Neuroanatomy, Central Nervous System (CNS)

Introduction
The nervous system is a complex network that enables an organism to interact with its surroundings. Sensory
components that detect environmental stimuli, and motor components that provide skeletal, cardiac, and smooth
muscle control, as well as control of glandular secretions, are coordinated in a system to compel
appropriate motor responses to the stimuli or sensory inputs that have been received, stored, and processed.
The nervous system is made up of vast neural networks; signaling within these circuits enables thinking,
language, feeling, learning, memory, and all function and sensation. It is well-established that through the
plasticity of existing cells our nervous systems can adapt to situations not previously encountered, but it also has
been shown that neural stem cells (NSCs) are plastic and involved in creating new connections in adaptation
and response to injury. NSCs play a fundamental role in development, and in the ability to respond to stimuli in
the environment and injury.

Structure and Function

The nervous system can be divided into the peripheral and central nervous systems (PNS and CNS
respectively). The brain is divided into four main parts: (1) the brain stem, consisting of the medulla, pons, and
midbrain; (2) the cerebellum; (3) the diencephalon, with the thalamus and hypothalamus; and (4) the cerebral
hemispheres, comprised of the cerebral cortex, basal ganglia, white matter, hippocampi, and amygdalae.
Cranial nerves III—XII arise from the brainstem, and provide sensory innervation to the head and neck, with
some extension of function into the region of the trapezius muscle through the spinal accessory nerve. The
medulla is a rostral continuation of the spinal cord and contains autonomic centers that control vital functions
and systems involved in breathing and the maintenance of appropriate blood pressure. These centers also
regulate diaphragmatic and pharyngeal reflexes. The pons is located between the medulla and midbrain and
contributes to the maintenance of posture and balance, and breathing. The pons carries information from the
cerebrum to the cerebellum through the corticopontocerebellar tract. The midbrain is the most rostral portion of
the brainstem and is involved in ocular movement as well as visual and auditory relay pathways via the lateral
geniculate nuclei and the medial geniculate nuclei respectively.
The cerebellum lies in the posterior fossa and coordinates head and eye movements, the planning and execution
of movement, and the maintenance of posture. In addition to its well-established role in motor function, the
cerebellum has been shown to be a critical component of many cognitive and sensory-motor processes,
including auditory pathways involved in functions such as speech recognition.
The thalamus and hypothalamus are located between the cerebral hemispheres and the brain stem. The thalamus
is a major processing region for sensory information going to the cerebral cortex and motor information
traveling in the opposite direction toward the brainstem and spinal cord. The hypothalamus controls pituitary
gland secretions by secreting hormones into the hypophysial portal blood that either stimulate or inhibit the
release of anterior pituitary hormones. The secretions of the posterior pituitary, which include antidiuretic
hormone and oxytocin, are also controlled by cell bodies located in the hypothalamus.
The basal ganglia or basal nuclei include the putamen, caudate, globus pallidus, ventral striatum, ventral
pallidum, substantia nigra, and subthalamic nucleus. These nuclei receive input from nearly the entire neocortex
and then project through basal ganglia-thalamocortical circuits to a relatively small part of the frontal lobe to aid
in movement regulation. The hippocampus primarily is involved with memory, and the amygdala processes
emotional information into effects on the autonomic system through the hypothalamus and hormone secretion.
The cerebral cortex is largely involved in perception and higher motor function through the processing of
sensory information and the integration of motor functions. The cortex contains primary, secondary, and tertiary
sensory and motor areas. Cortical function centers around its ability to integrate diverse signals and provide
direction in response.
The spinal cord is the caudal extension of the CNS. The spinal cord is segmented, as is the spinal column, and
projects 31 pairs of spinal nerves (with afferent and efferent components). There are eight pairs of cervical
spinal nerves, 12 pairs of thoracic nerves, five pairs of lumbar nerves, five pairs of sacral nerves, and one pair of
coccygeal nerves. The afferent nerves comprise the sensory nerves and carry information from the skin, joints,
muscles, and visceral organs; while the efferent nerves comprise the motor nerves, both somatic and autonomic,
and innervate skeletal, cardiac, and smooth muscle, as well as glandular tissue and secretory cells. The spinal
cord is responsible for transmitting signals between the periphery and the rest of the CNS through both
ascending and descending pathways. Due to unequal growth during development, the spinal cord is shorter than
the spinal column, with the cell bodies of the spinal nerves ending around the level of L1/L2 at the conus
medullaris. A structure called the cauda equina, which consists of spinal nerves L2 through C1, continues
caudally in the lumbar cistern ( subarachnoid space) as the spinal nerves leave the spinal column at their
respective levels. This subarachnoid space devoid of the spinal cord enables the safe performance of lumbar
punctures typically between the vertebral bodies of L3 and L4, or L4 and L5.
Impulse transmission throughout the nervous system is conducted via neurons employing synaptic connections.
Consequently, there are both electrical and chemical components involved in signal transmission. A variety of
neurotransmitters are used in various synapses, neuroeffector, and neuromuscular junctions; examples include
acetylcholine, norepinephrine, dopamine, serotonin, glutamate, gamma-aminobutyric acid (GABA),
neuropeptides, hormones, and even nitric oxide. Ion concentrations also play a significant role in impulse
generation and conduction. It is of consequent importance that healthy ion balances be maintained by using
active transport. The heavy use of Na+/K+-ATPase accounts for the neural demand for glucose. It has also been
shown that calcium is necessary for excitation at neuromuscular junctions and ganglionic synapses and that
magnesium inhibits excitability.

Embryology
The formation of the nervous system begins with the process called neurulation which follows gastrulation and
results in the development of the neural tube. During week three of development, the notochord secretes
signaling factors to induce the transformation of the overlying ectoderm to neuroectoderm and the formation of
the neural plate. Through folding and closure of the neural folds, the neural tube is formed. In the formation of
the spinal cord, the basal plate, largely expressing Sonic hedgehog (Shh), induces the differentiation of motor
areas ventrally, and the alar plate, primarily expressing bone morphogenic proteins (BMPs) and Wnt factors,
induces sensory area formation dorsally. It should be noted that these signaling factors induce
appropriate development along a concentration gradient with the involvement of modulating factors and other
signaling factors unmentioned here; the plates and their effects are not segregated.
The cranial parts of the CNS are formed from the prosencephalon, mesencephalon, and rhombencephalon
(cranial to caudal) which are present during week four of development. In week five, the
prosencephalon develops into the telencephalon and diencephalon, and the rhombencephalon becomes the
metencephalon and myelencephalon. The telencephalon will ultimately become the cerebral hemispheres and
basal nuclei; the diencephalon will develop into the thalamus, hypothalamus, and retinas; the mesencephalon
will give rise to the midbrain, including superior and inferior colliculi; the metencephalon will become the pons
and cerebellum; the myelencephalon will form the medulla.[14]

Nerves
Some of the largest nerves in the body include the sciatic nerve, the femoral nerve, the obturator nerve, the
median nerve, the ulnar nerve, the radial nerve, and the musculocutaneous nerve. The sciatic nerve is the largest
in the body and is divided into tibial and fibular parts, the distal extensions of which become the tibial and
common fibular (peroneal) nerves. The common fibular nerve splits into the deep and superficial fibular nerves.
The sciatic nerve innervates the posterior compartment of the thigh. The tibial nerve innervates the posterior
compartment of the leg. The fibular nerves innervate the anterior and lateral compartments of the leg.
The brachial plexus derives the nerves of the upper limb. The median nerve primarily innervates the lateral
portion of the antebrachium and hand, and the ulnar nerve innervates the medial portion. The radial nerve and
its branches innervate the posterior of the entire arm and hand. The musculocutaneous nerve innervates the
elbow flexors and provides sensory innervation to the lateral antebrachium.

Surgical Considerations
The specialty involved in the surgery of pathologies involving the CNS is neurosurgery.

Clinical Significance
Many neurological conditions affect the CNS. They range dramatically in scope, impact, and nature of the
effect. Some conditions can lead to progressively impaired movement such as in Parkinson disease. Huntington
chorea and hemiballismus cause excessive movement among other symptoms. The demyelination in multiple
sclerosis can cause acute attacks, and over time, chronic degradation of function. Others may impact cognition
such as the various dementias. Epilepsy can cause uncontrolled excitation. Headaches often impair the daily
function of patients. Traumatic injuries can cause plegia or paresis and may result in any number of deficits
depending on the location and extent of the lesion.[15]

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Physiology, Brain
Introduction
The human brain is perhaps the most complex of all biological systems, with the mature brain composed of
more than 100 billion information-processing cells called neurons.[1] The brain is an organ composed of
nervous tissue that commands task-evoked responses, movement, senses, emotions, language, communication,
thinking, and memory. The three main parts of the human brain are the cerebrum, cerebellum, and brainstem.
The cerebrum is divided into the right and left hemispheres and is the largest part of the brain. It contains folds
and convolutions on its surface, with the ridges found between the convolutions called gyri and the valleys
between the gyri called sulci (plural of sulcus). If the sulci are deep, they are called fissures. Both cerebral
hemispheres have an outer layer of gray matter called the cerebral cortex and inner subcortical white matter.
Located in the posterior cranial fossa, above the foramen magnum, the cerebellum's primary function is to
modulate motor coordination, posture, and balance. It is comprised of the cerebellar cortex and deep cerebellar
nuclei, with the cerebellar cortex being made up of three layers; the molecular, Purkinje, and granular layers.
The cerebellum connects to the brainstem via cerebellar peduncles.
The brainstem contains the midbrain, pons, and medulla. It is located anterior to the cerebellum, between the
base of the cerebrum and the spinal cord.

Issues of Concern
Studies of brain function have focused on analyzing the variations of the electrical activity produced by the
application of sensory stimuli. However, it is also essential to study additional features and functions of the
brain, including information processing and responding to environmental demands.[2]
The brain works precisely, making connections, and is a deeply divided structure that has remained not entirely
explained or examined.[3] Although researchers have made significant progress in experimental techniques, the
human cognitive function that emerges from neuronal structure and dynamics is not entirely understood.[4]

Cellular Level
At the beginning of the forebrain formation, the neuroepithelial cells undergo divisions at the inner surface of
the neural tube to generate new progenitors. These dividing neuroepithelial cells transform and diversify,
leading to radial glial cells (RGCs).
RGCs also work as progenitors with the capacity to regenerate themselves and produce other types of
progenitors, neurons, and glial cells.[5] RGCs have long processes that connect with the neuroepithelium and
function as a guide for the migration of neuron cells to ensure that neurons find their resting place, mature, and
send out axons and dendrites to participate directly in synapses and electrical signaling. Neurons get produced
along with glial cells; glial cells bring support and create an enclosed environment in which neurons can
perform their functions.
Glial cells (astrocytes, oligodendrocytes, microglial cells) have well-known roles, which include: keeping the
ionic medium of neurons, controlling the rate of nerve signal propagation and synaptic action by regulating the
uptake of neurotransmitters, providing a platform for some aspects of neural development, and aiding in
recovery from neural damage.
Gray matter is the main component of the central nervous system (CNS) and consists of neuronal cell bodies,
dendrites, myelinated and unmyelinated axons, glial cells, synapses, and capillaries. The cerebral cortex is made
up of layers of neurons that constitute the gray matter of the brain. The subcortical (beneath the cortex) area is
primarily white matter composed of myelinated axons with fewer quantities of cell bodies when compared to
gray matter.
Although neurons can have different morphologies, they all contain four common regions: the cell body, the
dendrites, the axon, and the axon terminals, each with its respective functions.
The cell body contains a nucleus where proteins and membranes are synthesized. These proteins travel through
microtubules down to the axons and terminals via a mechanism known as anterograde transport. In retrograde
transport, damaged membranes and organelles travel from the axon toward the cell body along axonal
microtubules. Lysosomes are only present in the cell body and are responsible for containing and degrading
damaged material. The axon is a thin continuation of a neuron that allows electrical impulses to be sent from
neuron to neuron.
Astrocytes occupy 25% of the total brain volume and are the most abundant glial cells.[6] They are classified
into two main groups: protoplasmic and fibrous. Protoplasmic astrocytes appear in gray matter and have several
branches that contact both synapses and blood vessels. Fibrous astrocytes are present in the white matter and
have long fiber-like processes that contact the nodes of Ranvier and the blood vessels. Astrocytes use their
connections to vessels to titrate blood flow in synaptic activity responses. Astrocytic endfeet, which forms tight
junctions between endothelial cells and the basal lamina, gives rise to the formation of the blood-brain barrier
(BBB).[7]
The primary function of oligodendrocytes is to make myelin, a proteolipid critical in maintaining electrical
impulse conduction and maximizing velocity. Myelin is located in segments separated by nodes of Ranvier, and
their function is equivalent to those of Schwan cells in the peripheral nervous system.
The macrophage populations of the CNS include microglia, perivascular macrophages, meningeal macrophages,
macrophages of the circumventricular organs (CVO), and the microglia of the choroid plexus. Microglia are
phagocytic cells representing the immune and support system of the CNS and are the most abundant cells of the
choroid plexus.[8]

Development
Human brain development starts with the neurulation process from the ectodermic layer of the embryo and
takes, on average, 20 to 25 years to mature.[9] It occurs in a sequential and organized manner beginning with
the neural tube formation at the third or fourth week of gestation. This is followed by cell migration and
proliferation that leads to the folding of the cerebral cortex to increase its size and surface area, creating a more
complex structure. Failure of this migration and proliferation leads to a smooth brain without sulci or gyri,
termed lissencephaly.[10] At birth, the general architecture of the brain is mostly complete, and by the age of 5
years, the total brain volume is about 95% of its adult size. Generally, the white matter increases with age, while
the gray matter decreases with age.
The most prominent white matter structure of the brain, the corpus callosum, increases by approximately 1.8%
per year between the ages of 3 and 18 years.[11] The corpus callosum conjugates the activity of the right and
left hemispheres and allows for the progress of higher-order cognitive abilities.
Gray matter in the frontal lobe undergoes continued structural development reaching its maximal volume at
11 to 12 years of age before slowing down during adolescence and early adulthood. The gray matter in the
temporal lobe follows a similar development pattern, reaching its maximum size at 16 to 17 years of age with a
slight decline afterward.[12]
Below is a list of the brain vesicles and the areas of the brain which develop from them.[13]
Prosencephalon (Forebrain)
• Telencephalon
o Cerebral cortex
o Basal ganglia (caudate nucleus, putamen, and globus pallidus)
 o Hippocampus
o Lateral ventricles
• Diencephalon
o Thalamus
o Hypothalamus
o Epithalamus (pineal gland)
o Subthalamus
o Posterior pituitary
o Retina
o Optic nerve
o Third ventricle
Mesencephalon (midbrain)
• Mesencephalon
o Midbrain
o Cerebral aqueduct
Rhombencephalon (hindbrain)
• Metencephalon
o Pons
o Cerebellum
o Fourth ventricle (rostral)
• Myelencephalon
o Medulla
o Fourth ventricle (caudal)

Organ Systems Involved

The brain and the spinal cord comprise the central nervous system (CNS). The peripheral nervous system (PNS)
subdivides into the somatic nervous system (SNS) and the autonomic nervous system (ANS). The SNS consists
of peripheral nerve fibers that collect sensory information to the CNS and motor fibers that send information
from the CNS to skeletal muscle. The ANS functions to control the smooth muscle of the viscera and glands
and consists of the sympathetic nervous system (SNS), the parasympathetic nervous system (PaNS), and the
enteric nervous system (ENS).
Nerves from the brain connect with multiple parts of the head and body, leading to various voluntary and
involuntary functions. The ANS drives basic functions that control unconscious activities such as breathing,
digestion, sweating, and trembling.
The ENS provides the intrinsic innervation of the gastrointestinal system and is the most neurochemically
diverse branch of the PNS.[14] Neurotransmitters such as norepinephrine, epinephrine, dopamine, and serotonin
have recently been a topic of interest due to their roles in gut physiology and CNS pathophysiology, as they aid
in regulating gut blood flow, motility, and absorption.[15]

Function
Cerebrum
The cerebrum controls motor and sensory information, conscious and unconscious behaviors, feelings,
intelligence, and memory. The left hemisphere controls speech and abstract thinking (the ability to think about
things that are not present). In contrast, the right hemisphere controls spatial thinking (thinking that finds
meaning in the shape, size, orientation, location, and phenomena).
The motor and sensory neurons descending from the brain cross to the opposite side in the brainstem. This
crossing means that the right side of the brain controls the motor and sensory functions of the left side of the
body, and the left side of the brain controls the motor and sensory functions of the right side of the body. Hence,
a stroke affecting the left brain hemisphere, for example, will exhibit motor and sensory deficits on the right
side of the body.
Sensory neurons bring sensory input from the body to the thalamus, which then relays this sensory information
to the cerebrum. For example, hunger, thirst, and sleep are under the control of the hypothalamus.
The cerebrum is composed of four lobes:
• Frontal lobe: Responsible for motor function, language, and cognitive processes, such as executive
function, attention, memory, affect, mood, personality, self-awareness, and social and moral
reasoning.[16] The Broca area is located in the left frontal lobe and is responsible for the production and
articulation of speech.
• Parietal lobe: Responsible for interpreting vision, hearing, motor, sensory, and memory functions.
• Temporal lobe: In the left temporal lobe, the Wernicke area is responsible for understanding spoken and
written language. The temporal lobe is also an essential part of the social brain, as it processes sensory
information to retain memories, language, and emotions.[17] The temporal lobe also plays a significant
role in hearing and spatial and visual perception.
• Occipital lobe: The visual cortex is located in the occipital lobe and is responsible for interpreting visual
information.
Cerebellum
The cerebellum controls the coordination of voluntary movement and receives sensory information from the
brain and spinal cord to fine-tune the precision and accuracy of motor activity. The cerebellum also aids in
various cognitive functions such as attention, language, pleasure response, and fear memory.[18]
Brainstem
The brainstem acts as a bridge that connects the cerebrum and cerebellum to the spinal cord. The brainstem
houses the principal centers which perform autonomic functions such as breathing, temperature
regulation, respiration, heart rate, wake-sleep cycles, coughing, sneezing, digestion, vomiting, and swallowing.
The brainstem contains both white and gray matter. The white matter consists of fiber tracts (neuronal cell
axons) traveling down from the cerebral cortex for voluntary motor function and up from the spinal cord and
peripheral nerves, allowing somatosensory information to travel to the highest parts of the brain.[19]

Mechanism
The brain represents 2% of the human body weight and consumes 15% of the cardiac output and 20% of total
body oxygen. The resting brain consumes 20% of the body's energy supply. When the brain performs a task, the
energy consumption increases by an additional 5%, proving that most of the brain's energy consumption
gets used for intrinsic functions.
The brain uses glucose as its principal source of energy. During low glucose states, the brain utilizes ketone
bodies as its primary energy source. During exercise, the brain can use lactate as a source of energy.
In the developing brain, neurons follow molecular signals from regulatory cells like astrocytes to determine
their location, the type of neurotransmitter they will secrete, and with which neurons they will communicate,
leading to the formation of a circuit between neurons that will be in place during adulthood. In the adult brain,
developed neurons fit in their corresponding place and develop axons and dendrites to connect with the
neighboring neurons.[20]
Neurons communicate via neurotransmitters released into the synaptic space, a 20 to 50-nanometer area
between neurons. The neuron that releases the neurotransmitter into the synaptic space is called the presynaptic
neuron, and the neuron that receives the neurotransmitter is called the postsynaptic neuron. An action
potential in the presynaptic neuron leads to calcium influx and the subsequent release of neurotransmitters from
their storage vesicle into the synaptic space. The neurotransmitter then travels to the postsynaptic neuron and
binds to receptors to influence its activity. Neurotransmitters are rapidly removed from the synaptic space by
enzymes.[21]
The oligodendrocytes in the CNS produce myelin. Myelin forms insulating sheaths around axons to allow the
swift travel of electrical impulses through the axons. The nodes of Ranvier are gaps in the myelin sheath of
axons, allowing sodium influx into the axon to help maintain the speed of the electrical impulse traveling
through the axon. This transmission is called saltatory nerve conduction, the "jumping" of electrical impulses
from one node to another. It ensures that electrical signals do not lose their velocity and can propagate long
distances without signal deterioration.[22]

Related Testing
Functional magnetic resonance imaging (fMRI) can track the effects of neural activity and the energy that the
brain consumes by measuring components of the metabolic chain. Other techniques, such as single-photon
emission computed tomography (SPECT), study cerebral blood flow and neuroreceptors. Positron emission
tomography (PET) assesses the glucose metabolism of the brain.[23] Electroencephalography (EEG) records
the brain's electrical activity and is very useful for detecting various brain disorders. Advancements in these
techniques have enabled a broader vision and objective perceptions of mental disorders, leading to improved
diagnosis, treatment, and prognosis.

Pathophysiology
Injury to the brain stimulates the proliferation of astrocytes, an immunological response to neurodegenerative
disorders called "reactive gliosis."[24] Damage to neural tissue promotes molecular and morphological
changes and is essential in the upregulation of the glial fibrillary acidic protein (GFAP). On the other hand,
epidermal growth factor receptor (EGFR) allows the transition from non-reactive to reactive astrocytes, and its
inhibition improves axonal regeneration and rapid recovery. This means that when astrocytes are reactive, they
proliferate and hypertrophy, leading to glial scar formation.
The microglia represent the immune and support system of the CNS. They are neuroprotective in the young
brain but can react abnormally to stimuli in the aged brain and become neurotoxic and destructive, leading to
neurodegeneration.[25] As the brain ages, microglia acquire an increasingly inflammatory and cytotoxic
phenotype, generating a hazardous environment for neurons.[26] Hence, aging is the most critical risk factor for
developing neurodegenerative diseases.
The brain is surrounded by cerebrospinal fluid and is isolated from the bloodstream by the blood-brain barrier
(BBB). In cases like infectious meningitis and meningoencephalitis, acute inflammation causes a breakdown of
the BBB, leading to the influx of blood-borne immune cells into the CNS. In other inflammatory brain disorders
such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), or X-linked
adrenoleukodystrophy, the primary insult is due to degenerative or metabolic processes, and there is no
breakdown of the BBB.[27]
Oligodendrocyte loss can occur due to the production of reactive oxygen species or the activation of
inflammatory cytokines, causing decreased myelin production and leading to conditions such as multiple
sclerosis (MS).[22]
Disturbances in the neurotransmitter systems are related to these substances' production, release, reuptake, or
receptor impairments and can cause neurologic or psychiatric disorders. Glutamate is the brain's most abundant
excitatory neurotransmitter, while GABA is the primary inhibitory transmitter. Glycine has a similar inhibitory
action in the posterior parts of the brain. Acetylcholine aids in processes such as muscle stimulation at the
neuromuscular junction (NMJ), digestion, arousal, salivation, and level of attention. Dopamine is involved in
the reward and motivational component, motor control, and the regulation of prolactin release.
Serotonin influences mood, feelings of happiness, and anxiety. Norepinephrine is involved in arousal, alertness,
vigilance, and attention.
Cerebral oxygen delivery and consumption rates are ten times higher than global body values.[28] Blood
glucose represents the primary energy source for the brain, and the BBB is highly permeable to it. During low
glucose states, the body has developed multiple ways to keep blood glucose within the normal range. As the
level drops below 80 mg/dL, pancreatic beta-cells decrease insulin secretion to avoid further glucose decrease.
If glucose drops further, pancreatic alpha-cells secrete glucagon, and the adrenal medulla releases epinephrine.
Glucagon and epinephrine increase blood glucose levels. Cortisol and growth hormone also act to increase
glucose, but they depend on the presence of glucagon and epinephrine to work.

Clinical Significance
Damage to the Cerebrum
• Frontal lobe - Damage to the frontal lobe causes interruption of the higher functioning brain processes,
including social behavior, planning, motivation, and speech production. Individuals with frontal lobe
damage may be unable to regulate their emotions, have meaningful or appropriate social interactions,
maintain their past personality traits, or make difficult decisions.[29]
• Temporal lobe - The Wernicke area is located in the superior temporal gyrus in an individual's
dominant hemisphere, which is the left hemisphere for 95% of people. Damage to the left (dominant)
temporal lobe can lead to Wernicke aphasia. This is typically referred to as "word salad" speech, where
the patient will speak fluently, but their words and sentences will lack meaning.[30] Damage to the right
(non-dominant) temporal lobe may lead to persistent talking and deficits in nonverbal memory,
processing certain aspects of sound or music (tone, rhythm, pitch), and facial recognition
(prosopagnosia).
• Parietal lobe - Damage to the frontal aspect of the parietal lobe may lead to impaired sensation and
numbness on the contralateral side of the body. An individual may have difficulty recognizing texture
and shape and may be unable to identify a sensation and its location on their body. Damage to the
middle aspect of the parietal lobe can lead to right-left disorientation and difficulty with proprioception.
Damage to the non-dominant (right) parietal lobe may lead to apraxia (difficulty with performing
purposeful motions such as combing hair or brushing teeth) and difficulty with spatial orientation and
navigation (they may get lost in a once familiar area). Patients with non-dominant parietal lobe damage,
usually from a middle cerebral artery stroke, may neglect the side opposite of the brain damage (usually
the left side), which may manifest as only shaving the right side of their face or drawing a clock with all
of the numbers on the right side of the circle.[31]
 • Occipital lobe - Damage to the occipital lobe may lead to visual defects, color agnosia (inability to
identify colors), movement agnosia (difficulty recognizing object movements), hallucinations, illusions,
and the inability to recognize written words (word blindness).
Damage to the Cerebellum
Damage to the cerebellum can lead to ataxia, dysmetria, dysarthria, scanning speech, dysdiadochokinesis,
tremor, nystagmus, and hypotonia. To test for possible cerebellar dysfunction, a bedside neurologic exam is
commonly the first step. This exam may include the Romberg test, heel-to-shin test, finger-to-nose test, and
rapid alternating movement test.[32]
Damage to the Brainstem
Damage to the brainstem may present as muscle weakness, visual changes, dysphagia, vertigo, speech
impairment, pupil abnormalities, insomnia, respiratory depression, or death.
Neurodegenerative Diseases
Neuronal degeneration worsens with age and can affect different areas of the brain leading to movement,
memory, and cognition problems.
Parkinson disease (PD) occurs due to the degeneration of the neurons that synthesize dopamine, leading to
motor function deficits. Alzheimer disease (AD) occurs due to abnormally folded protein deposition in the brain
leading to neuronal degeneration. Huntington disease occurs due to a genetic mutation that increases the
production of the neurotransmitter glutamate. Excessive amounts of glutamate lead to the death of neurons in
the basal ganglia producing movement, cognitive, and psychiatric deficits. Vascular dementia occurs due to the
death of neurons resulting from the interruption of blood supply.
Although neurodegenerative diseases are not classically caused by disturbed metabolism, research has shown
that there is a reduction in glucose metabolism in Alzheimer disease.[33]
Demyelinating Diseases
Demyelinating diseases result from damage to the myelin sheath that covers the nerve cells in the white matter
of the brain, spinal cord, and optic nerves. For example, multiple sclerosis and leukodystrophies are a
consequence of oligodendrocyte damage.
Stroke
A stroke is caused by an interruption in the blood supply to the brain, which may ultimately lead to neuronal
death. This condition can result in one of several neurological problems depending on the affected region.
Brain Death
Neurologic evaluation of brain death is a complicated process that non-specialists and families might
misunderstand.[34] Brain death is the complete and irreversible loss of brain activity, including the brainstem. It
requires verification through well-established clinical protocols and the support of specialized tests.
Hypoglycemia
Glucose is the primary energy source responsible for maintaining brain metabolism and function. The most
significant amount of glucose is used for information processing by neurons.[35] The brain requires a
continuous supply of glucose as it has limited glucose reserves. CNS symptoms and signs of hypoglycemia
include focal neurological deficits, confusion, stupor, seizure, cognitive impairment, or death.

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Figures

Brain, Encephalon, Connections of the several parts of the brain, Cerebrum, Cerebellum, Pons, Cerebral;
Superior; Middle; Inferior Peduncle, Medulla oblongata. Contributed by Gray's Anatomy Plates

The Fore-brain or Prosencephalon, Mesal aspect of a brain sectioned in the median sagittal plane, Foramen of
Monro, Middle commissure, Taenia thalami, Habenular commissure, Genu, Callosum, Fornix, Septum
Lucidum, Plenum, Pons, Oblongata, Thalamus. Contributed by Gray's Anatomy Plates

Areas of localization on lateral surface of hemisphere. Motor area in red, Area of general sensations in blue,
Auditory area in green, Visual area in yellow, Brain, Neurology. Contributed by Gray's Anatomy Plates
Pathways from the Brain to the Spinal Cord, The motor tract, Anterior nerve roots, Anterior and Lateral
cerebrospinal Fasciculus, Decussation of pyramids, Geniculate fibers, Internal capsule, Motor area of cortex.
Contributed by Gray's Anatomy Plates

Homonculus: sensory & motor. Image courtesy S. Bhimji MD

Physiology, Synapse

Authors
Michael J. Caire1; Vamsi Reddy2; Matthew Varacallo3.

Affiliations
1
LSU School of Medicine - Shreveport
2
McKinsey & Company
3
Penn Highlands Healthcare System

Last Update: March 27, 2023.

Introduction
The human brain is made up of approximately 86 billion neurons that “talk” to each other using a combination
of electrical and chemical (electrochemical) signals.
The places where neurons connect and communicate with each other are called synapses. Each neuron has
anywhere between a few to hundreds of thousands of synaptic connections, and these connections can be with
itself, neighboring neurons, or neurons in other regions of the brain. A synapse is made up of a presynaptic and
postsynaptic terminal.
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). The postsynaptic terminal membrane is
less than 50 nanometers away and contains specialized receptors. The neurotransmitter rapidly (in
microseconds) diffuses across the synaptic cleft and binds to specific receptors.
The type of neurotransmitter released from the presynaptic terminal and the specific receptors present on the
corresponding postsynaptic terminal is critical in determining the quality and intensity of information
transmitted by neurons. The postsynaptic neuron integrates all the signals it receives to determine what it does
next, for example, to fire an action potential of its own or not. [1][2]

Cellular Level
Neurons
In the simplest sense, the neuron consists of a cell body, axons, and dendrites.
Cell Body
The cell body contains the nucleus and is the site of metabolic activity. Most of the neurotransmitters that will
eventually be released at the synapse are synthesized here.
Dendrites
These are small projections from the cell body that serves a receptive role in the physiology of the neuron. They
receive incoming signals from other neurons and relay them to the cell body, where the signals are integrated,
and a response will be initiated.
Axons
Generally, the outflow tract of the neuron. It is a cylindrical tube that is covered by the axolemma and is
supported by neurofilaments and microtubules. The microtubules will help to transport the neurotransmitters
from the cell body down to the pre-synaptic terminal, where they will be released.
Synapses
The synapse itself is the site of transmission from the pre-synaptic neuron to the post-synaptic neuron. The
structures found on either side of the synapse vary depending on the type of synapse:
Axodendritic
A connection formed between the axon of one neuron and the dendrite of another. These tend to be excitatory
synapses.
Axosomatic
A direct connection between the axon of one neuron to the cell body of another neuron. These tend to be
inhibitory synapses.
Axoaxonic
A connection between the terminal of one axon and another axon. These synapses generate serve a regulatory
role; the afferent axon will modulate the release of neurotransmitters from the efferent axon.
The above discussion focuses on chemical synapses, which involve the release of a chemical neurotransmitter
between the 2 neurons. This is the most common type of synapse in the mammalian central nervous system
(CNS). However, it is important to note that there are electrical synapses, where electrical current (or signals)
will pass directly from one neuron to another through gap junctions. The differences between the two will be
expanded on in the mechanism section. [3][4]

Development
Two neurons form the neurological synapse, or in some instances, a neuron and an anatomical structure. This
review will focus on 2 neurons composing the synapse. Neurons initially develop from the embryonic neural
tube, which has 3 layers:
• The ventricular zone, which surrounds the central canal of the tube. This tube will eventually become
the ependyma.
• The intermediate zone, which is formed by dividing cells of the ventricular zone. This zone stretches
from the outermost portion of the ventricular zone to the outermost layer of the neural tube, known as
the pial layer.
• The marginal zone, which is formed by extensions of the nerve cells of the intermediate zone.
The intermediate zone will go on to form the gray matter, while the nerve processes that make up the marginal
zone will become white matter once myelinated.
The neurons must then differentiate from their precursors. The order in which they do this is based upon their
size, with the largest neurons (motor neurons) differentiating first. Around the time of birth, the smaller neurons
(sensory neurons) will develop, along with glial cells. Glial cells are cells that will aid in the differentiation of
the neurons and will facilitate their growth in the direction of their target locations. Later, glial cells will
participate in the reuptake of excess neurotransmitters in the synaptic cleft.

Mechanism
Synapses
As previously mentioned, there are 2 major types of synapses: electrical and chemical.
In mammals, the majority of synapses are chemical. Chemical synapses can be differentiated from electrical
synapses by a few distinguishing criteria: they use neurotransmitters to relay the signal and vesicles are used to
store and transport the neurotransmitter from the cell body to the terminal; furthermore, the pre-synaptic
terminal will have a very active membrane and the post-synaptic membrane consists of a thick cell membrane
made up of many receptors. In between these 2 membranes is a very distinct cleft (easily visualized with
electron microscopy) and the chemical neurotransmitter released must diffuse across this cleft to elicit a
response in the receptive neuron. Because of this, the synaptic delay, defined as the time it takes for current in
the pre-synaptic neuron to be transmitted to the post-synaptic neuron, is approximately 0.5 to 1.0 ms.
This is different from the electrical synapse, which will typically consist of 2 membranes located much closer to
each other than in a chemical synapse. These membranes possess channels formed by proteins known as
connexins, which allow the direct passage of current from one neuron to the next and do not rely on
neurotransmitters. The synaptic delay is significantly shorter in electrical synapses versus chemical synapses.
The rest of the discussion will focus on chemical synapses, which have a lot of variation and diversity of their
own. They vary not only between shape and structure, but also the chemical that is transmitted. Synapses can be
excitatory or inhibitory, and use a variety of chemical molecules and proteins that will be discussed shortly.
Multiple types of neurotransmitters used in synaptic communication including, but not limited to:
• Acetylcholine (ACh): One of the most important neurotransmitters found in multiple synapses in the
body, including, but not limited to, the neuromuscular junction, autonomic ganglia, caudate nucleus, and
the limbic system. Generally, ACh is an excitatory neurotransmitter at the neuromuscular junction and in
the autonomic ganglia. In the brain, Ach is synthesized in the basal nucleus of Meynert.
• Norepinephrine (NE): The most important molecule in sympathetic nervous system signaling, except for
the sweat glands. In the brain, NE is mainly found in the locus coeruleus and lateral tegmental nuclei.
• Dopamine (DA): Dopamine signaling is generally inhibitory. There are three major dopaminergic
pathways in the brain, the nigrostriatal, mesolimbic, and mesocortical; each of which serve different
roles. One of the most well-known disease states involving dopamine is Parkinson's disease, where there
is degeneration of dopaminergic neurons in the substantia nigra.
• Serotonin (5-HT): Produced from tryptophan using tryptophan hydroxylase, which is mostly found in
the brain (raphe nucleus) and the gastrointestinal (GI) tract. Serotonin is mostly known for its role as a
regulatory neurotransmitter and is therefore implicated in various mood states and diseases.
• Other common neurotransmitters include other catecholamines, gamma-aminobutyric acid (GABA),
glycine, and glutamic acid.
The easiest approach to understanding synaptic transmission is to think of it as a stepwise process beginning
with the synthesis of the neurotransmitter and ending with its release.
1. Synthesis: The neurotransmitter is synthesized in the cell body, where it will then be transmitted down
the microtubules of the axon to the pre-synaptic terminal, or it is synthesized directly in the pre-synaptic
terminal from recycled neurotransmitters. The neurotransmitter is then stored in presynaptic vesicles
until its release.
2. Release: The neurotransmitter is released in a regulated fashion from the pre-synaptic neuron into the
synaptic cleft.
3. Receptor activation: The neurotransmitter binds to post-synaptic receptors and produces a response in
the post-synaptic neuron.
4. Signal termination: The signal must be terminated by some mechanism, normally by the elimination of
excess neurotransmitters from the synaptic cleft.
Synthesis
Neurotransmitters are synthesized differently depending on which type they are. They can be a small molecule
chemical, such as dopamine and serotonin, or they can be small neuropeptides, such as enkephalin.
 • Neuropeptides are synthesized in the cell body using the typical protein synthesis and translation
pathways (rough endoplasmic reticulum and Golgi apparatus), then will be packaged into large, dense-
core vesicles along with a protease. These vesicles are rapidly transported down the axon using
microtubular proteins such as kinesin. When they arrive at the pre-synaptic terminal, they are ready to
be released.
• Small molecule neurotransmitters are synthesized in the cell body, where they are then transported down
the axon in small, clear core vesicles. Upon arriving at the pre-synaptic terminal, enzymes will modify
the small molecule neurotransmitter, and they can then be released from the vesicles into the cleft.
Release
Now that the neurotransmitters are stored in the vesicles in the pre-synaptic terminal, they must be released into
the cleft. Along the membrane of the vesicle and the presynaptic membrane are proteins known as SNARE
proteins; these proteins are essential in the binding of the vesicles to the membrane and the release of their
contents. As the action potential propagates down the pre-synaptic neuron, the membrane will depolarize. Once
the action potential arrives at the pre-synaptic terminal, the depolarization of the membrane will allow the
voltage-dependent calcium channels to open, allowing the rapid influx of calcium into the pre-synaptic terminal.
The influx of calcium causes the SNARE proteins to activate and change conformation, allowing the fusion of
vesicles to the membrane and the release of their contents. The neurotransmitter will spill into the synaptic cleft,
and the vesicle membrane is recovered via endocytosis.
Receptor Activation
Once the neurotransmitter binds to the post-synaptic neuron, it can generally cause one of 2 types of receptors
to be activated. It will either activate a ligand-gated ion channel or a G-protein receptor.
• Ligand-Gated Ion Channel: When the neurotransmitter binds to this receptor, there is a direct opening or
closing of the attached ion channel. In other words, the neurotransmitter acts directly on the target ion
channel. This type of receptor is described as “fast” because it generally only takes a few milliseconds to
produce a response and is terminated very quickly. Depending on which neurotransmitter is binding to
the receptor, these types of receptors can be excitatory or inhibitory.
• G-Protein Coupled Receptors: These types of receptors are will produce a response (open or close an ion
channel) by activating a signaling cascade involving secondary messengers. The most common
secondary messengers are cyclic adenosine monophosphate (cAMP), inositol triphosphate (IP3), and
diacylglycerol (DAG). When the neurotransmitter binds to the receptor, it activates the G-protein, which
binds to guanosine triphosphate (GTP), and is activated. This will activate the secondary messenger
cascade, which will eventually lead to the phosphorylation of ion channels. Due to multiple steps having
to take place to generate the final response, this pathway is generally described as “slow,” and
generally, the effects last longer (seconds to minutes).
Signal Termination
Inactivation of the signal must involve clearing the neurotransmitter from the synapse in at least 1 of 3 ways:
• Re-uptake: Re-uptake can either be pre-synaptic or by glial cells. One important point to remember
involving reuptake is that only small molecule chemical neurotransmitters can be taken back up,
neuropeptides cannot participate in re-uptake; they must be eliminated by other means, such as
degradation.
o In pre-synaptic reuptake, the pre-synaptic neuron will use either endocytosis or specific
transporters to remove the neurotransmitter from the synapse. The advantage of this mechanism
is that the neurotransmitter can be recycled, which will prevent the neuron from having to re-
synthesize the neurotransmitter every cycle of release.
 o In some cases, such as with glutamate, a glial cell will be involved in the re-uptake. Glutamate is
toxic to the cell, so it is stored inside the neuron as glutamine. When glutamate is released into
the synapse, it will be taken up by the glial cell using a specific transporter, converted into
glutamine via glutaminase, then returned to the neuron to be recycled.
• Enzymatic Destruction: The neurotransmitter can be destroyed directly either in the cleft or in the pre-
synaptic terminal using certain enzymes. Two major enzymes are involved in the destruction of the
neurotransmitter:
o Monoamine Oxidases (MAO): These enzymes are responsible for oxidizing, and therefore
inactivating, the monoamines. They do this by using oxygen to remove the amine group. These
are split into MAO-A and MAO-B based on substrates. MAO-A is mostly responsible for
breaking down serotonin, melatonin, norepinephrine, and epinephrine. Both forms break down
dopamine, tyramine, and tryptamine equally. MAO-B also breaks down phenethylamine and
benzylamine.
o Catechol-O-Methyltransferase (COMT): Generally, COMT is responsible for degrading
catecholamines, including dopamine, epinephrine, and norepinephrine, as well as most
substances with a catechol structure.
It is important to note that both of the above enzymes are very frequent targets of therapeutic medications. By
eliminating these enzymes, the neurotransmitter will remain in the synapse for longer, which can be beneficial
in eliminating the symptoms of many disease processes.
• Diffusion: In the simplest form of termination, the neurotransmitter can simply diffuse out of the
synaptic cleft and away from the receptors and into nearby blood vessels. This will decrease the
concentration of the neurotransmitter in the synapse, gradually reducing the effect the neurotransmitter
has on the post-synaptic neuron. [5][6]

Clinical Significance
The synapse is the fundamental functional unit of neuronal communication. Because of this, diseases that target
the synapse can present with severe clinical consequences. A few examples are listed below:
Myasthenia Gravis
Myasthenia gravis is an auto-immune disease process that causes muscle weakness that usually presents in a
descending fashion. It can cause ptosis, diminished facial expression, respiratory depression, and other
signs/symptoms of weakness. In general, it is worse after activity and better with rest. The pathogenesis of
myasthenia gravis involves diminished communication between the neuron and the muscle at the
neuromuscular junction (NMJ). The reason for this is that antibodies will either block or destroy the
acetylcholine receptors at the NMJ, preventing the ACh from binding and depolarizing the muscle, therefore,
inhibiting contraction. These antibodies block step three (receptor activation) of the synaptic communication
pathway.
Lambert-Eaton Syndrome
Lambert-Eaton syndrome is also an auto-immune condition producing dysfunction at the neuromuscular
junction; however, it involves the pre-synaptic neuron. Instead of antibodies directed against the ACh receptors
as in myasthenia gravis, the antibodies here are directed against the calcium channels on the pre-synaptic
neuron. This prevents calcium influx from occurring, which prevents the fusion of vesicles with the pre-
synaptic membrane and the release of the neurotransmitters into the synapse. These antibodies prevent step two
(neurotransmitter release) of the synaptic communication pathway.
Botulism/Tetanus
In both of these disease processes, the causative agent is a toxin produced by a bacteria that acts as a protease
that cleaves the SNARE proteins. This prevents the release of neurotransmitters at the junction by inhibiting
vesicular fusion.
• Botulism: The botulinum toxin, produced by Clostridium botulinum, prevents the release
of acetylcholine, which is a stimulatory neurotransmitter. This inhibits stimulatory effects, which
prevents muscle contraction and causes flaccid paralysis.
• Tetanus: The tetanus toxin, produced by Clostridium tetani, prevents the release of GABA and glycine,
both of which are inhibitory neurotransmitters. Specifically, their release is inhibited in the Renshaw
cells in the spinal cord. This produces symptoms resembling an upper motor neuron lesion: spastic
paralysis, lockjaw, and opisthotonus.

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Figures

Figure 1: A. Two connected neurons. Neurons have a soma which contains the nucleus, an axon and a dendritic
tree. A single synapse (red circle) is formed at the point where the axon of one neuron (black) connects to the
dendrite/some/axon of another (blue). B. A magnified view of a single synapse. On the arrival of an action
potential (AP) at the presynaptic terminal, Ca2+ triggers the release of neurotransmitter from synaptic vesicles
into the synaptic cleft. Neurotransmitter diffuses across the synaptic cleft to activate postsynaptic receptors.
Contributed Image by Karin Aubrey