(LECTURE)

Control and Regulation

The Central Nervous System

The brain and the spinal cord are the central nervous system, and they represent
the main organs of the nervous system. The spinal cord is a single structure,
whereas the adult brain is described in terms of four major regions: the cerebrum,
the diencephalon, the brain stem, and the cerebellum. A person’s conscious
experiences are based on neural activity in the brain. The regulation of homeostasis
is governed by a specialized region in the brain. The coordination of reflexes
depends on the integration of sensory and motor pathways in the spinal cord.

The Cerebrum

The iconic gray mantle of the human brain, which appears to make up most of the
mass of the brain, is the cerebrum (Figure 1). The wrinkled portion is
the cerebral cortex, and the rest of the structure is beneath that outer covering.
There is a large separation between the two sides of the cerebrum called
the longitudinal fissure. It separates the cerebrum into two distinct halves, a
right and left cerebral hemisphere. Deep within the cerebrum, the white matter
of the corpus callosum provides the major pathway for communication between
the two hemispheres of the cerebral cortex.
Figure 1. This figure shows the lateral view on the left panel and anterior view on
the right panel of the brain. The major parts including the cerebrum are labeled.
Many of the higher neurological functions, such as memory, emotion, and
consciousness, are the result of cerebral function. The complexity of the cerebrum
is different across vertebrate species. The cerebrum of the most primitive
vertebrates is not much more than the connection for the sense of smell. In
mammals, the cerebrum comprises the outer gray matter that is the cortex (from
the Latin word meaning “bark of a tree”) and several deep nuclei that belong to
three important functional groups. The basal nuclei are responsible for cognitive
processing, the most important function being that associated with planning
movements. The basal forebrain contains nuclei that are important in learning
and memory. The limbic cortex is the region of the cerebral cortex that is part of
the limbic system, a collection of structures involved in emotion, memory, and
behavior.

Cerebral Cortex

The cerebrum is covered by a continuous layer of gray matter that wraps around
either side of the forebrain—the cerebral cortex. This thin, extensive region of
wrinkled gray matter is responsible for the higher functions of the nervous system.
A gyrus (plural = gyri) is the ridge of one of those wrinkles, and a sulcus (plural
= sulci) is the groove between two gyri. The pattern of these folds of tissue
indicates specific regions of the cerebral cortex. The head is limited by the size of
the birth canal, and the brain must fit inside the cranial cavity of the skull.
Extensive folding in the cerebral cortex enables more gray matter to fit into this
limited space. If the gray matter of the cortex were peeled off of the cerebrum and
laid out flat, its surface area would be roughly equal to one square meter. The
folding of the cortex maximizes the amount of gray matter in the cranial cavity.
During embryonic development, as the telencephalon expands within the skull, the
brain goes through a regular course of growth that results in everyone’s brain
having a similar pattern of folds. The surface of the brain can be mapped on the
basis of the locations of large gyri and sulci. Using these landmarks, the cortex can
be separated into four major regions, or lobes (Figure 2).
Figure 2. Lobes of the Cerebral Cortex. The cerebral cortex is divided into four
lobes. Extensive folding increases the surface area available for cerebral functions.
The lateral sulcus that separates the temporal lobe from the other regions is one
such landmark. Superior to the lateral sulcus are the parietal lobe and frontal
lobe, which are separated from each other by the central sulcus. The posterior
region of the cortex is the occipital lobe, which has no obvious anatomical border
between it and the parietal or temporal lobes on the lateral surface of the brain.
From the medial surface, an obvious landmark separating the parietal and occipital
lobes is called the parieto-occipital sulcus. The fact that there is no obvious
anatomical border between these lobes is consistent with the functions of these
regions being interrelated.
Different regions of the cerebral cortex can be associated with particular functions,
a concept known as localization of function. In the early 1900s, a German
neuroscientist named Korbinian Brodmann performed an extensive study of the
microscopic anatomy—the cytoarchitecture—of the cerebral cortex and divided the
cortex into 52 separate regions on the basis of the histology of the cortex. His work
resulted in a system of classification known as Brodmann’s areas, which is still
used today to describe the anatomical distinctions within the cortex (Figure 3). The
results from Brodmann’s work on the anatomy align very well with the functional
differences within the cortex. Areas 17 and 18 in the occipital lobe are responsible
for primary visual perception. That visual information is complex, so it is processed
in the temporal and parietal lobes as well. The temporal lobe is associated with
primary auditory sensation, known as Brodmann’s areas 41 and 42 in the superior
temporal lobe.
Figure 3. Brodmann’s Areas of the Cerebral Cortex. Brodmann mapping of
functionally distinct regions of the cortex was based on its cytoarchitecture at a
microscopic level.
Because regions of the temporal lobe are part of the limbic system, memory is an
important function associated with that lobe. Memory is essentially a sensory
function; memories are recalled sensations such as the smell of Mom’s baking or
the sound of a barking dog. Even memories of movement are really the memory of
sensory feedback from those movements, such as stretching muscles or the
movement of the skin around a joint. Structures in the temporal lobe are
responsible for establishing long-term memory, but the ultimate location of those
memories is usually in the region in which the sensory perception was processed.
The main sensation associated with the parietal lobe is somatosensation,
meaning the general sensations associated with the body.
Posterior to the central sulcus is the postcentral gyrus, the primary
somatosensory cortex, which is identified as Brodmann’s areas 1, 2, and 3. All of
the tactile senses are processed in this area, including touch, pressure, tickle, pain,
itch, and vibration, as well as more general senses of the body such
as proprioception and kinesthesia, which are the senses of body position and
movement, respectively.
Anterior to the central sulcus is the frontal lobe, which is primarily associated with
motor functions. The precentral gyrus is the primary motor cortex. Cells from this
region of the cerebral cortex are the upper motor neurons that instruct cells in the
spinal cord to move skeletal muscles.
Anterior to this region are a few areas that are associated with planned
movements. The premotor area is responsible for thinking of a movement to be
made. The frontal eye fields are important in eliciting eye movements and in
attending to visual stimuli. Broca’s area is responsible for the production of
language, or controlling movements responsible for speech; in the vast majority of
people, it is located only on the left side. Anterior to these regions is the prefrontal
lobe, which serves cognitive functions that can be the basis of personality, short-
term memory, and consciousness. The prefrontal lobotomy is an outdated mode of
treatment for personality disorders (psychiatric conditions) that profoundly affected
the personality of the patient.

 Subcortical Structures

Figure 4. Frontal Section of Cerebral Cortex and Basal Nuclei. The major

components of the basal nuclei, shown in a frontal section of the brain, are the
caudate (just lateral to the lateral ventricle), the putamen (inferior to the caudate
and separated by the large white-matter structure called the internal capsule), and
the globus pallidus (medial to the putamen).
Beneath the cerebral cortex are sets of nuclei known as subcortical nuclei that
augment cortical processes. The nuclei of the basal forebrain serve as the primary
location for acetylcholine production, which modulates the overall activity of the
cortex, possibly leading to greater attention to sensory stimuli. Alzheimer’s disease
is associated with a loss of neurons in the basal forebrain.
The hippocampus and amygdala are medial-lobe structures that, along with the
adjacent cortex, are involved in long-term memory formation and emotional
responses. The basal nuclei are a set of nuclei in the cerebrum responsible for
comparing cortical processing with the general state of activity in the nervous
system to influence the likelihood of movement taking place. For example, while a
student is sitting in a classroom listening to a lecture, the basal nuclei will keep the
urge to jump up and scream from actually happening. (The basal nuclei are also
referred to as the basal ganglia, although that is potentially confusing because the
term ganglia is typically used for peripheral structures.)
The major structures of the basal nuclei that control movement are
the caudate, putamen, and globus pallidus, which are located deep in the
cerebrum. The caudate is a long nucleus that follows the basic C-shape of the
cerebrum from the frontal lobe, through the parietal and occipital lobes, into the
temporal lobe. The putamen is mostly deep in the anterior regions of the frontal
and parietal lobes. Together, the caudate and putamen are called the striatum.
The globus pallidus is a layered nucleus that lies just medial to the putamen; they
are called the lenticular nuclei because they look like curved pieces fitting together
like lenses. The globus pallidus has two subdivisions, the external and internal
segments, which are lateral and medial, respectively. These nuclei are depicted in a
frontal section of the brain in Figure 4.
Figure 5. Connections of Basal Nuclei. Input to the basal nuclei is from the
cerebral cortex, which is an excitatory connection releasing glutamate as a
neurotransmitter. This input is to the striatum, or the caudate and putamen. In the
direct pathway, the striatum projects to the internal segment of the globus pallidus
and the substantia nigra pars reticulata (GPi/SNr). This is an inhibitory pathway, in
which GABA is released at the synapse, and the target cells are hyperpolarized and
less likely to fire. The output from the basal nuclei is to the thalamus, which is an
inhibitory projection using GABA.
The basal nuclei in the cerebrum are connected with a few more nuclei in the brain
stem that together act as a functional group that forms a motor pathway. Two
streams of information processing take place in the basal nuclei. All input to the
basal nuclei is from the cortex into the striatum (Figure 5).
The direct pathway is the projection of axons from the striatum to the globus
pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr).
The GPi/SNr then projects to the thalamus, which projects back to the cortex.
The indirect pathway is the projection of axons from the striatum to the globus
pallidus external segment (GPe), then to the subthalamic nucleus (STN), and finally
to GPi/SNr. The two streams both target the GPi/SNr, but one has a direct
projection and the other goes through a few intervening nuclei. The direct pathway
causes the disinhibition of the thalamus (inhibition of one cell on a target cell that
then inhibits the first cell), whereas the indirect pathway causes, or reinforces, the
normal inhibition of the thalamus. The thalamus then can either excite the cortex
(as a result of the direct pathway) or fail to excite the cortex (as a result of the
indirect pathway).
The switch between the two pathways is the substantia nigra pars compacta,
which projects to the striatum and releases the neurotransmitter dopamine.
Dopamine receptors are either excitatory (D1-type receptors) or inhibitory (D2-type
receptors). The direct pathway is activated by dopamine, and the indirect pathway
is inhibited by dopamine.
When the substantia nigra pars compacta is firing, it signals to the basal nuclei that
the body is in an active state, and movement will be more likely. When the
substantia nigra pars compacta is silent, the body is in a passive state, and
movement is inhibited. To illustrate this situation, while a student is sitting listening
to a lecture, the substantia nigra pars compacta would be silent and the student
less likely to get up and walk around. Likewise, while the professor is lecturing, and
walking around at the front of the classroom, the professor’s substantia nigra pars
compacta would be active, in keeping with his or her activity level.
 
Watch this video to learn about the basal nuclei (also known as the basal ganglia),
which have two pathways that process information within the cerebrum.
 
As shown in this video, the direct pathway is the shorter pathway through the
system that results in increased activity in the cerebral cortex and increased motor
activity. The direct pathway is described as resulting in “disinhibition” of the
thalamus. What does disinhibition mean? What are the two neurons doing
individually to cause this?

The Diencephalon

Figure 6. The Diencephalon. The diencephalon is composed primarily of the

thalamus and hypothalamus, which together define the walls of the third ventricle.
The thalami are two elongated, ovoid structures on either side of the midline that
make contact in the middle. The hypothalamus is inferior and anterior to the
thalamus, culminating in a sharp angle to which the pituitary gland is attached.
The diencephalon is the one region of the adult brain that retains its name from
embryologic development. The etymology of the word diencephalon translates to
“through brain.” It is the connection between the cerebrum and the rest of the
nervous system, with one exception. The rest of the brain, the spinal cord, and the
PNS all send information to the cerebrum through the diencephalon. Output from
the cerebrum passes through the diencephalon. The single exception is the system
associated with olfaction, or the sense of smell, which connects directly with the
cerebrum. In the earliest vertebrate species, the cerebrum was not much more
than olfactory bulbs that received peripheral information about the chemical
environment (to call it smell in these organisms is imprecise because they lived in
the ocean). The diencephalon is deep beneath the cerebrum and constitutes the
walls of the third ventricle. The diencephalon can be described as any region of the
brain with “thalamus” in its name. The two major regions of the diencephalon are
the thalamus itself and the hypothalamus (Figure 6). There are other structures,
such as the epithalamus, which contains the pineal gland, or the subthalamus,
which includes the subthalamic nucleus that is part of the basal nuclei.

Thalamus
The thalamus is a collection of nuclei that relay information between the cerebral
cortex and the periphery, spinal cord, or brain stem. All sensory information, except
for the sense of smell, passes through the thalamus before processing by the
cortex. Axons from the peripheral sensory organs, or intermediate nuclei, synapse
in the thalamus, and thalamic neurons project directly to the cerebrum. It is a
requisite synapse in any sensory pathway, except for olfaction. The thalamus does
not just pass the information on, it also processes that information. For example,
the portion of the thalamus that receives visual information will influence what
visual stimuli are important, or what receives attention. The cerebrum also sends
information down to the thalamus, which usually communicates motor commands.
This involves interactions with the cerebellum and other nuclei in the brain stem.
The cerebrum interacts with the basal nuclei, which involves connections with the
thalamus. The primary output of the basal nuclei is to the thalamus, which relays
that output to the cerebral cortex. The cortex also sends information to the
thalamus that will then influence the effects of the basal nuclei.

Hypothalamus

Inferior and slightly anterior to the thalamus is the hypothalamus, the other

major region of the diencephalon. The hypothalamus is a collection of nuclei that
are largely involved in regulating homeostasis. The hypothalamus is the executive
region in charge of the autonomic nervous system and the endocrine system
through its regulation of the anterior pituitary gland. Other parts of the
hypothalamus are involved in memory and emotion as part of the limbic system.

Brain Stem

Figure 7. The Brain Stem. The brain stem comprises three regions: the midbrain,
the pons, and the medulla.
The midbrain and hindbrain (composed of the pons and the medulla) are
collectively referred to as the brain stem (Figure 7). The structure emerges from
the ventral surface of the forebrain as a tapering cone that connects the brain to
the spinal cord. Attached to the brain stem, but considered a separate region of the
adult brain, is the cerebellum. The midbrain coordinates sensory representations of
the visual, auditory, and somatosensory perceptual spaces. The pons is the main
connection with the cerebellum. The pons and the medulla regulate several crucial
functions, including the cardiovascular and respiratory systems and rates.
The cranial nerves connect through the brain stem and provide the brain with the
sensory input and motor output associated with the head and neck, including most
of the special senses. The major ascending and descending pathways between the
spinal cord and brain, specifically the cerebrum, pass through the brain stem.

Midbrain
One of the original regions of the embryonic brain, the midbrain is a small region
between the thalamus and pons. It is separated into the tectum and tegmentum,
from the Latin words for roof and floor, respectively. The cerebral aqueduct passes
through the center of the midbrain, such that these regions are the roof and floor of
that canal. The tectum is composed of four bumps known as the colliculi (singular =
colliculus), which means “little hill” in Latin. The inferior colliculus is the inferior
pair of these enlargements and is part of the auditory brain stem pathway. Neurons
of the inferior colliculus project to the thalamus, which then sends auditory
information to the cerebrum for the conscious perception of sound. The superior
colliculus is the superior pair and combines sensory information about visual
space, auditory space, and somatosensory space. Activity in the superior colliculus
is related to orienting the eyes to a sound or touch stimulus. If you are walking
along the sidewalk on campus and you hear chirping, the superior colliculus
coordinates that information with your awareness of the visual location of the tree
right above you. That is the correlation of auditory and visual maps. If you suddenly
feel something wet fall on your head, your superior colliculus integrates that with
the auditory and visual maps and you know that the chirping bird just relieved itself
on you. You want to look up to see the culprit, but do not. The tegmentum is
continuous with the gray matter of the rest of the brain stem. Throughout the
midbrain, pons, and medulla, the tegmentum contains the nuclei that receive and
send information through the cranial nerves, as well as regions that regulate
important functions such as those of the cardiovascular and respiratory systems.

Pons

The word pons comes from the Latin word for bridge. It is visible on the anterior
surface of the brain stem as the thick bundle of white matter attached to the
cerebellum. The pons is the main connection between the cerebellum and the brain
stem. The bridge-like white matter is only the anterior surface of the pons; the gray
matter beneath that is a continuation of the tegmentum from the midbrain. Gray
matter in the tegmentum region of the pons contains neurons receiving descending
input from the forebrain that is sent to the cerebellum.

Medulla

The medulla is the region known as the myelencephalon in the embryonic brain.
The initial portion of the name, “myel,” refers to the significant white matter found
in this region—especially on its exterior, which is continuous with the white matter
of the spinal cord. The tegmentum of the midbrain and pons continues into the
medulla because this gray matter is responsible for processing cranial nerve
information. A diffuse region of gray matter throughout the brain stem, known as
the reticular formation, is related to sleep and wakefulness, such as general brain
activity and attention.

The Cerebellum
The cerebellum, as the name suggests, is the “little brain.” It is covered in gyri
and sulci like the cerebrum, and looks like a miniature version of that part of the
brain (Figure 8). The cerebellum is largely responsible for comparing information
from the cerebrum with sensory feedback from the periphery through the spinal
cord. It accounts for approximately 10 percent of the mass of the brain.
Figure 8. The Cerebellum. The cerebellum is situated on the posterior surface of
the brain stem. Descending input from the cerebellum enters through the large
white matter structure of the pons. Ascending input from the periphery and spinal
cord enters through the fibers of the inferior olive. Output goes to the midbrain,
which sends a descending signal to the spinal cord.
Descending fibers from the cerebrum have branches that connect to neurons in the
pons. Those neurons project into the cerebellum, providing a copy of motor
commands sent to the spinal cord. Sensory information from the periphery, which
enters through spinal or cranial nerves, is copied to a nucleus in the medulla known
as the inferior olive. Fibers from this nucleus enter the cerebellum and are
compared with the descending commands from the cerebrum. If the primary motor
cortex of the frontal lobe sends a command down to the spinal cord to initiate
walking, a copy of that instruction is sent to the cerebellum. Sensory feedback from
the muscles and joints, proprioceptive information about the movements of
walking, and sensations of balance are sent to the cerebellum through the inferior
olive and the cerebellum compares them. If walking is not coordinated, perhaps
because the ground is uneven or a strong wind is blowing, then the cerebellum
sends out a corrective command to compensate for the difference between the
original cortical command and the sensory feedback. The output of the cerebellum
is into the midbrain, which then sends a descending input to the spinal cord to
correct the messages going to skeletal muscles.

The Spinal Cord

The description of the CNS is concentrated on the structures of the brain, but the
spinal cord is another major organ of the system. Whereas the brain develops out
of expansions of the neural tube into primary and then secondary vesicles, the
spinal cord maintains the tube structure and is only specialized into certain regions.
As the spinal cord continues to develop in the newborn, anatomical features mark
its surface. The anterior midline is marked by the anterior median fissure, and
the posterior midline is marked by the posterior median sulcus. Axons enter the
posterior side through the dorsal (posterior) nerve root, which marks
the posterolateral sulcus on either side. The axons emerging from the anterior
side do so through the ventral (anterior) nerve root. Note that it is common to
see the terms dorsal (dorsal = “back”) and ventral (ventral = “belly”) used
interchangeably with posterior and anterior, particularly in reference to nerves and
the structures of the spinal cord. You should learn to be comfortable with both.
On the whole, the posterior regions are responsible for sensory functions and the
anterior regions are associated with motor functions. This comes from the initial
development of the spinal cord, which is divided into the basal plate and the alar
plate. The basal plate is closest to the ventral midline of the neural tube, which will
become the anterior face of the spinal cord and gives rise to motor neurons. The
alar plate is on the dorsal side of the neural tube and gives rise to neurons that will
receive sensory input from the periphery. The length of the spinal cord is divided
into regions that correspond to the regions of the vertebral column. The name of a
spinal cord region corresponds to the level at which spinal nerves pass through the
intervertebral foramina.
Immediately adjacent to the brain stem is the cervical region, followed by the
thoracic, then the lumbar, and finally the sacral region. The spinal cord is not the
full length of the vertebral column because the spinal cord does not grow
significantly longer after the first or second year, but the skeleton continues to
grow. The nerves that emerge from the spinal cord pass through the intervertebral
formina at the respective levels. As the vertebral column grows, these nerves grow
with it and result in a long bundle of nerves that resembles a horse’s tail and is
named the cauda equina. The sacral spinal cord is at the level of the upper lumbar
vertebral bones. The spinal nerves extend from their various levels to the proper
level of the vertebral column.

Gray Horns

In cross-section, the gray matter of the spinal cord has the appearance of an ink-
blot test, with the spread of the gray matter on one side replicated on the other—a
shape reminiscent of a bulbous capital “H.” As shown in Figure 9, the gray matter is
subdivided into regions that are referred to as horns. The posterior horn is
responsible for sensory processing. The anterior horn sends out motor signals to
the skeletal muscles. The lateral horn, which is only found in the thoracic, upper
lumbar, and sacral regions, is the central component of the sympathetic division of
the autonomic nervous system. Some of the largest neurons of the spinal cord are
the multipolar motor neurons in the anterior horn. The fibers that cause contraction
of skeletal muscles are the axons of these neurons. The motor neuron that causes
contraction of the big toe, for example, is located in the sacral spinal cord. The
axon that has to reach all the way to the belly of that muscle may be a meter in
length. The neuronal cell body that maintains that long fiber must be quite large,
possibly several hundred micrometers in diameter, making it one of the largest cells
in the body.
Figure 9. Cross-section of Spinal Cord. The cross-section of a thoracic spinal
cord segment shows the posterior, anterior, and lateral horns of gray matter, as
well as the posterior, anterior, and lateral columns of white matter. LM × 40.
(Micrograph provided by the Regents of University of Michigan Medical School ©
2012)

White Columns

Just as the gray matter is separated into horns, the white matter of the spinal cord
is separated into columns. Ascending tracts of nervous system fibers in these
columns carry sensory information up to the brain, whereas descending
tracts carry motor commands from the brain. Looking at the spinal cord
longitudinally, the columns extend along its length as continuous bands of white
matter. Between the two posterior horns of gray matter are the posterior
columns. Between the two anterior horns, and bounded by the axons of motor
neurons emerging from that gray matter area, are the anterior columns. The
white matter on either side of the spinal cord, between the posterior horn and the
axons of the anterior horn neurons, are the lateral columns. The posterior
columns are composed of axons of ascending tracts. The anterior and lateral
columns are composed of many different groups of axons of both ascending and
descending tracts—the latter carrying motor commands down from the brain to the
spinal cord to control output to the periphery.