I. GrossOrganization of the Nervous System
   The nervous system is the organ system responsible forproducing, controlling and guiding our acts, thoughts and responses to theworld around us.  Duringembryological development it is derived from cells similar to those which go onto form our skin, but those precursor cells to the nervous system becomeincredibly specialized and diverse, working together more complexly andintricately than any other organ system in the body.  The basic plan arises from the form of a simple hollow tubethat expands and differentiates itself into something that looks and functionsvery different from the tube it once was. We will examine its major divisions (the central, CNS, and peripheral,PNS, nervous systems) and its subdivisions, both in architecture and infunction.


   The most "available" division of the nervous system to the early anatomists for examination is the peripheral nervous system (PNS).  It consists of the nerves whichdirectly connect to the skin, muscles, blood vessels and organs of thebody.  As a general simplification,if nerve tissue not encased in bone (skull, spinal column), it is part of thePNS.


1. Somatic(Voluntary)
   The somatic nervoussystem at one time was called the voluntarynervous system.  This accurately describes the role and distribution of itsconnections.  The somatic nervoussystem innervates the muscles, and connective tissues attached to the skeleton andour skin.  It is responsible forour voluntary movements and the physical sensations (heat, cold, pressure,vibration, pain) we experience. The individual nerves are typically made up of both afferent and efferent nerve fibers.  Such anerve can be roughly thought of as a bidirectional cable that has wires, someof which send impulses out to the body from the nervous system and some ofwhich carry impulses from the body to the nervous system.


a. Afferent Nerves
   To describe a nerve fiberas afferent means simply that the direction of the impulses it transmits go toward the nervous system from the body's muscles and skin.  Therefore, afferent nerves conduct sensory information towards the nervous system.


b. Efferent Nerves
   An efferent nerve fibersends impulses away from the nervous system in the direction of the body's muscles.  The efferent fibers generate movements of the skeleton andhence are motor nerve fiberssince their activation causes the locomotion of our limbs, torso and facialfeatures.


2. Autonomic(Involuntary)
   The autonomicnervous system used to be called the involuntarynervous system.  The autonomic system is responsible for sensory and motorfunctions outside of our voluntary control, such as internal organs and glands,smooth muscles in our gastrointestinal tract and blood vessels and the smoothmuscles attached to our skin.  Its subdivisions, the sympathetic and parasympathetic, have opposite and complementary actions on our bodies' organs and tissues. Autonomic nervous system activity is constantly balancing between its two components.  Neither one is ever completely inactive but at theappropriate times one activity of one subdivision will overshadow the activityof the other.


a. Sympathetic (Fight or Flight)
   The sympathetic nervoussystem is involved in preparing us for theexpenditure of energy.  Because ofthe effects its activation has on its target tissues and organs it can bereferred to as the fight or flightnervous system.  For instance, SNSactivation cause rises in bold flow to the skeletal muscles, an increases inheart rate, blood pressure and respiration rate and a reduction in blood flowto tissues on the body surface (i.e., skin) and the gastrointestinal tract and aslowing of intestinal movement.


b. Parasympathetic (Rest &Recuperation)
   The parasympatheticnervous system is involved in acquiring andstoring energy and restoration of the body.  It can be referred to as the rest and relaxation nervous system and is most active during digestionand resting, causing a rise in blood flow to the gastrointestinal tract andstimulating digestive activity and decreases in heart rate, blood pressure andrespiration rate.


   During most of our day, neither the sympathetic andparasympathetic systems predominate but are balanced in their activity.  However, during times of crisis andarousal or digestion and recovery from exertion, the system specialized forstimulating each of those functions overshadows the activity of the other forthe duration of that episode. Afterwards, the two systems go back into balance.


B. Central
  The components of the centralnervous system (CNS) can be identified as those that are encased inbone for protection, namely the brainand spinal cord.  Within the bony confines of the skulland spinal vertebrae they are surrounded by three layers of membranes, theouter dura mater (Latin for "hard mother"; a tough plastic like covering), the arachnoid membrane (it acts like cushioning and has a spider web-likeappearance) and the inner pia mater (Latin for the "soft mother"; a thin, relatively fragile covering).  Together these membranes are called themeninges and help to isolate theCNS from the rest of the body and protect it from possible infections.   The brain and spinal cord float ona thin layer of liquid called cerebrospinal fluid contained between the meninges.  The blood vessels of the brain alsohave an exceptionally tight form of gap junctions between the cells which makethem up, far tighter than the rest of the circulatory system.  These unusually tight gap junctions arecalled the blood brain barrierand closely regulate the types of materials and substances which can cross fromthe circulatory system into the CNS.


1. SpinalCord
   The main function ofthe spinal cord is to conduct nerve impulses from the afferent (sensory) nervesto the brain and efferent (motor) impulses to the peripheral nervous system(PNS).  The sensory fibers PNS enter the spinal cord through its dorsal surface (towards the back) and motor fibers exit the spinal cord from the spinal cord's ventral surface (towards the stomach).  Just outside the spinal cord the twotypes of fibers attach to each other to form the compound sensory/motor nervesof the PNS.  The cell bodies ofmost of the sensory nerve cells associated with the spinal cord are actually inthe PNS just outside the spinal cord. Within the spinal cord, the ascending sensory and descending motorfibers form the outer part of the spinal cord and the central core of thespinal cord consists of the cell bodies of motor nerve cells as well as specialclass of nerve cells called interneurons,which are also found throughout the CNS. These spinal cord interneurons control reflex responses which areenacted without a command from the brain. An example of this is the knee-jerk reflex sometimes performed during a doctor's examination.  When aphysician gently taps the tendon just below the knee cap, the incoming informationtraveling down sensory nerve fibers activates spinal cord interneurons inpassing towards the brain.  Theinterneurons activate spinal cord motor neurons which trigger the knee movementwhich is already executed by the time the brain receives the sensory signalthat the knee tendon has been struck.  Structurally, the center of spinal cord has a tube filledwith cerebrospinal fluid runningthrough it called the central canalof the spinal cord.  This tube is a vestigial reminder of the nervous system's early development from a hollow tube of neural cells.


2. Brain
   The brain is the organresponsible for guiding and controlling behavior.  It does so by processing sensory information, storinginformation about past experiences (i.e., learning and memory), and executingactions based those processed sensations and/or memories.  Across animal species, the more complexand highly developed the brain, the more complex the forms of sensoryprocessing, the greater memory capacity and the wider range of motor responsesthan can be made.


a. Ventricles
   The ventricles are a systemof interconnected fluid-filled chambers in the brain that are contiguous with thecentral canal of the spinal cord. They are a reservoir for and the producer of the cerebrospinal fluid (CSF).  Amembranous structure rich in blood vessels called the choroid plexus floatswithin the ventricles and generates fresh CSF from the blood and also recyclesold CSF into the blood stream. 

   In cases of diffuse neural death and cell loss such asin disorders like schizophrenia or Alzheimer’s disease, one sign of thedisorders can be enlarged ventricles. When the brain loses large numbers of cells across a wide area of thebrain, the brain does not shrink much from the inner surface of the skull,outside-in.  Rather, the shrinkageoccurs inside-out, hence the enlargement of the ventricles in those cases.


b. Hemispheres
   The gross structure of thebrain is divided into two symmetrical structurally identical hemispheres, rightand left, connected by several fiber pathways, the largest and most importantbeing the corpus callosum, which allowsthe two hemispheres to communicate. The two hemispheres do differ operationally, with each side specializingin different functions to some degree, especially in males.  The left hemisphere is predominantlyinvolved in analytical tasks, breaking down problems, and in languageproduction and comprehension.  The right hemisphere specializes in emotional processing, math, music, and synthetic processing, i.e., perceiving "wholes" out of individual component elements.


II.Structural Organization of the Brain
   The brain's organization proceeds from its lowest levels which control simple, basic functions necessary for life and awareness to progressively more complex structures which are eventually associated with thought, creativity and reasoning. Superficially, the lowest levels of the brain look very similar to thespinal cord which is connected to it. However, higher brain areas are marked by a large increase in physicalsize and dimensions as well as extensive folds and ridges.


A. Hindbrain
   The structures of the hindbrain are responsible forfunctions not under voluntary control which maintain general physiologicalfunctions of the body and both voluntary and involuntary movements.


a. Medulla
   The medulla is the region of the brain where centers whichcontrol autonomic functions such heart rate, blood pressure, respiration,arousal, startle and sleep/wake are located.  It is through these centers that the actions of thesympathetic and parasympathetic nervous systems manipulate these physiologicalresponses.


b. Pons
   The primary function of thepons is to serve as an input and outputfiber pathway connecting the brain and the cerebellum.  Initial motor commands to producemovement from the brain enter the cerebellum via the pons for furtherprocessing and the finished signals exit the pons and descend into the spinalcord to activate the spinal cord motor neurons to trigger the movements.


c. Cerebellum
   The cerebellum while a relatively small part of the brain hasalmost half the nerve cells of the entire brain.  The primary job of the cerebellum is to fine-tune the motorsignals generated by higher brain motor centers.  Damage to the cerebellum can disrupt the smoothness andgrace of movements as well as impair their timing, force, coordination and balance.


B. Midbrain
   The structures of the midbrain control functions that are more complex than the basic ones controlled by the hindbrain but they are still processes not typically under conscious control.  However, these functions are morelinked to our awareness of the world around us and coping and attending to newstimuli and as well as the roots of motivation (positive and negative) and theproduction of certain behaviors.  Thereare even motor areas in the midbrain which, when electrically stimulated, canby themselves generate walking, rearing and eating behaviors.

   The colliculi process visual and auditoryinformation.  The superiorcolliculus controls involuntary eyemovements and the targeting of the eyes. When our eyes scan an image or track an object thrown at us or directour gaze and attention to some fluttering object on the periphery of ourvision, the superior colliculus is in control.  The inferior colliculus does similar processing of auditory information, bringing the sourceof sounds in our environment to our attention and locating them relative to ourposition. 

   The periqueductal gray helps process information regarding pain.  It can reduce the perception of pain, analgesia, as well as generate active (fighting) and passive(freezing all movement) behaviors to cope with painful or threateningstimuli.  The neighboring substantianigra and the ventral tegmentalarea are involved in the producingessential neurotransmitters for forebrain circuits which are involved involuntary movements (substantia nigra) and pleasure, reward and attention(ventral tegmental area).

   The reticular activating system is a group of interconnected structures which extendfrom the hindbrain to midbrain and make contact with the forebrain.  This system alerts the forebrain tonovel or significant stimuli or changes in the state of the sensory informationbeing processed.  For instance, wemay come to ignore the steady hum of an air conditioner, but when it suddenlystops the sudden change may make us take notice.  Or we may see a sudden flash of movement on the floor out ofthe corner of our eye and turn to target our eyes on a large roach scurryingacross the room.  Or we maysuddenly raise our heads from our book when we hear the sound of a familiar voicein the next room.  In all of thecases, the reticular activating system is doing its job.


C. Forebrain
   The forebrain is the most highly developed part of themammalian brain, increasing in complexity as the behavior and cognitivecapacity of animals increase.  Thatincreased forebrain complexity in humans is what allows the enormousflexibility in our behaviors and problem solving skills relative to othercreatures.


a. Hypothalamus
   The hypothalamus is located below the thalamus and can be thought ofas the seat of most our behaviors which would be called emotional.  But itis also involved in other basic functions such as hunger, thirst, bodytemperature regulation, fear, aggression, mating and our response to stressamong other things.  The hypothalamus also controls the release of hormones from the pituitary gland (the body's master gland, in a sense), which is directly below it.  Through the hypothalamus our emotions, memories, thoughts, expectations can influence the function of the body's endocrine hormonal control over our physiological processes.


b. Thalamus
   The most prominent function of the thalamus for our purposes is the gating of incoming sensoryinformation (taste, touch, hearing, vision, but NOT smell) to the appropriate brain regions for furtherprocessing.  Those brain regionsalso send projections back to the thalamus to regulate their own sensoryinput.  In essence, the thalamusfunctions like an old-time telephone switchboard, routing incoming signals tothe appropriate destination.


c. LimbicSystem
   The limbic system is a group of various specialized structures, eachwith different functions spanning from memory, planning, emotion, reinforcementand attention.  Together, theiractions to provide us with the ability to compare our internal physiologicaland psychological states with the conditions in the external environment andselect an appropriate response based on our expected or desired outcomes.  We'll talk more about the limbic system shortly.


   The cerebrum constitutes the bulk of the forebrain.  The outermost part of the cerebrum isthe cortex, which makes up mostof the visible surface of the human brain. The term cortex comes from a Latinword for tree bark.  The cortex isthe sight of the most extensive and complex sensory processing as well as areaswhich receive that highly processed information, reason, solve problems andinitiate our movements.  The cortexis highly folded with ridges called gyri and grooves called sulci.  The purpose of the folding of the corticalsurface into gyri and sulci is though to be to provide a greater total corticalsurface area within the space limitations found within the skull.  Smaller animals with simpler brainsoften have smooth cortical surfaces, but larger animals, especially those withgreater behavioral complexity such as canines and primates for example, havegyri and sulci. 

   The cerebrum and its cortical area can be divided intofour regions, called lobes, which areassociated with some specific functions. The occipital lobe at theback of the brain is primarily concerned with processing visual information. The parietal lobeprocesses somatosensory (forexample, touch, cold, heat pain, etc., on the body surface) information as wellas forming associations between other multiple sensory stimuli.  The temporal lobe's functions can be divided by the lateral (or outside) surface and its medial (inner) surface.  The lateral temporal lobe is responsible for auditory processing and spoken language.  The medial temporal lobe is involved inmemory functions.  The frontal lobes are involved in planning, foresight,understanding the consequences of actions and the selection and initiation ofmotor movements.


III.Functional Organization of the Brain
   The basic functions of the brain in allmammals and can be generally categorized into processing sensory information,generating motor movements and integrating information about both the internalstate of the organism (for example, hunger, thirst or injury) and emotions andmemories of past learning and experiences to guide the selection of anappropriate motor response to a given set of sensory stimuli.  The systems which perform thesefunctions all interact and work together to guide and direct ongoing behavior.


A. SensorySystems
   The basic scheme of the sensory systems is thatsensory stimulation of the sense organs is transmitted into the CNS where in somecases very basic initial sensory processing is done in lower brain regions (forexample, the reticular activating system) in passing.  However, the incoming fibers' main target is the thalamus where the projections are organized and sent to the appropriate cerebral cortical target for intensive processing.  The only exception is for the sense ofsmell (olfaction) which bypasses the thalamus.  The projections from olfactory receptors descend from the brain's olfactory bulb directly into the tissues lining the nasal cavity and send their information directly to the olfactory cortex beneath the frontal lobes. All other sensory modalities (vision, hearing, touch, taste) make theirfirst major stop in the thalamus. At the appropriate part of the cerebral cortex, each sensory cortex hasfirst a primary sensory cortex whichdoes the initial intensive sensory processing.  It is this level of sensory processing at the primarysensory cortical level that is necessary for us to have conscious experience ofthat sensory modality.  There arehigher order sensory cortices (for example, secondary and so forth) which do evenmore complex analysis of the sensory information.  Eventually, the highest level processed sensory informationis sent to associational cortexin the parietal lobes where information about all the sensory modalitiesengaged by an object or experience converges.


B. Motor System
   The motor system has its beginnings in the frontallobes.  The premotorcortex and supplemental motor area areinvolved in the planning of voluntary motor movements.  They project to the primarymotor cortex which is responsible for thenerve impulses initiating the movements. The primary motor cortex projects to a group of structures called the basalganglia (which includes the caudate nucleusand/or putamen).  The basal gangliaprojects to midbrain motor areas which then project to the motor neurons of thespinal cord.  Repeated skilledmovements which become habitual rely on a loop from the basal ganglia to thethalamus and back to the prefrontal cortex.  Each time such a skilledmovement is executed (playing a guitar, riding a bike, juggling) the specificcircuits controlling that movement are strengthened through that loop until theact is automatic.  If damage occursto this cortical-basal ganglia circuit then voluntary movements becomedifficult, and in some cases, impossible. As an example in Parkinson's disease the basal ganglia (while intact) is deprived of a critical chemical messenger, dopamine. Without it voluntary movements become difficult and slow and in advancedcases and eventually cease. However, there is a second direct corticospinal (from primary motor cortex and spinal cord neurons) projection which can trigger movements but the activation of this second direct system is extremely difficult and in Parkinson's patients is only typically seen under periods of great emotional arousal. 


C. Limbic System
   The limbic system is a constellation of structuresthat involve the temporal lobes, the hypothalamus and the cerebral cortex (mostnotably the frontal lobes).  The mostprominent structures for the purposes of our discussion are the hypothalamicstructures called the mammillary bodies, the hippocampus and amygdala in the temporal lobe, the cingulate cortex, and the prefrontal cortex.  The hippocampus is involved intransferring information from our short-term memory to our long-termmemory.  The amygdala addsemotional impact and significance to the facts and events being transferredinto our long-term memories.  Thehippocampus is connected to the mammillary bodies which allow memories andexpectations to activate and be activated by our internal states such ashunger, anger, fear and the like. The mammillary bodies, hippocampus and amygdala all project to corticalregions such as the prefrontal cortex (which is involved in planning andworking memory and selecting the appropriate behaviors in a given situation).  The prefrontal cortex then caninfluence the upper part of the motor system, such as the premotor cortex, toinitiate a specific behavior.


D. Limbic/Endocrine SystemInteractions
   The limbic system, via its connection through thehypothalamic mammillary bodies can influence hypothalamic areas which directlycontrol the activity of the pituitary, which is the master gland of theendocrine system.  Through this limbic/endocrine interaction the brain and hence our thoughts, urges, memories, emotions, expectations, frustrations, etc., can influence our bodies responses to stress and other physiological responses via the pituitary's control of the body's endocrine glands.  While it's sometimes unintentional and unspecific, our psychological state can, in fact, influence our physiological condition because of this mind-body neuroendocrine interaction.


IV. Cellsof the Nervous System
   Nerve cells, neurons, are not the onlycells of the nervous system.  Infact, they are not even the most numerous type of cell in the nervous system.Depending, on the brain region or neuroanatomical structure, neurons may onlycomprise 10-50% of the cells found in a given area. The majority of cells inthe nervous system are cells called glia, the name of which is Latin for "glue."


A. Glia
   Glial cells are support cells for the neurons. Neuronsare highly specialized and are far less robust and self-sufficient than othertypes of cells, like muscle cells or liver cells.  They rely heavily on glia for a variety of functions whichallow the neurons to function effectively.  There are even three major types of glial cells to meet thevariety of roles that neurons need to be filled.


1. Schwann Cells &Oligodendrocytes
   One job of glial cells isto provide a type of electrical insulation, called myelin, for neurons and their projections.  Schwann cells are the myelin producing cells of the PNS, theonly place where they are found. Each Schwann cell provides one segment ofinsulation for one projection of a single neuron. This is done by the cellwrapping itself around the neuronal projection forming a tubular sheath-likesegment. Schwann cells are the only type of glial cell found in the PNS. Oligodendrocytes are myelin producing cells found only in theCNS.  Each oligodendrocyte is star-shaped and provides a segment of myelin insulation for neurons. Each star-like "branch" of an oligodendrocyte, however, provides myelin segment for the projection of a different neuron.


2. Astrocytes
   Astrocytes are the general housekeepers, environmentalengineers and nurses of the CNS. They maintain the stability and buffer the chemical content of theextracellular fluid surrounding neurons. They store starch as an energy reserve for neurons and also contributeto the formation of scar tissue at the site of injuries and clear away cellulardebris.


3. Microglia
   Microglia are the resident immune system cells of theCNS.  They are embryologicallyderived from the immune system cells of the rest of the body.  Because of the blood-brain barrier's effectiveness at preventing access to the CNS, microglia do the job of the immune system within the CNS. However, immune cells can eventually enter to supplement the activity ofthe microglia.


B. Neurons
   Nerve cells are called neurons.  Neurons are highly specialized for themaintenance of a slight electrical charge across the entire surface of theirmembranes, intercellular communication, processing electrochemical signals andstoring information.  While cellsof other organs are remarkably similar and uniform with respect to each other,neurons display a wide variety of sizes, shapes and chemical messengers betweencells. However, they do share some things in common.


V.Neuronal Structure
   Because of the common requirements of their specializedfunction, neurons share a few structural similarities, despite the greatvariety of their shapes and sizes.


A. Dendrite
   Given the role of neurons as a communicators andsignal processors, all neurons have dendrites, which can be thought of as the "input" side of a neuron.  Neurons receive signals from other neurons though theirdendrites.  Neurons have numerousdendrites forming what is called a dendritic arbor or dendritic field, a highly branched and sub-branched structure whichcan resemble a tree without leaves. Inputs from thousands of other neurons, three to ten thousand, can make contact with a single neuron's dendritic field.


B. Soma
   The soma is the neuronal cell body. Like the cell bodies found in other tissues the neuronal soma is the site of the neuron's nucleus, organelles and protein manufacturing and metabolic machinery. At one end of the soma is the dendritic arbor at the other side of the soma is the axon.


C. Axon
   If the dendrites are the "input" side of the neuron, then the axon is the "output" side of the neuron.  The neurons signals other neurons viaelectrical activation of its axon. While numerous dendrites attach to the soma,only one axon exits the soma. However, once the axon proceeds some distance from the soma it cansubdivide and branch up to several thousand times.  Just as a neuron can receive inputs from three to tenthousand neurons, the same neuron can make just as many contacts with otherneurons.


D. Terminal Button
   The terminal button is the tip of theaxon which makes contact with the dendrite of the next neuron and enableselectrochemical communication between the two neurons. The junction where theterminal button of one neuron meets the dendrite of the next and intercellularsignal processing and communication occurs is called the synapse.


VI.Neuronal Physiology
   Neurons devote most of their energy to generating andmaintaining a slight electrical charge imbalance.  The energy requirements (oxygen and nutrients) of this task is so great that the brain uses about 20% (1/5) of the body's available blood flow despite that fact that the brain weighs about 2-3 pounds, making it only about 2% of the body's total weight. The brain's metabolic requirements are constant, each second of every day, even while we sleep.  The electrical charge imbalance is what powers the neuron's ability to receive signals from other neurons, process those signals and send signals to yet other neurons. This set of processes basically makes each neuron similar to a small battery that is always running downand constantly being recharged. This combination of factors is whythe energy requirements are so high for brain tissue.


A.Electrical Potentials
   The slight electrical charge found across the membraneof the neuron is very slight and only exists just near the surface of theneuron.  If one were to measurefrom deep inside the neuron and from far outside it, a voltmeter would readzero volts. But the active forcible movement of electrically charged chemicalions (mostly dissolved salts) just inside and just outside the surface of theneuron generates neuronal electric potentials.


1. The (Resting) Membrane Potential
   The baseline difference inelectrical charge between the inside of the neuron and the exterior is typically-70 millivolts and is called the resting membrane potential, sometimes just called the resting potential.  This value can vary slightly indifferent neurons and in different animal species, but most mammalian specieshave a resting potential of -70 millivolts. The inside of the neuron is just slightlymore negative than the outside of the cell; -70 millivolts is -0.07 volts, lessthan one-tenth of a volt.  Theestablishment of the resting potential is generated by moving electricallycharged ions against their chemical concentration gradients or against their electrical gradients or sometimes both gradients.

   The concentration gradient is determined by simplechemical diffusion, i.e., that atoms ormolecules tend to move from regions of higher concentration to lowerconcentration. The higher the concentration of a chemical, the stronger thediffusion force is pushing all the atoms or molecules of that chemical awayfrom each other.  Hence, the higherthe concentration, the greater the energy needed to resist or overcome thediffusion force.

   The electrical gradient is present because the atomsor molecules being moved across the neuronal membranes carry either positive ornegative electric charges.  Likecharges repel each other.  When particlesof similar (same sign) charge are moved physically closer together, energy isrequired to overcome the electrical repulsion between those similarly chargedparticles.


a. The Ions
   Ions are electrically charged atoms or molecules.Positively charged ions are called cations. Negatively charged ions are called anions.  Themost important ions for neuronal function are potassium (K+),sodium, (Na+) chloride (Cl-), calcium (Ca++)and large structural proteins with negatively charged groups attached to themcalled large protein anions (A-). The protein anions are embeddednear the neuron’s inner cell surface as part of the cellular structuralframework and can never leave the cell. They basically establish the initialconditions that will make the resting potential possible. At rest, K+is the only ion that can freely move across the cell membrane. It comes intothe neuron and builds up to high concentration in the vicinity of the proteinanions until the electrical attraction between A- and K+is balanced by the diffusion force trying to push K+ outward.  This “break-even point” betweenelectrical attraction and chemical repulsion is what sets the resting membranepotential at -70 millivolts; hence K+ is basically responsible forthe potential.

   Under these baseline conditions, K+ is inhigh concentration inside the cell and low concentration outside. In contrast, Na+,Cl- and Ca++ are in extremely low concentration insidethe neuron and relatively high concentration outside.  In the case of Na+ and Ca++, diffusionand electrical forces are trying to force their entry into the cell at the -70millivolt resting potential. In the case of Cl- diffusion forcetries to force the anion in and electrical forces are opposing its entry.  When a cell fires in the act of signalinganother neuron or when it receives a signal from another neuron these otherions can enter as part of that process and basically temporarily and verybriefly (for a few milliseconds) “short out the battery.”  But then the neuron then goes through processesto reset the membrane potential.


b. Pumps & Channels
   The management andregulation of the ion imbalance is due in part to a series of ion-specificchannels made of proteins that span the membrane.  The basic shape of these ion channels once assembled andimplanted in the neuronal membrane is that of a hollow tube.  Some are constantly open (only K+has some channels that are always open and the rest are normally “pinched”closed and only open very, very briefly under some specific conditions ofchanges in membrane voltage. The specificity of the channels (K+, Na+,Cl- and Ca++) of the hole or pore in the tubular channel.For instance Na+ is smaller than Ca++, and therefore the poreof a Na+ is smaller than the pore of a Ca++ specificchannel. Also, since the channels are proteins and like the protein anions,charged particles can be incorporated into their structure, positive chargesare incorporated along the inside of the channel pore that is selective for Cl-and vice-versa for channels selective for the positively charged ions.

   When these channels open and close and cause changesin the chemical concentration of ions, there are protein-based pumps (whichrequire energy to operate) that correct the imbalances and work to maintain therelative ion imbalances that sustain the resting potential.  The most prominent pump is the Na+/K+ATPase, also called the Na+/K+pump, which pumps K+ into thecell and Na+ out of the cell at the cost of one molecule of adenosinetriphosphate (ATP), the energy currency ofthe cell, for each cycle of ion transfer that it completes. This pump runscontinuously as long as the cell is alive and is a major component of theneuron’s total energy requirement.


2. The Action Potential
   The action potential is a very rapid rise away from the resting membranepotential and then the equally rapid reversal back to the restingpotential.  When we refer to a neuron "firing" we're referring to the production of an action potential.  This phenomenon only appears on theaxon and travels down the axon to each and every terminal button of the axon.The action potential, once initiated, never decreases in peak strength all theway to the terminal button, no matter how long the axon. When an actionpotential occurs voltage-dependent Na+ channels open briefly and Na+rushes in and the membrane potential rises until the electrical and diffusionforces on Na+ cancel each other out (at about +55 millivolts) andthe electrical force pushing Na+ out matches the magnitude of thediffusion force pushing it in. At this point the Na+ channels close.However, some there are also some voltage-dependent K+ channels thatopen while the membrane potential is rising. Once the Na+ channelsclose, K+ leaves the neuron (taking its positive charges with it)through these additional open voltage-dependent K+ channels, as wellas the other constantly open K+ channels. This exit of K+and its charge is what returns the neuron to the resting potential.  These two types of ion-selectivevoltage-dependent channels exist from the base of the axon where it attaches tothe soma, called the axon hillock,or the spike initiation zone(SIZ), all the way to the terminal buttons.  Once an action potential starts at the SIZ, the actionpotential starts a chain reaction, of sorts, which triggers the activation ofall the neighboring voltage-dependent Na+ and K+ channelsall along the axons length and allows the action potential to propagate downthe entire length of the axon without diminishing in its peak voltage along theway.  This chain reaction openingof voltage-dependent channels is called active conduction.


a. Threshold
   You might ask, "How does this action potential stuff start in the first place," and that would be a good question.  Here's how:  When a neuron receives a signal fromanother neuron at its dendrite, it usually triggers an electrical responsewhich also involves Na+ entering the receiving neuron and a rise inthe membrane potential to +55 millivolts. However, this entry of Na+ only occurs at that synapse. Thereare no voltage-dependent Na+ channels on the dendrites and soma sothe potential generated at the synapse does not regenerate but only decreasesas K+ leaves through the constantly open K+ channels.  This is called an electrotonicpotential (also called a graded potential)and since no voltage-dependent channels open along the way it travels by passiveconduction.  This form of conduction is very, very fast; faster than anaction potential. But it doesn’t regenerate itself so it decays rapidly, alsounlike the action potential.  But if the electrotonic/graded potential is strong enoughwhen it reaches the axon hillock/SIZ (sufficiently high above restingpotential), then it will meet or exceed the threshold potential ofactivation, sometimes just called thethreshold potential, which is the voltage level required to open the voltage-dependentNa+ channels.  So, ifmembrane at the SIZ is sufficiently depolarized (more positive/less negativethan the resting potential) to reach the threshold potential, then the gradedpotential triggers the opening of voltage-dependent Na+ channels andan action potential is born.


   Once the action potential is generated, there are twopossibilities.  One is the active conduction of the action potential we've talked about already. That occurs in only a relatively few nerve fibers in most animals. This is because overwhelming majority of nerve fibers in most vertebrate animals are wrapped in myelin for electrical insulation and that presents a complication for simple active conduction.  Myelin may sound like a problem then but it's not. Here is why.  Invertebrates like insects and snails slugs and cephalopods don't have myelin.  Their axons,like vertebrate axons posses a characteristic very similar to the electrical resistancefound in electronic components. Many invertebrates like flying insects and squid need very fast actionpotentials to control the muscles which quickly propel them through air orwater. Because of the electrical resistance and the lack of myelin they areforced to have very large diameter axons to achieve the sort of conductionvelocity they need, because like in electrical wiring, electrical resistancegoes down as the diameter of the conducting element (a wire or an axon)increases. For example, the squid has a single axon which leads to it's main propulsion muscle in its mantle that is so large it is visible to the naked eye, about 1 millimeter in diameter.  This adds to the energyrequirements for the cell because the large axon is alive and Na+ions cross the membrane over the entire length of the large axon and thatincrease the workload of the Na+/K+ pump.

   In myelinated vertebrate axons, however, the myelincovers most of the axon and the action potential travels along the axon in acombination of fast (yet decaying) passive conduction and slower (yetnon-decaying) active conduction. This hybrid from of conduction is called saltatoryconduction.  In this form of action potential, the axon hillock fires andstarts at full strength but it encounters a segment of myelin.  Under the myelin sheath, the signal nowspeeds up and propagates via passive conduction.  Before the fast moving potential decays in strength belowthe threshold potential of voltage-dependent Na+ channels, thepotential encounters a bare spot on the axon called a node of Ranvier where the action potential is now able to fullyregenerate in strength before traveling again at high speed under the nextmyelinated segment.  Thusmyelination allows for very fast conduction of nerve signals with smaller axonsand Na+ ions only enter the axon at the nodes of Ranvier.  Together the smaller size of the axonand the lower total Na+ levels serve to minimize the neuron's energy requirements.


b. Refractory periods
   Another question might behow fast can a neuron fire? The answer is 500-100 times per second, maximum;though in practice the limit is about 500 times a second.  What determines this is the refractoryperiod, the minimum time required for theneuron to prepare for firing another action potential.  The refractory period has twocomponents, the absolute refractory period and the relative refractory period.  Theabsolute refractory period is caused by the voltage-dependent Na+ channels which have to physically and mechanically "reset" themselves after they close but before they can reopen. When they open voltage-dependent Na+ channels stay open for about 1 millisecond and the "reset" process takes about 1-2 milliseconds. Hence, the absolute refractory period is about 1-2 milliseconds.  During the absolute refractory periodit is physically impossible for the neuron to fire another actionpotential; cannot be done.  Theduration of the relative refractory period varies but typically it lastsseveral milliseconds.  The basis ofthe relative refractory period lies in the movement of K+ throughthe constantly open and voltage-dependent K+ channels in response tothe depolarization phase of the action potential.  As K+ leaves the cell, repolarizing the neuron back towards the resting potential, moreK+ than is necessary to repolarize leaves the neuron due to all theadditional open channels. This excess loss of K+ results in hyperpolarization, the membrane potential becoming more negative thanresting potential, but the membrane quickly returns to resting.  Unlike the absolute refractory period,the neuron can fire during the relative refractory period.  However, since the neuron ishyperpolarized, slightly more negative than usual, the task of the incominggraded potential is more difficult. The electrotonic potential must still reach the threshold potentialdespite the more negative membrane potential.  So, only unusually strong signals can trigger a secondaction potential during the relative refractory period.


c. Summation
   You might ask how easy is it to make a neuron fire an action potential. Well, it's not that easy.  Because of all the K+channels and how well they can counter the effects of any depolarization, onelone signal from one synapse has no chance in practical terms to trigger anaction potential at the axon hillock. Multiple electrotonic potentials are required.  These potentials are either excitatory potentials (depolarizing, where a positively chargedion enters at the synapse) or inhibitory (hyperpolarizing, where a negatively charged ion enters at the synapse)potentials. The excitatory signals and inhibitory signals compete and if the total effect of the excitatory signals is strong enough anaction potential is triggered. This totaling of all the excitatory and inhibitorysignals is called summation.  Summation is a practical requirementfor an action potential to be generated. However, there are two types ofsummation.


i. Temporal
   One type of summation is temporalsummation, in which one terminal button atone synapse is firing repeatedly, over and over.  Each excitatory postsynaptic potential (EPSP) in the receiving neuron has not completely died away before the following EPSP is generated. Therefore, each EPSP "piggybacks" on the tail-end of the other, all of them merging together.  This merging can yield a strong enoughEPSP traveling electrotonically to trigger an action potential at the SIZ.  The term temporal summation refers to the repeated rapid-fire signals from a single synapse "summing up" in time.


ii. Spatial
   The second type ofsummation is called spatial summation,where individual signals from separate synapses located at differentspatial locations across the neuron, occur close enough in time that they converge and "add up" as they travel across the neuron.  If the sum of the EPSPsand any inhibitory postsynaptic potentials (IPSPs) from the various activated synapses is strong enough, thespatially summated graded potential will trigger an action potential.


B. The Synapse
   The synapse is a structure where neuronal signalingand communication occurs that includes parts of both the sending (presynaptic)and receiving (postsynaptic) neurons. Itis also thought that some long-lasting psychological changes such as learning,memory, habits, recovery from a brain injury and even addiction may reflectlong-term changes in the function of the synapses involved in those functions.The structural integrity of the synapse is partially maintained by proteinscalled neuronal cell adhesion molecules (NCAMs), which act like velcro and serve to anchor the terminal buttonto the dendrite.


1. The Terminal Button
   The terminal button is thetip of the axon, but it does have some unique properties that make itspecialized for communication.  Forinstance, while it does have voltage-dependent Na+ channels like therest of the axon, the button also has voltage-dependent Ca++channels which are not found elsewhere on the axon.  It is the entry of Ca++ into the terminal buttonthat is absolutely critical for the releaseof chemical messengers, called neurotransmitters, from the terminal button. If Ca++ doesn't enter the terminal button, it doesnÕt matter what else happens, noneurotransmitter will be released. The terminal button is also the site of manufacture and storage of theneurotransmitters. All the machinery to synthesize them, store them and releasethem as well as generate the energy to power all these processes is found inthe terminal button.


2. The Synaptic Cleft
   The gap between theterminal button and the dendrite is incredibly small, only 20 to 50 nanometers.That is smaller than the shortest visible wavelength of light which is about400 nanometers.  Theneurotransmitter released from the terminal button only takes 1-2 millisecondsto passively diffuse across the gap/cleft where the transmitter molecules makecontact with receptors for them.


3. The Postsynaptic Density
   The postsynaptic density isthe dendritic part of the synapse where the receptors for theneurotransmitters, as well as other structural and biochemical machineryinvolved in generating a response to the transmitter, are located and anchored.


   Each neuron only makes one type of neurotransmitterand releases only that transmitter from all of its terminal buttons. When anaction potential reaches the terminal button voltage-dependent Ca++ channelsopen and Ca++ enters the button which triggers a series of cellularevents which cause small membrane packets (vesicles) filled with a chemicaltransmitter to move forward within the terminal button.  The vesicles closest to the cellmembrane move forward and fuse with the membrane and dump their contents intothe synaptic cleft. The transmitter molecules drift across the gap and makecontact with receptors specialized to respond to only those specific molecules.Once the transmitter binds to the receptors, the receptors are activated and apostsynaptic response occurs, the chemical message being received by thepostsynaptic neuron.  Because thesignaling involves both electrical and chemical elements, neurons are said toengage in electrochemical signaling.

   However, such signaling between neurons would beessentially meaningless if the signal cannot be also turned off as well ason.  There are two major ways in whichtransmitter signals are terminated. The overwhelmingly most prevalent manner isthrough the process of reuptake. Inreuptake after the transmitter disengages from the receptor, it is transportedback inside the terminal button of the releasing neuron where the molecules arebroken down for remanufacture.  Thereuptake is accomplished via a transporter protein that functions much like theNa+/K+ pump. All transmitters except for one rely on reuptake to terminate the chemicalsignaling.  The only transmitterwhich does not rely on reuptake is a molecule called acetylcholine.  Thattransmitter system utilizes enzymatic degradation in the synaptic cleft. An enzyme, acetylcholinesterase, is attached to the postsynaptic density. Theacetylcholine released by the terminal button which doesn’t make contact withthe receptors or disengages from them is broken apart by the enzyme. One of thetwo break-down fragments of acetylcholine, choline, is transported back insidethe terminal button for reprocessing. The other break-down fragment, acetate, is allowed to drift away intothe extracellular fluid. The acetylcholine transmitter system is the only transmitter system that does not terminate theneurotransmitter signal by reuptake.


   There have been over one hundred compounds that havebeen identified or proposed as neurotransmitters.  Transmitters must be synthesized, packaged and stored,released, activate a receptor and metabolized.  The terminal button is the site of all these functions.  The receptors have specific bindingsites on them that allow the transmitters to activate them.  The action of the transmitters at theirreceptors depends primarily on the physical shape of the transmitter moleculeand its chemical nature. With over a hundred transmitters, we will concernourselves with only a few of the most studied and most important ones.

   It is important to note thatevery drug that has a psychological effect, whether as a medicine or a drug ofabuse, has that effect by somehow influencing the activity of a neurotransmittersystem that is already present in the brain. These drugs may influence thetransmitter system at any one of the following levels: synthesis, storage,vesicle release, receptor activation, enzymatic breakdown or reuptake. If thedrug increases or facilitates the activity or effect of the transmitter it iscalled an agonist. If the drugdecreases, interferes with or blocks the activity of the transmitter, it iscalled an antagonist. It is alsoimportant to note that if the drug successfully impersonates the transmitter atthe receptor and activates it, it is referred to as a direct agonist. In fact the transmitter itself may be referred toas a direct agonist for its receptor. If the drug unsuccessfully impersonatesthe transmitter at the receptor, attaching itself to it, but not activating it,it is then referred to as a direct antagonist.


   Acetylcholine (ACh) is our lone transmitter thatrelies on enzymatic degradation in the cleft to terminate its signal. ACh issynthesized from choline, which is a typically used as a component of the cellmembrane, and the enzyme Acetyl-CoA. By an enzyme called choline acetyltransferase (ChAT). It is broken downby acetylcholinesterase (AChase). Most of the limbic system's and cerebral cortex's source of ACh comes from a group of structures called the cholinergic basal forebrain (BF).The two most prominent structures of the basal forebrain are the septum and the nucleus basalis. ACh is involved in learning, memory, sleeping andwaking and sensory processing.


B. The Monoamines
   The monoamines are grouped together because they sharea lone amino group at one end of their chemical structure. The monoamines arein turn classified further into two groups, catecholamines and indolamines based on their chemical structures at the other endof the molecules.


1. Tyrosine-based
   Tyrosine is an amino acidfound in the diet that is the basic building block for the catecholamines. Theterm catecholamine denotes that the compounds share a catechol as part of theirstructure (a benzene ring with two hydroxide groups attached to it).


a. Dopamine (DA)
   For the synthesis of dopamine, tyrosine is first converted to L-DOPA by arelatively slow-acting enzyme called tyrosine hydroxylase.  Thenthe L-DOPA is converted to dopamine by an enzyme called DOPAdecarboxylase.  There are two major sources for the brain's supply of dopamine.  One is the substantianigra (SN; literally, the black substancein Latin) which provides its dopamine exclusively to systems in charge ofvoluntary movements. The other is the ventral tegmental area (VTA) which provides its dopamine to brain systemsinvolved in learning, memory, reward and cognition.


b. Norepinephrine (NE)
   The brain's supply of norepinephrine, is produced by the locus ceruleus (LC; Latin forthe blue spot). Norepinephrine cells first go through all the steps ofmanufacturing DA and then dopamine-beta-hydroxylase converts dopamine into norepinephrine.  The LC, which is associated with thereticular activating system, provides NE for the entire forebrain and thistransmitter seems to be especially important in memory, attention, emotionalarousal and response to novelty.


c. Epinephrine (E)

   There are very, very few epinephrine producing cells in the brain. The few cells that doare in the lower parts of the brain and produce epinephrine from norepinephrineby way of the enzyme phenylethanolamine N-methyltransferase.


2. Tryptophan-based
   Tryptophan is another aminoacid found in the diet that is the basic building block for an indolamineneurotransmitter. The term indolamine denotes that the compound has an indolering as part of its structure (a benzene ring with another five member nitrogencontaining ring four attached to it).


a. Serotonin (5HT)
   The majority of the brain's serotonin is produced and distributed throughout the entire forebrain by the cells of the dorsal raphe nucleus, which is also associated with the reticular activating system. Serotonin is among the most widely distributed transmitters and has roles in learning, memory, attention, mood, aggression, appetite, sleeping and waking, sensory processing, and arousal. Serotonin is often referred to as 5HT, for 5-hydroxytryptamine, serotonin's official chemical name.


C. The Amino Acids
   Along with serotonin, the most widely used andimportant transmitters are the amino acid neurotransmitters.


1. Glutamate (excitatory)
   Glutamate is the most common neurotransmitter in the brain andis the primary excitatory transmitter in the brain. Glutamate is found in thediet but it can also be synthesized as a byproduct from the Krebs citric acidcycle in the mitochondria. It is especially important in sensory processing andlearning and memory.


2. GABA (inhibitory)
   GABA, gamma-aminobutyric acid, is far less common than glutamate but it is theprimary inhibitory neurotransmitter in the brain. While the diet is not aprimary source of GABA, it can be synthesized from glutamate. By virtue of itsrole in quieting the activity of nerve cells, it plays a role learning, memory,sensory processing, sleep and waking and relief from anxiety.


D. Peptides
   As neurotransmitters, peptides are an exception to therule that transmitters are manufactured at the terminal button.  All peptides, which are short proteins,are made in the cell body and shipped in vesicles out the axon and to theterminal buttons.  There areseveral peptides used as neurotransmitters. Many of them, outside of the brain,act as hormones. But within the brain because the blood-brain barrierprevents them from exiting, the same peptide molecules serve a second use asneurotransmitters. One example is cholecystokinin, which in the digestive system is a hormone which stimulates thepancreas and the liver, but in the brain is a neurotransmitter with roles inpain, memory, anxiety and coincidentally, hunger, as well.


VIII.Neurotransmitter Receptors
   Every neurotransmitter receptor is a complex proteinthat spans the neuron’s membrane and has an external and an internal facingside. All receptors have TWOseparate binding sites for the transmitter. These binding sites are depressionsor pits in the receptor that can be though of as keyholes in a door lock andtheir shape is a match for the shape of the transmitter molecules.  When two molecules of the transmitter,or any other direct agonist, attach to the receptor binding sites simultaneously, the receptor is activated. There are however, twogeneral classes of receptor for almost each transmitter.


A.Ligand-Gated Ion Channels (Ionotropic)
   The ligand-gated ion channels are distant relatives ifthe voltage-dependent ion channels found on the axon.  The most obvious difference is that the voltage-dependentchannels had a mechanism for sensing changes in electrical charge, while theligand-gated ion channels have receptor binding sites what act as a mechanismfor detecting the presence of the transmitter.  Other than that they are tubes that are normally pinchedclosed until the binding sites have been activated and then they briefly openand allow charged ions to enter for a short time. It is the entrance of theseions that cause the EPSPs and IPSPs we talked about earlier.  These receptors are also calledionotropic since they allow ions to pass into the neurons.


B. G-Protein Linked (Metabotropic)
   The second general class of receptor is the G-protein linked, also called metabotropic since they do not directly cause an electrical response but cause biochemical changes within the neuron which can cause widespread changes in the neuron's metabolism.  The G-protein linked does nothave a pore as part of the receptor. It is bound to the membrane. Within thetwo layers of the membrane are entities, separate from the receptor, calledG-proteins.  When the receptor isactivated, the G-protein that comes in contact with the receptor is, in turn,also activated. The activated G-protein then disengages from the receptor andthe active subunit of the G-protein travels along the inner part of themembrane coming into contact with distant ion channels or membrane-boundenzymes and changes their activity. Often the result of this G-protein caused activation is the release ofother signaling compounds into the cell’s interior, called second messengers since the neurotransmitter is considered the firstmessenger.  These second messengerscan go from the dendrite to as far as the cell nucleus, activating otherenzymes or triggering the new manufacture of cellular proteins along the way.


   These two classes of receptors work together, oftenwithin the same synapse.  The ionotropic cause EPSPs or IPSPs, the electrical signals which directly determine if an action potential will occur. But the metabotropic, by changing the neuron's metabolic state, can also make the cell more or less sensitive to the EPSPs or IPSPs making it indirectly easier or harder to trigger an action potential.  The ionotropicreceptors are in a sense like a telegraph key sending a message, but themetabotropic receptors can be thought of as volume controls, making the messagelouder or fainter.

   Within each class of receptor, there can be furthersubtypes of receptor for each transmitter. In all this makes each transmittercapable of generating many different types of responses in the range of neuronsthat are responsive to that transmitter. For instance, for serotonin in humans there are 13 subtypes of receptor:one ligand-gated (the 5HT3) and 12 G-protein linked subtypes. Inanother example, dopamine has 5 subtypes, all G-protein linked (called D1,D2, D3, D4, and D5) with no ligand-gatedsubtypes at all, while glutamate has 2 types of ligand-gated receptors (calledAMPA and NMDA) and one metabotropic (called ACPD).  The variety of receptor subtypes, while sometimes confusing,does offer some hope for treating disorders. If a disorder is found to be moreclosely linked to a particular receptor subtype, it may be possible to targetpharmaceutical treatments specifically to that receptor and hopefully treatthat disorder with a minimum of side-effects.