What is the structure and function of the nervous system? - Chapter 2

The goal of cognitive neuroscientists is to figure out what the 89 billion neurons of the human brain do and how their collective action enables us to function. 

What are the cells of the nervous system?

The nervous system is composed of two main classes of cells: neurons and glial cells. The neurons are the basic signaling units that transmit information throughout the nervous system. They vary in form, interconnectivity and location. Glial cells serve various functions in the nervous system, providing structural support and electrical insulation to neurons and modulating neuronal activity. 

Glial Cells

There are roughly as many glial cells as there are neurons in the human brain, the central nervous system has three types of glial cells: astrocytes, microglial cells, and oligodendrocytes. 

Astrocytes: are large glial cells with round or radially symmetrical forms, they surround neurons and are in close contact with the brain's vasculature. They make contact with blood vessels, which permits the astrocyte to transport ions across the vascular wall.

The astrocytes create the Blood Brain Barrier. This lies between the tissues of the central nervous system and the blood. The BBB makes sure certain microscopic objects, such as bacteria, can't diffuse into the blood vessels. The astrocytes also have an active role in brain function. They may either directly or indirectly regulate the reuptake of neurotransmitters. 

The glial cells also form the substance myelin in the nervous system. In the central nervous system the oligondendrocytes form the myelin, in the peripheral nervous system the Schwann Cells perform this task. Myelin is a good electrical insulator, preventing loss of electical current across the cell membrane. It increases the speed and distance that information can travel along a neuron. 

The microglial cells are very small and irregular shaped. They devour and remove damaged cells. 

The Neurons

A neuron consists out of the standard components found in almost all cells. They have a cell membrane, sometimes called a soma that encases the cell body. It contains the nucleus, endoplasmic reticulum, cytoskeleton, mitochondria, Golgi apparatus and other organelles. The neuron itself sits in a bath of salty extracellular fluid, which is made up out of a mixture of ions (positive or negative electrical charge; potassium, sodium, chloride and calcium). 

Neurons possess two unique cellular components: the dendrites and the axon. The dendrites are branching extensions of the neuron that receive inputs from other neurons, they can have varied and complex forms depending on the task and location of the neuron. Most dendrites also have specialized processes called spines, little knobs attached to the surface of the dendrites. The axon is a dingle process that extends from the cell body. Electrical signals travel along the length of the axon to its end, axon terminals, where the neuron transmits the signal to other neurons or other targets. The transmission of the signal occurs in the synaps. Some axons can branch to form a axon collaterals that can transmit signals to more than one cell. 

Neurons receive, evaluate, and transmit information, this is called neuronal signaling. Information is received by the neuron at its input synapses, passes through the cell body, via the axon, to the output synapses on the axon terminals. Within the neuron information moves from input synapses to output synapses through changes in the electrical state of the neuron caused by the flow of electrical currents within the neuron and across its membrane. Most neurons are both presynaptic - when their axon's output synapses make connections to other neurons or targets - or postsynaptic - when other neurons make a connection at the input synapses onto their dendrites or elsewhere on the receiving neuron. 

How does the neuron generate signals, and what are these signals? To answer these questions you first have to understand several things about a neuron:

1. Energy is needed to generate the signals

2. This energy is in the form of an electrical potential across the neuronal membrane, this is defined as the difference between the voltage inside the neuron versus outside the neuron

3. These two voltages depend on the concentrations of potassium, sodium and chloride ions, as well as on the charged protein molecules both inside and outside the cell

4. When a neuron is in its resting state and not actively signaling, the inside of a neuron is more negatively charged than the outside, this difference is typically -70 mV, this is known as the resting membrane potential

Also, the neuron membrane is peppered with transmembrane proteins, these are of two main types: ion channels and ion pumps. Ion channels are proteins with a pore through the center and they allow certain ions to flow down their electrochemical and concentration gradient. Ion pumps use energy to actively transport ions across the membrane against the concentration gradient. 

The extent to which a particular ion can cross the membrane is referred to as its permeability. This characteristic gives the neuronal membrane the attribute of selective permeability. The neuronal membrane is more permeable to K⁺ than Na⁺. Unlike most cells in the body, neurons are excitable, meaning that their membrane permeability can change, such proteins are called gated ion channels. 

Regarding the ion pumps; Under normal conditions, the NA⁺ and the Cl^- concentrations are greater outside the cell, and K⁺ concentrations are greater inside the cell. Why don't the K⁺ just flow out of the cell until the concentrations are equal inside and outside the cell? Neurons use active transport proteins known as ion pumps. They pump Na⁺ out of the cell and K⁺ into the cell, but this costs energy. Each pump is an enzyme that hydrolyzes ATP to get that energy. The inside and outside voltages are different because the membrane is more permeable to K⁺ than to Na⁺. The force of the K⁺ concentration gradient pushing the ions out of the cell, leaving the inside of the cell slightly more negative than the outside. This difference creates another force called electrical gradient. Eventually, the force of the concentration gradient pushing K⁺ out of the cell through the channels is equal to the force of the electrical gradient driving the K⁺ in. When this happens there is said to be reached an electrochemical equilibrium. 

The action potential

Neurons have evolved a clever mechanism to regenerate and pass along the signal received at synapses on the dendrite: the action potential. An action potential is rapid depolarization and repolarization of a small region of the membrane. Action potentials enable signals to travel for meters with no loss in signal strength, because they continually regenerate the signal at each patch of membrane on the axon. The action potential can regenerate itself by voltage-gated ion channels. The ion channels are also found along the axon. In myelinated axons, voltage-gated ion channels along the axon's length are restricted to the nodes of Ranvier

1. The depolarized membrane (-55mV) is the potential value for the threshold for initiating an action potential. When the threshold is reached the voltage-gated Na⁺ channels open and the ions flow rapidly into the neuron. This influx of positive ions further depolarizes the neuron, continuing the cycle by causing even more Na⁺ channels te open. 

2. This is called the Hodgkin-Huxley cycle. This lasts about 1 ms and generates the large depolarization that is the first portion of the action potential. Then the K⁺ channels open, allowing the ion to flow out of the neuron to down its concentration gradient. This outward flow of positive ions shifts the membrane back toward its resting potential. 

3. The opening of the K⁺ channels outlasts the closing of the Na⁺ channels, causing a second repolarizing phase of the action potential. This drives the membrane toward the equilibrium potential of K^+.. The membrane is temporarily hyperpolarized (-80 mV). 

4. Hyperpolarisation causes the K⁺ channels to close, in reponse to which the membrane potential gradually returns to its resting state. (-70 mV).

5. During this transient hyperpolarisation state, the voltage-gated Na⁺ channels are unable to open, so not other action potential can be generated. This is called the absolute refractory period. This last only a couple of milliseconds and has two consequences:

   1. The neuron's speed for generating action potentials is limited to about 200 action potentials per second. 

   2. The passive current that flows from the action potential cannot reopen the ion-gated channels that generate it. The result is that the action potential moves down the axon in one direction only, from the axon hillock to the axon terminal.

What holds the synaptic transmission?

Most neurons send a signal to the cells across the synapse by releasing chemical neurotransmitters into the synaptic cleft, gap between neurons at the synapse. 

1. The action potential at the axon terminal leads to depolarization of the terminal membrane and opening of the voltage-gated ion Ca²⁺ channels. 

2. This opening triggers small vesicles containing neurotransmitter to fuse with the membrane at the synapse and release transmitter into the synaptic cleft.

There are two types of postsynaptic receptors: ligand-gated ion channels - where neurotransmitter binding directly gates (opens) the ion channel, and the G protein-coupled receptors where biochemical signals indirectly cause the gating of the ion channels, this works via a second messenger. 

The neurotransmitter

What makes a molecule a neurotransmitter?

• It is synthesized by and localized within the presynaptic neuron, and stored in the presynaptic terminal before release. 

• It is released by the presynaptic neuron when action potentials depolarize the terminal

• The postsynaptic neuron contains receptors specific for it

• When artificially applied to a postsynaptic cell, it elicits the same response that stimulating the presynaptic neuron would.

Some neurotransmitters are amino acids: aspartate, GABA, glutamate, and glycerine. Other neurotransmitters are dopamine, norepinephrine, and epinephrine, serotonin and histamine. Another large group of neurotransmitters consists of slightly larger molecules and are called the neuropeptides; tachykinins, neurohypophyseal hormones, hypothalamic releasing hormones, opioid peptides and other neuropeptides. A particular neurotransmitter may have more than one type of postsynaptic receptor to which it binds, mediating different responses. The neurotransmitters that usually have an excitatory effect include ACh, catecholamines, glutamate, histamine, serotonin, and some other neuropeptides. The neurotransmitters that usually have inhibitory effect include GABA, glycine and some of the neuropeptides. 

The two primary players in balancing act between excitation and inhibition are glutamate and GABA. Glutamate is released by the pyramidal cells of the cortex, therefor it is the most prevalent neurotransmitter and is found in most of the fast excitatory synapses in the brain and spinal cord. GABA is synthesized from glutamate. It is found in most of the fast inhibitory synapses across the brain. 

Acetylcholine is present in the synapses between neurons and between neurons and muscles, where it has an excitatory effect and activates muscles. 

The primary sites of dopamine production are the adrenal glands and a few small areas of the brain. This include the striatum, substantia nigra and hypothalamus. There are several dopaminergic pathways, each sprouting from one of the small brain areas and is involved in several functions including cognitive and motor control, motivation, arousal, reinforcement, reward etc. 

Serotonin in the brain is released largely by the neurons of the raphe nuclei, in the brainstem. The serotonergic pathways are involved in the regulation of mood, temperature, appetite, behavior, muscle contraction, sleep and the cardiovascular and endocrine systems. 

Norepinephrine or noradrenaline is the sympathic nervous system's go-to neurotransmitter. It is produced by neurons with cell bodies in the locus coerculeus - area in the brain involved in physiological reactions to stress and located in the brainstem, more precisely the pons. Outside the brain NE is released by the adrenal glands. There are two types of receptors for NE: alpha-1 and alpha-2, and beta. The alpha-2 receptors tend to have excitatory effects, the alpha-1 and beta receptors tend to have inhibitory effects. 

Some neurons communicate via electrical synapses, which are very different from chemical synapses because there is no synaptic cleft that separates the neurons. The neuronal membranes touch at specializations called gap junctions, and the cytoplasms of the two neurons are essentially continuous. As a result, the two neurons are isopotential, meaning that electrical changes in one are reflected instantaneously in the other. 

What is the overview of the nervous system structure?

Neural communication depends on patterns of connectivity in the nervous system, the neural 'highways' along which information travels from one place to another. But identifying those patterns is tricky because neurons are extensively connected in both serial and parallel circuits. Localized interconnected neurons form a microcircuit. They process specific kinds of information and can accomplish sophisticated tasks such as processing sensory information, generating movements and mediating learning and memory. 

There are long-lasting connections between various brain regions, those are called neural networks, which are macrocircuits that are made up of multiple embedded microcircuits. 

The two main divisions of the nervous system are: the central nervous system (CNS) consisting of the brain and spinal cord and the peripheral nervous system (PNS) consisting of nerves and ganglia outside the CNS. 

The autonomic nervous system

The autonomic nervous system is involved in controlling the involuntary action of smooth muscles, the heart and various glands. It has two subdivisions: sympathetic and parasymphathetic branches. In general, the sympathetic system uses the neurotransmitter norepinephrine, and the parasympathetic system uses the neurotransmitters acetylcholine. The two systems frequently operate antagonistically. 

The central nervous system

The CNS is made up of the brain and spinal cord, and each is covered with three protective membranes, the meninges. Between two membranes is the subarachnoid space filled with cerebrospinal fluid (CSF). Within the brain there are four large interconnected cavities called ventricles. The largest are the two lateral ventricels in the cerebrum, which are connected to the more caudal third ventricle in the brain's midline and the fourth ventricle in the brainstem below the cerebellum. The CNS neurons are bunched together in various ways, two of the most common organizational clusters are the nucleus and the layer. Nuclei are located throughout both the brain and the spinal cord. The cerebral cortex of the brain, on the other hand, has billions of neurons. The cerebellum is the other structure of the brain that is highly layered, containing billions of neurons, also having white and gray regions. The gray matter in these layers is composed of neuronal cell bodies, the white matter consists of axons and glial cells. Finally, axons may project from one cerebral hemisphere to the other in bundles that are called commissures. The largest of these interhemispheric projections is the main commissure crossing the hemispheres called the corpus callosum.

How does the brain get its blood supply?

The brain needs oxygen and energy, which its extracts from blood. Two sets of arteries bring blood to the brain: the vertebral arteries, which supply blood to the caudal portion of the brain, and the internal carotid arteries, which supply blood to wider brain regions. The primary purpose of increased blood flow is not to increase the delivery of oxygen and glucose to the active tissue, but rather to hasten removal of the resultant metabolic by-products of the increased neuronal activity.

A guided tour of the brain

The spinal cord

The spinal cord takes in sensory information from the body's peripheral sensory receptors, relays it to the brain, and conducts the outgoing motor signals from the brain to the muscles. The spinal cord runs from the brainstem at about the first spinal vertebra to its termination in the cauda equina. It is enclosed in the bony vertebral column that extend from the base of the skull to the fused vertebrae at the coccyx (tailbone). 

The brainstem: medulla, pons, cerebellum and midbrain

We usually think of the brainstem as having three main parts: the medulla, the pons and the cerebellum, and the midbrain. The brainstem contains groups of motor and sensory nuclei, nuclei of widespread modulatory neurotransmitter systems, and white matter tracts of ascending sensory information and descending motor signals. 

The brainstems most caudal region is the medulla, which is continuous with the spinal cord. It houses the cell bodies of 12 cranial nerves, providing sensory and motor innervations to the face. Functionally, the medulla is a relay station for sensory and motor information between body and brain, it is the crossroads for most of the body's motor fibers. 

The pons is latin for 'bridge' and it is named that way because it is the main connection between the brain and the cerebellum. The pons is important for some eye movement as well as movements of the face and mouth. The reticular formation as three colomns of nuclei: raphe nuclei, parvocellular reticular nuclei, gigantocellular nuclei. 

The cerebellum clings to the brainstem at the level of the pons. Most of the fibers arriving at the cerebellum project to the cerebellar cotex, conveying information about motor outputs and sensory inputs describing body position. 

The midbrain lies superior tot he pons and can only be seen in medial view. Large fiber tracts course through the midbrain's ventral region from the forebrain to the spinal cord, cerebellum and other parts of the brainstem. The midbrain also contains some of the cranial nerve ganglia and the superior and inferior colliculus - they play a important role in perceiving objects and locating and orienting towards auditory stimuli. 

The Diencephalon: thalamus and hypothalamus

The thalamus is almost exactly in the center of the brain and perched on top of the brainstem. It is divided in two parts: one in the right hemisphere and one in the left - that straddle the third ventricle. The thalamus has been referred to as the 'gateway to the cortex' because all of the sensory (except the olfactory nerve) modalities make synaptic relays in the thalamus before continuing to the primary cortical sensory receiving areas. 

The main link between the nervous system and the endocrine system is the hypothalamus, which is the chief site for hormone production and control. It lies on the floor of the third ventricle. The hypothalamus controls the functions necessary for maintaining the normal state of the body: basal temperature and metabolic rate, glucose levels, hormonal state, sexual phase, cicadian cycle etc. It accomplishes much of this work through the endocrine system via control of the pituitary gland. The hypothalamus produces hormones as well as factors that can regulate those hormones. 

The telencephalon: cerebrum

The telencephalon develops into the cerebrum which includes most of the limbic system's structures, the basal ganglia, the olfactory bulb, and the cerebral cortex - covering it all. WIllis observed that the brainstem appeared to sport a cortical border encircling it. The classical limbic lobe is made up of the cingulate gyrus of cerebral cortex that extends above the corpus callosum in the anterior-posterior direction and spans both the hypothalamus, the anterior thalamic nuclei, and the hippocampus (memory system).

MacLean named it the limbic system when he suggested to include the amygdala into the group, this is anterior to the hippocampus. The structures included in the limbic system are tightly interconnected with many distinct circuits and share the characteristic that they are the most capable of plasticity in the cortex. 

The basal ganglia are a collection of nuclei bilaterally located deep in the brain beneath the anterior portion of the lateral ventricles, near the thalamus. They include: the caudate nucleus, putamen, globus pallidus, subthalamic nucleus and substantia nigra. The caudate nucleus and the putamen together are known as the striatum. 

What holds the cerebral cortex?

The cerebral cortex is the outermost tissue of the cerebrum. The cerebral cortex sits over the top of the core structures that we have been discussing the last few paragraphs. The folds of the human cortex serve two important functions:

1. They enable more cortical surface to be packed into the skull, if the human cortex were smoothed out to resemble that of a rat, humans would need to have very large heads. 

2. Having a highly folded cortex brings neurons that are located at some distance from each other along the cortical sheet into closer three-dimensional relationships. The axons that make the long-distance corticocortical connections run under the cortex through the white matter and do not follow the foldings of the cortical surface in their paths, so they project directly tot he neurons brought closer together because of the folding. 

The cerebral cortex can be divided by four main divisions: the frontal, parietal, temporal and occipital lobe. The central sulcus divides the frontal lobe from the parietal lobe, and the Sylvian (lateral) fissure separates the temporal lobe from the frontal and parietal lobe. 

How do you divide the cortex by cell architecture?

Cytoarchitectionics uses the microanatomy of cells and their organizations to subdivide the cortex. The cortex can now be divided in almost 200 defined areas. We use the Brodmann system to number the system and anatomical names for the cerebral cortex. This often seems very unsystematic, but the numbering has more to do with the order in which Brodmann sampled a region than with any meaningful relations between areas that may or may not exist. 

When using microscopic anatomical criteria, it is also possible to subdivide the cerebral cortex according to the general patterns of the cortical layers. 90% of the cortex is composed of neocortex - cortex that contains six cortical layers or that passed through a developmental stage involving six cortical layers. The mesocortex is a term for the so-called paralimbic system. 

How do you divide the cortex by function?

The different lobes in the cerebral cortex have a variety of functional roles in neural processing. Typically, cognitive brain systems are composed of networks whose component parts are located in different lobes of the cortex. 

• The frontal lobe has two main functional subdivisions; the prefrontal cortex and the motor cortex. It receives input from the cerebellum and basal ganglia via the thalamus and the premotor area. It is mainly responsible for generating neural signals that control movement. The motor association areas modulate inhibition, planning and sensory guidance. 

• The parietal lobe receives sensory information about touch, pain, temperature sense and limb proprioception via the receptor cells on the skin.

• The specific cortical regions of the somatosensory and motor cortices that process the sensations and motor control of specific parts of the body have been mapped out. The mapping of specific parts of the body to specific areas of the somatosensory cortex is known as somatotopy - but these maps are not set in stone and do not have necessarily distinct borders. 

• The occipital lobe is related to vision. The visual information from the outside world is processed by multiple layers of cells in the retina and transmitted via the optic nerve to the lateral geniculate nucleus of the thalamus. 

• Neural projections from the cohclea (auditory sensory organ in the inner ear) proceed through the subcortical relays to the medial geniculate nucleus of the thalamus and then tot the primary auditory cortex. The auditory cortex has a tonotopic organization which means that the physical layout of the neurons is based on the frequency of sound. 

• A good portion of the neocortex that is netiher primary sensory cortex nor primary motor cortex is traditionally been termed as association cortex

• The more anterior region of the frontal lobe, the prefrontal cortex, is the last to develop and is evolutionary the youngest region of the brain. It is therefor also proportionately larger in humans compared to the brain of other primates. The main regions are: the dorsolateral PFC, the ventrolateral PFC, the orbitofrontal cortex and the medial PFC. It takes part in the more complex aspects of planning, organizing, controlling and executing behavior, also known as the executive functions. 

• The paralimbic ares form a belt around the basal ganglia and medial aspects of the cerebral hemispheres and don't reside in a single lobe. Processing in these areas provides critical information about the relevance of a stimulus for behavior, rather than just its physical characteristics, which are provided by the sensory areas. 

The advantage we have over other primates is that our brains are larger in absolute volume and weight; therefore, we have more neurons. In addition to neuron number, other aspects of brain structure might affect cognitive ability. But the number of neurons that an average neuron connects to actually does not change with increasing brain sizes. By maintaining absolute connectivity, not proportional connectivity, larger brains became less interconnected. But evolution came up with two clever solutions:

1. Minimizing connection lengths: short connections keep processing localized, with the result that the connection costs are less. Shorter axons take up less space, less energy is required for building and signaling is faster over shorter distance. 

2. Retaining a small number of very long connections between distant rites: primate brains in general and human brains in particular have developed what is known as 'a small-world' architecture. It combines very short, fast local connections with a few long-distance connections to communicate the results of local processing. This design allows both a high degree of local efficiency and, at the same time, quick communication to the global network. 

How does the development of the nervous system look like?

Fertilization of the egg is followed by a series of events that lead to the formation of a multicellular blastula, that is already begun to specialize. The early processes that go into forming the nervous system are called neurulation. As the nervous system continues to develop, the cells at the lateral borders of the neural plate push upwards. This causes the more central cells of the neural plate to invaginate to form the neural groove. As the groove deepens the cells form the neural tube.

At the end of 6 weeks, when there is a stockpile of cells, asymmetrical division begins. After every cell division, one of the two cells formed becomes a migratory cell destined to be part of another layer.

A host of behavioral changes takes place during the first months and yeard of life. Although the brain nearly quadruples in size from birth to adulthood, the change is not due to an increase in neuron number. A substantial amount of that growth comes from synaptogenesis - the formation of synapses, and the growth of the dendrites. At roughly the same time as the synaptogenesis the neurons in the brain are increasing the size of their dendrites. The synaptogenesis is followed by the synapse elimination, or pruning. The person you become is shaped by the growth and elimination of the synapses, which in turn are shaped by the world you're exposed to and the experiences you have.