, it must trigger the release of neurotransmitters which can then carry the impulse
across the synapse to the next neuron.

Once a nerve impulse has triggered the release of neurotransmitters, these chemical
messengers cross the tiny synaptic gap and are taken up by receptors on the surface of the
next cell (Kendra Cherry, 2022).

Components of Synapses

Synapses are composed of three main components:

 Presynaptic membrane
 Synaptic cleft
 Postsynaptic membrane

Presynaptic Membrane

The presynaptic terminal is at the end of an axon and is the place where the electrical
signal (the action potential) is converted into a chemical signal (neurotransmitter release).

Postsynaptic Membrane

The postsynaptic membrane formed from a segment of dendrite or cell body. The
postsynaptic terminal membrane is less than 50 nanometers away and contains specialized
receptors.

Synaptic Cleft

There is a small gap between the axon terminal of the presynaptic neuron and the
membrane of the postsynaptic cell, and this gap is called the synaptic cleft.

Types of Synapses

There are two main types of synapses

 Chemical Synapse
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 Electrical Synapses

Chemical Synapses

In a chemical synapse, the electrical activity in the presynaptic neuron triggers the
release of chemical messengers, the neurotransmitters. Most synapses are chemical. The
neurotransmitters diffuse across the synapse and bind to the specialized receptors of the
postsynaptic cell.

The neurotransmitter then either excites or inhibits the postsynaptic neuron.

Excitation leads to the firing of an action potential while inhibition prevents the propagation
of a signal.

Electrical Synapses

In electrical synapses, two neurons are connected by specialized channels known as

gap junctions. Electrical synapses allow electrical signals to travel quickly from the
presynaptic cell to the postsynaptic cell, rapidly speeding up the transfer of signals.

The special protein channels that connect the two cells make it possible for the
positive current from the presynaptic neuron to flow directly into the postsynaptic cell
(Kendra Cherry, 2022).

Synaptic Transmission (Chemical Transmission)

There are five aspects of synaptic transmission

 The structure of synapses

 The synthesis, packaging and transport of neurotransmitters molecule
 The release of neurotransmitters molecule
 The activation of receptors by neurotransmitter molecule
 The reuptake, enzymatic degradation and recycling of neurotransmitters molecule

Structure of Synapses

Most communication among neurons occurs across synapses. Neurotransmitters molecule

is released from buttons into synaptic cleft, where they induce EPSPs or IPSPs in other
neurons by binding to receptors on their postsynaptic membranes. The synapses are
axodendritic synapse.
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 Axodendritic Synapse: Synapses of axon terminal buttons on dendrites. Many excitatory

synapses terminate on dendritic spines (nodules of various shape that are located on the
surface of many dendrites).
 Axosomatic Synapses: Synapses of axon terminal buttons on somas (cell body).
Although axodendritic and axosomatic synapses are the most common synaptic
arrangement, there are several other.
 Dendrodendritic Synapse: They are often capable of transmission in either direction
 Axoaxonal Synapses: Some of them mediate presynaptic inhibition (Wu & Saggau,
1997).
 Directed Synapses: Synapses at which the site of neurotransmitter release and the site of
neurotransmitter reception are in close proximity.
 Nondirected Synapses: Synapses at which the site of release is at some distance from the
site of reception. One type of nondirected synapses is varicosity.
 Varicosity: In this type of arrangement, neurotransmitters molecules are released from a
series of varicosities along the axon and its branches and thus are widely dispersed to
surrounding targets. Because of their appearance, these synapses are often referred to as
string-beads synapses.

Synthesis, Packaging, and Transport of Neurotransmitter Molecule

There are two basic categories of neurotransmitter molecule.

 Small neurotransmitters molecule

 Large neurotransmitters molecule

Small Neurotransmitter

Small neurotransmitter are of several type. Small- molecule neurotransmitter are

typically synthesized in the cytoplasm of the terminal button and packaged in synaptic
vesicles by the button’s Golgi complex (Brittle & Waters, 2000). Once filled with
neurotransmitters, the vesicle are stored in clusters next to the presynaptic membrane.

Large Neurotransmitter

Large neurotransmitter are all peptides. Peptides are amino acid chains that are
composed of 10 or fewer amino acids; in effect they are short proteins. They may be small for
protein but they are large for neurotransmitters.
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Peptide neurotransmitter, like other proteins, are assembled in the cytoplasm of the
cell body on ribosomes; they are then packaged in vesicles by the cell body’s Golgi complex
and transported by microtubules to the terminal buttons at a rate of about 40 centimeters per
day.

Release of Neurotransmitter Molecule

Exocytosis

When a neuron is at rest, synaptic vesicles that contain small-molecule

neurotransmitters congregate next to sections of the presynaptic membrane that are
particularly rich in voltage-activated calcium channel. When stimulated by action potentials,
these channels open, and Ca2+ ions enter the button. The entry of the Ca2+ ions cause the
synaptic vesicles to fuse with the presynaptic membrane and empty their contents into the
synaptic cleft (Retting & Neher,2002).

The exocytosis of small-molecule neurotransmitters differs from the exocytosis of

peptide neurotransmitters in one important respect. Small-molecule neurotransmitters are
typically released in a pulse each time an action potential triggers a momentary influx of
Ca2+ ions through the presynaptic membrane.

Peptide neurotransmitters are typically released gradually in response to general

increases in the level of intracellular Ca2+ ions, such as might occur during a general increase
in the rate of neuron firing.

Activation of Receptors by Neurotransmitter Molecule

Once released, neurotransmitter molecule produces signals in postsynaptic neurons by

binding to receptors in the postsynaptic membrane. Each receptor is a protein that contain
binding sites for only particular neurotransmitters and can influence only those cell that have
receptors for it. Any molecule that binds to another is referred to as its ligand, and a
neurotransmitter is thus said to be a ligand of its receptors.

The types of receptors are as follow:

Receptor Subtypes

Most neurotransmitters bind to several different types of receptors. The different types
of receptors to which a particular neurotransmitter can bind are called receptor subtypes for
that neurotransmitter. The receptor subtype for neurotransmitter are typically located in
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different brain areas, and they typically respond to the neurotransmitter in different ways
(Darlison & Richter, 1999).

Ionotropic Receptor

Ionotropic receptor are those receptors that are associated with ligand- activated ion-
channels. When a neurotransmitter molecule binds to ionotropic receptor, the associated ion
channel usually opens or closes immediately, thereby inducing an immediate postsynaptic
potential. In some neurons, EPSPs (depolarization) occur because the neurotransmitter open
sodium channel, thereby increasing the flow of Na+ ions into the neuron.

In contrast, IPSPs (hyperpolarization) often occur because the neurotransmitter open

potassium channel or chloride channels, thereby increasing the flow of K+ Ions out of
neutron or the flow of Cl- ions into it.

Metabotropic Receptor

Metabotropic receptors are those receptors that are associated with signal proteins and
G proteins (guanosine-triphosphate-sensitive proteins). They are more prevalent than
ionotropic receptors, and their effect are slower to develop, longer lasting, more diffuse and
more varied.

When a neurotransmitter binds to a metabotropic receptor, a subunit of associated G

protein breaks away. Then one of two things happens, depending on G protein. The subunit
may move along the inside surface of the membrane and bind to a nearby ion channel,
thereby inducing an EPSPs or IPSPs or it may trigger the synthesis of a chemical called
second messenger. Once created, a second messenger diffuses through the cytoplasm and
may influence the activities of the neuron in a variety of ways (Neves, Ram, & Iyengar,
2002).

G Protein

A protein coupled to a metabotropic receptor conveys messages to other molecules

when a ligand binds with and activates the receptors.

One type of metabotropic receptor are auto receptors.

Auto receptors
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Auto receptors are metabotropic receptors that have two unconventional

characteristics. They bind to their neuron’s own neurotransmitter molecule and they are
located on the presynaptic, rather than the postsynaptic, membrane. Their usual function is to
monitor the number of neurotransmitter molecule in the synapse, to reduce subsequent
release when the level are high and to increase subsequent release when they are low (Parnas
et al., 2000).

Reuptake, Enzymatic Degradation and Recycling

Neurotransmitter molecule would remain active in the synapses, in effect clogging

that channel of communication. There are two message-terminating mechanism.

Reuptake

Reuptake is the more common of the two deactivating mechanisms. The majority of
neurotransmitters, once released, are almost immediately drawn back into the presynaptic
buttons (Clements et al., 1992).

Enzymatic Degradation

Neurotransmitters are degraded (broken apart) in the synapse by the action of

enzymes proteins that stimulate or inhibit biochemical reactions without being affected by
them. For example, acetylcholine, one of the few neurotransmitters for which enzymatic
degradation is the main mechanism of synaptic deactivation, is broken down by the enzyme
acetylcholinesterase.

Electrical Transmission

Glial Function and Synaptic Transmission

Glial cells playing merely supportive roles in the nervous system. For example,
astrocytes have been shown to release chemical transmitters, to contain receptors for
neurotransmitters to conduct signal and to participate in neurotransmitter reuptake (Oliet,
Piet, & Poulain, 2001).

The importance of glial cells in brain function may be reflected in the greater
prevalence of these cells in intelligent organism. Many simple organisms have more neuron
than glial cells outnumber neurons in the human brain by about 10 to 1.

Gap Junctions
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Gap junctions are narrow spaces between adjacent neurons that are bridged by fine
tubular channels that contain cytoplasm. Consequently, the cytoplasm is continuous allowing
electrical signals and small molecules to pass readily from one neuron to the next. Gap
junctions are sometime called electrical synapses.

Gap junctions are commonplace in invertebrate nervous systems, but their existence
was more difficult to establish in mammals (Bennett, 2000). Gap junctions play important
roles in human brain function.

Neurotransmitters

Neurotransmitter is a chemical substance released by electrical impulse from the

presynaptic membrane into the synaptic cleft. They are released in vesicles and attach to the
postsynaptic receptor eliciting a response initiating electrical signals or inhibiting the
postsynaptic neuron.

Figure 1 Depiction of Synaptic Transmission

Steps of synaptic transmission

Communication between two neurons occurs at the synapse in the synaptic cleft.
Neuron send impulse from the presynaptic neurons to the postsynaptic neuron where the
signals are received. Action potential arrives at the presynaptic terminal causing Voltage
gated Ca2+ channel opens and Ca2+ flows in the presynaptic neuron. Ca2+ influx causes
Vesicles to attach to presynaptic membrane releasing neurotransmitter into synaptic cleft. The
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neurotransmitter attaches to the receptors at the postsynaptic cleft becoming activated causing
an inhibitory or excitatory response (Lieberman et al., 2012).

Neurotransmitters are cleared from the synaptic cleft through diffusion, reuptake or
enzyme degradation. Diffusion of neurotransmitter occur from a high concentration to a
lower concentration in presynaptic area. Neurotransmitters can be taken back to the
presynaptic neuron for recycle and reuse. They can also be degraded by enzymes breaking
them down and sending the components back to the presynaptic neuron (Vaskovic, 2023).

Neurotransmitter can be either excitatory or inhibitory. Excitatory neurotransmitter

such as acetylcholine or glutamate activate Na+ or Ca2+ channels causing depolarization
generating an action potential. Inhibitory neurotransmitters on the other hand decrease the
likelihood of an action potential to be fired (Pinel, 2007).

There are several different classifications of neurotransmitters such as amine, amino

acids and soluble gases. Amines consist of dopamine, norepinephrine, epinephrine, serotonin
and histamine. Amino acids have four neurotransmitters, Gamma-aminobutyric acid
(GABA), Glycine, Glutamate and Aspartate. Soluble gases consist of nitric oxide and carbon
monoxide.

Figure 2 Structural Depiction of Amino Acids

There are two classes of receptor neurotransmitters act on, metabotropic and
inotropic. There are two types of inotropic receptors. Cation channels allow positively
charged ions like sodium, potassium and calcium to pass through. This usually causes the
membrane to depolarize through action potential, exciting the neuron. Neurotransmitters
which act by using these channels are called excitatory neurotransmitter, example
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acetylcholine. Anion channels are also type of inotropic receptors which mainly allows
chloride ion to pass through causing hyperpolarization (Vaskovic, 2023).

Neurotransmitter such as GABA act through this channel is therefore called inhibitory
neurotransmitter. Metabotropic receptors are trans membrane receptors which usually act
through a secondary messenger. The most common type is G protein. These receptors have
prolonged postsynaptic neuron excitation or inhibition.

Drugs such as barbiturate act by activating GABA gated Cl- channels, evoking
hyperpolarization of the neurons. They are used in the long-term control of seizures (Pinel,
2007). However, the drug is not useful for an ongoing seizure as it takes 20 minutes for its
onset. Benzo diazepam also has similar mechanism of action as barbiturate. It is used in the
treatment of status epilepticus where there is continuous seizure activity lasting more than 5
minutes or recurrent seizures. E.g. Diazepam, clonazepam, lorazepam are used as
anticonvulsant.

Acetylcholine, both an excitatory and inhibitory neurotransmitter, is secreted by

motor neurons innervating the muscle cells. It is present in the preganglionic neuron of the
autonomic nervous system, postganglionic neuron of the sympathetic and parasympathetic
nervous system (Lieberman et al., 2012).

In the brain Acetylcholine producing neurons called cholinergic neurons are mainly
present in the basal forebrain and the mesopontine tegmental area (Vaskovic, 2023).
Acetylcholine acts on cholinergic receptor called the nicotinic and muscarinic receptor.
Nicotinic receptors are excitatory ligand gated ion channels mainly present in the central
nervous system. There are two subtypes, N1 also known as muscle receptor type and N2
known as neuronal receptor type. These receptors can be blocked by curare, a muscle
relaxant and hexamethonium respectively. Muscarinic receptor is both excitatory and
inhibitory consisting of 5 subtypes, M1-M5. Acetylcholine has an inhibitory effect at the
peripheral parasympathetic nerve endings, inhibiting the heart by vague nerve, decreasing the
blood pressure through vasodilation.

Acetylcholine is involved in learning, memory process, alertness, sleep wake-cycle

and essential for muscle functioning where its main function is muscle contraction (Vaskovic,
2023). Curare, a poisonous plant, causes paralysis of the muscle by blocking the
acetylcholine receptor site on muscle cell. Botulin, well known as Botox used for cosmetic
purposes causing muscle paralysis acts by blocking release of acetylcholine from the vesicles
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in the presynaptic neuron (Pinel, 2007). Acetylcholine is involved in disorders such as

Alzheimer’s disease which is due to low level of acetylcholine as there is damage to the cells
producing it in the basal forebrain. Deficiency in acetylcholine also leads to myasthenia
gravis (Vaskovic, 2023). Acetylcholine levels are also deranged in conditions such as bipolar
disorder, mood swings and depression.

Figure 3 Areas of Acetylcholine Secretion

Acetylcholine plays a vital role in the normal functioning of muscles. Poisonous

plants like curare cause paralysis of muscles by blocking the acetylcholine receptor sites of
myocytes. It is used in surgeries as muscle relaxant. (e.g. pancuronium). Botulin poison, a
neurotoxin, works by prevention of release of Ach from its vesicles in the presynaptic
blocking release of the acetylcholine at the neuromuscular junction thus leading to paralysis
of the effector muscle (Pinel, 2007).

Glutamate is the most abundant neurotransmitter found in the brain. It is released

from sensory neuron and cerebral cortex. It is a major excitatory neurotransmitter regulating
excitability of the central nervous system (Vaskovic, 2023). It is involved in learning and
memory process. It is the major neurotransmitter involved in neuroplasticity. There are two
types of glutamate receptors; metabotropic and ionotropic receptor.

Metabotropic are G protein coupled receptors (mGluR) found in the hippocampus,

cerebellum and the cerebral cortex. They act through second messenger (Lieberman et al.,
2012). There are three type of inotropic ligand gated ion channels; AMPA receptors (α-
amino-3-hydroxy-5-methylisoxazo le- 4-propionate), Kainate receptors and NMDA (fN-
methyl D-aspartate). NMDA receptor sustains long term potentiation therefore involved in
memory storage and learning. Excess glutamate can lead to developing epilepsy causing
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seizures. Low level of glutamate is also found in conditions such as stroke, autism,
Amyotrophic Lateral Sclerosis and Alzheimer’s disease (Pinel, 2007).

GABA (gamma-Aminobutyric acid) is the main inhibitory neurotransmitter in the

central nervous system. It also acts as excitatory neurotransmitter and involved in the
structural the development of neurons in the cortex. It is released from cerebral cortex,
hippocampus, cerebral cortex and cerebellar cortex. It plays a role in reducing the neuronal
excitability throughout the nervous system (Vaskovic, 2023). It’s formed by decarboxylation
of glutamate. There are three types of GABA receptors. GABA A and GABA B are found in
the CNS while GABA C is only present in the retina. In contrast to glutamate, low level of
GABA can cause seizures and anxiety.

Norepinephrine, a monoamine, is an excitatory neurotransmitter released from the

hypothalamus, brainstem and adrenal glands. It is secreted in the body by most of the
postganglionic sympathetic nerves. It is made by converting dopamine from tyrosine into
norepinephrine by the enzyme Dopamine beta hydroxylase (Lieberman et al., 2012). It has a
role in memory and sleep cycle. It also increases the level of alertness and wakefulness. It is
also a hormone and functions in the flight or fight response. Low level of norepinephrine is
found in mood disorders such as depression. Excess norepinephrine can cause impairment of
the sleep cycle. Anxiety and stress-related disorders such as panic disorder is also caused due
to high level of norepinephrine. excitatory neurotransmitter. Another neurotransmitter,
Epinephrine, produced by chromaffin cells of the adrenal gland prepares body for fight or
flight response. It increases heart rate and blood pressure. It causes glycogenolysis in the liver
increasing glucose level.

Serotonin is an inhibitory neurotransmitter synthesized from essential amino acid;

tryptophan usually found in meat. It is involved in emotion and mood. It is found in the
neurons of the brainstem, neurons that innervate gastrointestinal tract and in thrombocytes
(Lieberman et al., 2012). Seven types of serotonin receptors found in the brain most of which
are metabotropic. They are used in the regulation of body temperature, perception of pain,
emption and sleep cycle. It also causes decrease in appetite. Low level may cause depression,
OCD, anger control issues and even suicidal tendencies. Serotonin is related to anxiety when
the levels are found to be high. Selective serotonin reuptake inhibitor is used in the treatment
of depression, OCD, PTSD, panic disorder. Some examples are Citalopram, Sertraline and
Fluoxetine. They work by blocking the reuptake of serotonin leading to increase
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concentration of serotonin in the synaptic cleft. Side effects include diarrhea, sleeping issue
and weight changes (Pinel, 2007).

Dopamine, a monoamine, both an excitatory and inhibitory neurotransmitter is

derived from tyrosine. Dopamine is involved in movement coordination by inhibiting
unnecessary movements. It is both an excitatory and inhibitory which is released from
substantia nigra (Pinel, 2007). It is associated with reward mechanism in brain through the
mesolimbic dopamine pathway. It also helps in controlling memory, mood, sleep, learning
and concentration. Hyperactivity of dopamine in mesolimbic pathway can cause positive
symptoms of schizophrenia. While too little dopamine causes Parkinson's disease
characterized by tremor, slow movements, rigid muscles, impaired posture and balance
(Vaskovic, 2023). This is caused by loss of dopaminergic neurons in basal ganglia.

Cocaine blocks monoamine reuptake transporters casing in increase concentration of

monoamines in the synaptic cleft resulting in enhanced and prolonged effects (Pinel, 2007).
Mesocorticolimbic pathway rich in dopamine neurons project from region of brainstem called
ventral tegmental areas to many areas of the limbic system and frontal cortex. Cocaine intake
cause increase of dopamine in the nucleus accumbens, important in addiction and activated
whenever someone is rewarded.

Neuroplastic Responses to Nervous System Damage

Damage to the nervous system may trigger four neuro-plastic responses:

1. Degeneration,

2. Regeneration,

3. Reorganization

4. Recovery of function

Each of these four responses is discussed in this section.

1. Neural Degeneration

A widely used method for the controlled study of the responses of neurons to damage is to
cut their axons. (Coleman & Perry, 2002)

There are three types of neural degeneration.

 Anterograde Degeneration
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 Retrograde Degeneration

 Trans-neuronal Degeneration

Anterograde Degeneration

Anterograde degeneration is the degeneration of the distal segment—the segment of a

cut axon be- tween the cut and the synaptic terminals. Anterograde degeneration occurs
quickly following axotomy, because the cut separates the distal segment of the axon from the
cell body, which is the metabolic center of the neuron. The entire distal segment becomes
badly swollen within a few hours, and it breaks into frag- ments within a few days.
(Syntichaki & Tavernararkis, 2003)

Retrograde Degeneration

Retrograde degeneration is the degeneration of the proximal seg- ment—the segment

of a cut axon between the cut and the cell body. The course of retrograde degeneration is
different; it progresses gradually back from the cut to the cell body. In about 2 or 3 days,
major changes become apparent in the cell bodies of most axotomized neurons. These early
cell body changes are degenerative in nature. Early degenerative changes to the cell body
(e.g., a decrease in size) suggest that the neuron will ultimately die—usually by apoptosis but
sometimes by necrosis or a combination of both. (Syntichaki & Tavernararkis, 2003)

Trans-neuronal Degeneration

Sometimes, degeneration spreads from damaged neurons to neurons that are linked to
them by synapses, this is called transneuronal degeneration. (Syntichaki & Tavernararkis,
2003)

There are two kinds of transneuronal degeneration.

 Anterograde transneuronal degeneration

 Retrograde transneuronal degeneration

Anterograde transneuronal degeneration

In some cases, transneuronal degeneration spreads from dam- aged neurons to the
neurons on which they synapse; this is called anterograde transneuronal degeneration.

Retrograde transneuronal degeneration

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In some cases, it spreads from damaged neurons to the neurons that synapse on them; this
is called retrograde transneuronal degeneration.

2. Neural Regeneration

Neural regeneration the regrowth of damaged neurons does not proceed as successfully in
mammals and other higher vertebrates as it does in most invertebrates and lower vertebrates.
The capacity for accurate axonal growth, which is possessed by higher vertebrates during
their original development, is lost once they reach ma- turity. Regeneration is virtually
nonexistent in the CNS of adult mammals, and is at best a hit-or-miss affair in the PNS. In the
mammalian PNS, regrowth from the proximal stump of a damaged nerve usually begins 2 or
3 days after axonal damage. What happens next depends on the nature of the injury. The PNS
neurons are inherently capable of regeneration while CNS neurons are not. There is
something about environment of PNS that promotes regeneration while The CNS not.
(Goldberg & Barres, 2000).

Schwann cells, which myelinate PNS axons, promote regeneration in the mammalian
PNS by producing both neurotrophic factors and cell-adhesion molecules (CAMs). The
neurotrophic factors released by Schwann cells stimulate the growth of new axons, and the
cell- adhesion molecules on the cell membranes of Schwann cells provide the paths along
which regenerating PNS axons grow. In contrast, oligodendroglia, which myelin- ate CNS
axons, do not stimulate or guide regeneration; indeed, they release factors that actively block
regeneration (Filbin, 2003).

Collateral Sprouting

When an axon degenerates, axon branches grow out from adjacent healthy axons and
synapse at the sites vacated by the degenerating axon; this is called collat- eral sprouting.
Collateral sprouts may grow out from the axon terminal branches or the nodes of Ranvier on
adjacent neurons. (Fournier & Strittmatter, 2001)

According to Tonge & Golding, 1993 there are three possibilities.

 First, if the original Schwann cell myelin sheaths remain intact, the regenerating
peripheral axons grow through them to their original targets at a rate of a few
millimeters per day.
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 Second, if the peripheral nerve is severed and the cut ends become sepa- rated by a
few millimeters, regenerating axon tips often grow into incorrect sheaths and are
guided by them to incorrect destinations; that is why it is often difficult to regain the
coordinated use of a limb affected by nerve damage even if there has been substantial
regeneration.

 Third, if the cut ends of a severed mammalian peripheral nerve become widely
separated or if a lengthy section of the nerve is damaged, there may be no mean-
ingful regeneration at all; regenerating axon tips grow in a tangled mass around the
proximal stump, and the neurons ultimately die.

3. Neural Reorganization

It has long been assumed that major changes in mammalian nervous systems were limited
to the period of early development. Adult mammalian nervous systems were thought to be
limited to the subtle functional changes that mediate learning and memory. However, it was
recently discovered that adult mammalian brains retain the ability to reorganize themselves in
response to experience. They also retain the ability to reorganize themselves in response to
damage.

Examples of Cortical Reorganization Following Nervous System Damage

Most studies of neural reorganization following damage have focused on adult

sensory and motor systems. Sensory and motor systems are ideally suited to the study of
neural reorganization because of their topographic layout. (Xu, & Wang, 2002)

According to Buonomano & Merzenich, 1998 the damage-induced reor- ganization of the
primary sensory and motor systems has been studied in two fundamentally different
conditions.

 following damage to peripheral nerves

 following damage to the primary cortical areas

Studies are given that illustrate these two approaches.

Kaas and colleagues (1990) assessed the effect of making a small lesion in one retina
and removing the other. Several months after the retinal lesions were made, primary visual
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cortex neurons that originally had recep- tive fields in the lesioned area of the retina were
found to have receptive fields in the area of the retina next to the lesion; remarkably, this
change began within minutes of the lesion. (Gilbert & Wiesel, 1992)

Working with rats, Sanes, Suner, and Donoghue (1990) transected the motor neurons that
controlled the muscles of the rats’ vibrissae (whiskers). A few weeks later, stimulation of the
area of motor cortex that had previous- ly elicited vibrissae movement now activated other
muscles of the face. (Donoghue, 1995)

Mechanisms of Neural Reorganization

Two kinds of mechanisms have been proposed to account for the reorganization of neural
circuits.

 Strengthening of existing connections, possibly through release from inhibition

 Establishment of new connections by collateral sprouting

Support for the first mechanism comes from two observations: Reorganization often occurs
too quickly to be explained by neural growth, and rapid reorganization never involves
changes of more than 2 millimeters of cortical surface. Support for the second mechanism
comes from the observation that the magnitude of long-term reorganization can be too great
to be explained by changes in existing connections.

4. Recovery of Function after Brain Damage

Understanding the mechanisms that underlie the recovery of function after nervous
system damage is a high priority for neuroscientists. However, recovery of function after
nervous system damage is a poorly understood phenomenon. Little is known about recovery
of function after nervous system damage.

There are two reasons of it.

 The first is that it is difficult to conduct controlled experiments on popu- lations of

brain-damaged patients.

 The ssecond is that nervous system damage may results in a variety of compensatory
changes that can easily be confused with true recovery of functions.

 For example, any improvement in the week or two after damage could reflect a
decline in cerebral edema (brain swelling) rather than a recovery from the neural
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damage itself, and any gradual im- provement in the months after damage could
reflect the learning of new cognitive and behavioral strategies (i.e., substitution of
functions) rather than the return of lost functions. (Wilson, 1998)

Consequently, true recovery of function is less common than most believe However,
substantial recovery of function is most likely when lesions are small and the patient is
young. Cognitive reserve (roughly equivalent to education and intelligence) is thought to play
an important role in the apparent recovery of cognitive function after brain damage. (Payne
& Lomber, 2001).

Kapur (1997) conducted a biographical study of doctors and neuroscientists with brain
damage, and he observed a great deal of cognitive recovery. He con- cluded that the observed
improvement did not occur because these patients had actually recovered lost cognitive
function but because their cognitive reserve allowed them to accomplish cognitive tasks in
alternative ways. (Holmes et al., 2004)

The mechanisms of recovery of function remain unknown. It seems likely that neural
reorganization contributes to recovery, but so far most of the evidence or this hypothesis has
been indirect. The strongest evidence comes from a study in which the degree of motor
recovery in stroke patients was found to be correlated with the degree of motor cortex
reorgani- zation (Lipert et al., 2000).

For years, neural reorganization seemed to be the only explanation for recovery from
CNS damage. However, the discovery of adult neurogenesis raised another possibility:
Perhaps the growth of new neurons plays a role in such recovery, particularly when the
damage af- fects the hippocampus. It has recently been shown that cerebral ischemia, which
preferentially damages the hippocampus, increases adult neurogenesis; that many of the new
cells become part of the hippocampus; and that these new cells establish synapses and
develop into mature neurons. (Kokaia & Lindvall, 2003)

Neuroplasticity and the Treatment of Nervous System Damage

The study of neuroplasticity is currently one of the most active and exciting areas of
research in neuroscience. Most of this research has focused on animal models, but some of it
has progressed to clinical trials with human patients. The following four subsections describe
research on some major new treatment approaches.

o Reducing brain damage by blocking neurodegeneration

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o Promoting recovery from CNS damage by promoting regeneration

o Promoting recovery from CNS damage by neurotransplantation

o Promoting recovery from CNS damage by rehabilitative training

Reducing brain damage by Blocking Neurodegeneration

Several studies have shown that it may be possible to re- duce brain damage by
blocking neural degeneration in human patients. For example, in one study, Xu and col-
leagues (1999) induced cerebral ischemia in rats by lim- iting blood flow to the brain. This
had two major effects in the control group of rats: It produced damage in the hippocampus, a
structure that is particularly susceptible to ischemic damage, and it produced deficits in the
rats’ performance in the Morris water maze. The hippocampuses of rats in the experimental
group were treated with viruses genetically engineered to release apoptosis inhibitor protein.
Amazingly, the apoptosis inhibitor protein prevented both the loss of hippocampal neurons
and the deficits in Morris water maze performance. In addition to apoptosis inhibitor protein,
several other neurochemicals have been shown to block the de- generation of damaged
neurons. The most widely stud- ied of these is nerve growth factor. (Sofroniew et al., 2001)

Estrogens are a class of steroid hormones that are released in large amounts by the
ovaries (the female gonads). These hormones have several important effects on the
maturation of the female body, but they also have a variety of influences on the brain.
Estrogens have been shown to limit or de- lay neuron death in animal models and in cell
cultures, and there are also some supportive findings from human patients. These
neuroprotective effects of estrogens may explain why several brain disorders (e.g.,
Parkinson’s disease) are more prevalent in males than in females. In general, molecules that
limit neural degeneration also promote regeneration. (Wise et al., 2001)

Promoting Recovery from CNS Damage by Promoting Regeneration

Although regeneration does not normally occur in the mammalian CNS, several
studies have shown that it can be induced. The following two studies are particularly
promising because they have shown that such regeneration can be associated with functional
recovery.

Eitan and colleagues (1994) transected the left optic nerves of rats. In the control rats,
the retinal ganglion cells, which compose the left optic nerve, permanently degenerated. The
 20

experimental rats received injections of an agent that is toxic to oligodendrocytes, thus

eliminating these cells’ ability to block regeneration. In these experimental subjects, the optic
nerves regenerated, and 6 weeks after the injury, evoked potentials could be recorded from
the optic nerve in response to light flashes presented to the left eye. (Barnett & Chang, 2004)

Cheng, Cao, and Olson (1996) transected the spinal cords of rats, thus rendering them
paraplegic (paralyzed in the posterior portion of their bodies). The research- ers then
transplanted sections of myelinated peripheral nerve across the transection. As a result, spinal
cord neurons regenerated through the implanted Schwann cell myelin sheaths, and the
regeneration allowed the rats to regain use of their hindquarters. (Edgerton & Roy, 2002)

Promoting Recovery from CNS damage by Neurotransplantation

A few years ago, the idea of brain transplantation was little more than science fiction.
Today, the treatment of brain damage by transplanting neural tissue is approach- ing reality.
Efforts to treat CNS damage by neurotrans- plantation have taken two different approaches
(Björklund & Lindvall, 2000).

 To transplant fetal tissue

 To transplant stem cells

Transplanting Fetal Tissue

The first approach to neurotransplantation was to replace a damaged struc- ture with
fetal tissue that would develop into the same structure. Could the donor tissue develop and
become integrated into the host brain, and in so doing alleviate the symptoms? This approach
focused on Parkinson’s disease. Parkinson’s patients lack the dopamine-releasing cells of the
nigrostriatal pathway. Early signs were positive. Bilateral transplantation of fetal substantia
nigra cells was successful in treating the monkey model of Parkinson’s disease. Fetal
substantia nigra transplants survived in the treated monkeys; they innervated adjacent striatal
tissue, released dopamine, and, most importantly, alleviated the severe poverty of movement,
tremor, and rigidity produced by the MPTP. (Bankie- wicz et al., 1990)

Soon after the favorable effects of neurotransplants in the MPTP monkey model were
reported, neurotrans- plantation was offered as a treatment for Parkinson’s dis- ease at major
research hospitals. The results of the first case studies were promising. The fetal substantia
 21

nigra implants survived, and they released dopamine into the host striatum. More impo tantly,
some of the patients improved. (Sawle & Myers, 1993)

The results of these case studies triggered a large- scale double-blind evaluation study
of patients suffering from advanced Parkinson’s disease. The study was ex- tremely thorough;
it even included placebo controls— patients who received surgery but no implants. The ini-
tial results were encouraging: Although control patients showed no improvement, the
implants survived in the experimental patients, and some displayed a modest im- provement.
Unfortunately, however, about 15% of these patients started to display a variety of
uncontrollable writhing and chewing movements about a year after the surgery (Greene et al.,
1999).

The case of Roberto Garcia D’orta

D’Orta, who suffered from Parkin- son’s disease, initially responded to L-dopa
therapy; but, after 3 years of therapy, his condition worsened. Then he responded to treatment
with a dopamine agonist, but again the improvement was only temporary. D’Orta, was in a
desperate state when he heard about adrenal medulla autotransplantation (transplanting a
patient’s own adre- nal medulla cells into her or his striatum, usually for the treatment of
Parkinson’s disease). Adrenal medulla cells release small amounts of dopamine, and there
were some early indications that adrenal medulla autotransplanta- tion might alleviate the
symptoms of Parkinson’s disease.

D’Orta demanded adrenal medulla autotransplan- tation from his doctor. When his
doctor refused, on the grounds that the effectiveness of the treatment was still in doubt,
d’Orta found himself another doctor—a neu- rosurgeon who was not nearly so cautious.

Roberto underwent the procedure.

He flew back home two weeks later. He was no bet- ter. He was told that it took time for the
cells to grow and make the needed chemicals. . . .

Then I received an unexpected call from Roberto’s wife. Roberto was dead. . . .

He’d died of a stroke. . . . Had the stroke been a complication of his surgery? It was more
than a mere possibility. (Klawans, 1990)

Drawbacks of Fetal Tissue Transplantation

 Large-scale clinical trial was premature.

 22

 Researchers do not yet know how to maximize the survival and growth of
neurotransplants and how to minimize their side effects.

 It is important to achieve a balance between the pressure to develop new treatments

quickly and the need to base treatments on a carefully constructed foundation of
scientific understanding.

Transplanting Stem Cells

Embryonic neural stem cells, which are multipo- tent (having the capacity to develop
into many types of mature neurons). Investigators are trying to develop procedures for
repairing brain damage by injecting em- bryonic neural stem cells into the damaged site.
Once injected, the stem cells could develop and replace the damaged cells, under guidance
from surrounding tis- sue. This line of research received a major boost from the development
of renewable cultures of stem cells , which can serve as a source for transplantation and
research injected, the stem cells could develop and replace the damaged cells, under guidance
from surrounding tissue. This line of research received a major boost from the development
of renewable cultures of stem cells. ( Wakayama et al., 2001)

The study by McDonald and colleagues (1999) illustrates the poten- tial of this
method. McDonald and colleagues injected embryonic neu- ral stem cells into an area of
spinal damage. Their sub- jects were rats that had been rendered paraplegic by a blow. The
stem cells migrated to different areas around the damaged area, where they developed into
mature neurons. Remarkably, the rats receiving the implants became capable of supporting
their weight with their hindlimbs and walking, albeit awkwardly. (Gage, 2000)

However, it quickly became apparent that much research still needs to be done ( Rossi
& Cattaneo, 2002; Wexler & Palmer, 2002). First, effective methods of propagating popula-
tions of neural stem cells must be developed (Gott- lieb, 2002). Because sources of
embryonic stem cells have been limited by law in some parts of the world, efforts have
focused on harvesting neural stem cells from adult brains or on trying to cause other types of
adult stem cells (e.g., blood stem cells) to develop into neural stem cells. Neither approach
has as yet achieved unqualified succes. Second, techniques for promoting the survival and
appropriate maturation of the neural stem cells once they have been implanted need to be
developed. Third, the factors that promote the establishment of correct connections with
surviving cells need to be identified. And fourth, methods for encouraging functional
recovery have to be developed. (Wagers et al., 2002)
 23

Promoting Recovery from CNS Damage by Rehabilitative Training

Several demonstrations of the important role of expe- rience in the organization of the
developing and adult brain kindled a renewed interest in the use of rehabili- tative training to
promote recovery from CNS damage.

The following innovative rehabilitative training programs were derived from such findings.

 Strokes

Small strokes produce a core of brain dam- age, which is often followed by a gradually
expanding loss of neural function around this core. Nudo and col- leagues (1996) produced
small ischemic lesions (lesions produced by an interruption of blood supply) in the hand area
of the motor cortex of monkeys. Then, 5 days later, a program of hand training and practice
was ini- tiated. During the ensuing 3 or 4 weeks, the monkeys plucked hundreds of tiny food
pellets from food wells of different sizes. This practice substantially reduced the expansion of
cortical damage. The monkeys that received the rehabilitative training also showed greater
recovery in the use of their affected hand.

One of the principles that has emerged from the study of neurodevelopment is that
neurons seem to be in a competitive situation: They compete with other neurons for synaptic
sites and neurotrophins, and the losers die. Weiller and Rijntjes (1999) designed a reha
bilitative program based on this principle, tested it on monkeys, and then tested it on
unilateral stroke patients who had difficulty using one arm. Their procedure, called
constraint-induced therapy (Taub & Uswatte, 2002), was to tie down the functioning arm for
2 weeks while the affected arm received intensive training. Performance with the affected
arm improved markedly over the 2 weeks, and there was an increase in the area of motor
cortex controlling that arm.

 Spinal Injury

In one approach to treating patients with spinal injuries (Wolpaw & Tennissen, 2001),
patients incapable of walking were sup- ported by a harness over a moving treadmill. With
most of their weight supported and the treadmill providing appropriate feedback, the patients
gradually learned to make walking movements. Then, as they improved, the amount of
support was gradually reduced. In one study using this technique, over 90% of the trained
patients eventually became independent walkers, compared with only 50% of those receiving
conventional physiotherapy.
 24

 Phantom Limbs

Most amputees continue to experi- ence limbs that have been amputated—a condition re-
ferred to as phantom limb. The most striking feature of phantom limbs is their reality. Their
existence is so com- pelling that a patient may try to jump out of bed onto a nonexistent leg
or to lift a cup with a nonexistent hand. In most cases, the amputated limb behaves like a
normal limb; for example, as an amputee walks, a phantom arm seems to swing back and
forth in perfect coordination with the intact arm. However, sometimes an amputee feels that
the amputated limb is stuck in a peculiar posi- tion. For example, one amputee felt that his
phantom arm extended straight out from the shoulder, and as a result, he turned sideways
whenever he passed through door- ways (Melzack, 1992).

About 50% of amputees experience chronic severe pain in their phantom limbs. A
typical complaint is that an amputated hand is clenched so tightly that the finger- nails are
digging into the palm of the hand. Occasionally, phantom limb pain can be treated by having
the ampu- tee concentrate on opening the amputated hand. How- ever, when this does not
work, the pain can become so intense that desperate measures are attempted. (Melzack,
1992).

The Phantom Limb case of Tom

According to Dr. Ramachandran a neuropsychologist perhaps phantom limbs were not

in the stump at all, but in the brain; perhaps the perception of a phantom arm originated from
parts of the body that now innervated the original arm area of the somatosensory cortex
(Ramachandran & Blakeslee, 1998).

Excited by his hypothesis, Dr. Ramachandran asked one of his patients, Tom, if he
would participate in a simple test. He touched various parts of Tom’s body and asked Tom
what he felt. Remarkably, when he touched the side of Tom’s face on the same side as his
amputated arm, Tom felt sensations from various parts of his phantom hand as well as his
face. Indeed, when some warm water was dropped on his face, he felt it running down his
phantom hand. A second map of his hand was found on his shoulder. (Ramachandran &
Blakeslee, 1998).
 25

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