Chapter 11
"Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter and jests, as well as our pains, sorrows, griefs and fears. It is the same thing that makes us mad or delirious, inspires us with dread and fear, whether by night brings sleeplessness, inopportune mistakes, aimless anxieties, absentmindedness and acts that are contrary to habit. These things that we suffer come from the brain when it was not healthy." Attributed to Hippocrates.
Organization: Central and Peripheral Nervous Systems
Central: Brain and Spinal cord
* What do they have in common?
Peripheral Nervous System: neurons and neuron processes located outside the CNS.
In Peripheral Nervous System (PNS), nerves are either sensory (afferent = going toward CNS), or motor (efferent = going away from CNS).
Somatic and Visceral Divisions of PNS
* Somatic refers to muscle & skin (joints, bones, eyes and ears also)
* Visceral refers to "viscera" and glands -- respiratory, digestive, urinary, circulatory, and reproductive systems. Some sensory structures.
Autonomic Nervous System (ANS) is part of PNS. It is "visceral efferent system"
ANS has two subdivisions: sympathetic and parasympathetic. (Chapter 15)
NEURONS are the functional units of nervous system. Specialized for conducting impulses.
Basic Histology of Nervous Tissue was also covered in Chapter 4. (remember?)
General Overview of Neurons
Excitability: neurons can generate electrical potentials
Conductivity: neurons can conduct electrical potentials
Parts of a generic neuron:
* Cell Body: nucleus and other organelles.
* Nissl bodies: high concentration of rough endoplasmic reticulum (protein synthesis).
* Dendrites: numerous, tapering processes. Receptive.
* Axon: single, non-tapering process. Conductive.
Subdivisions of Axon: axon hillock, initial segment, axon proper (fiber), telodendria, end bulb (bouton). Collaterals. Synapse formed at end.
Collections of neuron cell bodies: nuclei in CNS, ganglia in PNS.
Collections of axons: tracts in CNS, nerves in PNS.
Axons are usually "myelinated" - Myelin sheath is a wrapping of supportive glial cell (oligodendrocyte or Schwann cell) around axon. Acts like electrical tape: insulates and helps to speed conduction of nerve impulses.
Gaps between myelin sheaths are called nodes of Ranvier.
Nodes of Ranvier: as seen in conventional stain of whole nerve
The gaps help speed the conduction of action potentials (nerve impulses)
Neuron types Defined on the basis of:
Function: afferent (sensory), efferent (motor), and interneurons.
Structure: multipolar, bipolar, unipolar (pseudounipolar)
Associated Cells: Neuroglia. Not neurons. Metabolically and physically support neurons. Outnumber neurons 10:1. Take part in blood brain barrier. Note: the "barrier" is both physical (the structure of the capillary endothelial cells act as a barrier) and physiological (transport processes serve as a barrier).
Blood Brain Barrier: modifications of capillaries and glial cells (go to Introduction) which act to restrict the entry and exit of certain molecules. Generally, large proteins don't pass barrier.
In CNS:
1. Astrocytes: "Star-shaped" cells. Between capillaries and neurons. Take part in the Blood Brain Barrier.
Modulate synaptic transmission
2. Oligodendrocyte: myelin forming. "Oligo" means few, as in few branches.
3. Microglia: scavengers. Derived from white blood cells (not true neuroglia). Involved in many neurological diseases. Electron Micrograph of Microglial Cell Note lysosomal inclusions.
4. Ependymal: form internal linings of brain. Part of blood brain barrier.
In PNS:
Satellite cells: protective. Found in ganglia.
Schwann cells (neurolemmocyte): forms myelin in PNS.
Neuroglia cells influence nerve regeneration. Form scars.
Glioma: tumor consisting of glial cells. Why are glial cells more likely to form tumors than neurons?
Physiology of Neurons
Neurons are "excitable" cells - they can generate and conduct electrical impulses. Impulse is due to flow of sodium and potassium ions across the cell membrane.
Resting Membrane Potential
Inside of neurons is slightly negative compared to outside, between -50 and -80 millivolts (mV). Cell is considered electrically "polarized."
Polarization is due to the unequal distribution of ions.
Most important ions: sodium (Na+), potassium (K+), chloride (Cl-) and large organic ions.
At rest:
* Sodium has a low concentration inside of cell
* Potassium has high concentration inside of cell.
* Unequal concentrations maintained by Na/K ATPase Pump.
* Potassium is more permeable than Sodium at rest.
Generation of the Action Potential (aka "the impulse"):
To generate an impulse, something must change.
Ions enter and leave cell via "electrically- or voltage-regulated gates" or channels.
Key event: voltage reached. Generally 15 mV above resting membrane potential.
First event: Sodium becomes more permeable -- enters via specific sodium channels in cell membrane. Positive ions entering cell make cell less negative (depolarization) and that area of the cell becomes positively charged. Sodium entry is via positive feedback loop -- the more sodium ions that enter, the more positive cell becomes, which stimulates more sodium entry, etc....... This is called the Hodgkin Cycle.
Historical Note: Alan Hodgkin, along with Eccles and Huxley, won the Nobel Prize in 1963 for their research on the mechanism of action potentials. Score one for the neuronerds!
Second event: Potassium leaves cell via potassium channels. Positive ions leaving cell makes cell more negative (repolarization). Cell may become more negative than usual (hyperpolarization). Plus, sodium channels shut via built-in mechanism.
Resting membrane potential established again. Na/K ATPase pump pumps sodium out, brings potassium in.
How is impulse conducted?
Depolarization of one area of membrane will excite (open sodium channels) in neighboring area of membrane. Threshold is reached at this area - another action potential is generated.
Action potentials are self-generating, All-or-Nothing events. Influx of sodium ions generates sufficient current to bring neighboring membrane to threshold.
What keeps action potential from going "backwards?" Membrane is refractory to stimulation for a short time.
Conduction velocity:
* Influenced by myelin and axon diameter.
* Conduction velocity is increased by myelin sheaths.
Action potentials occur at Nodes of Ranvier rather than at each segment of cell membrane. Action potential skips from node to node -- saltatory conduction.
Since intensity or amplitude of an action potential is relatively constant, the nervous system codes for stimulus intensity by frequency of action potentials.
The number of action potentials that can be generated in a unit of time depends on refractory period.
Synaptic Transmission
The Synapse
* Types: Chemical or Electrical (gap junction)
* Structure: Terminal bouton -- synaptic cleft -- post-synaptic cell
* Presynaptic - Postsynaptic
Electrical junctions (gap junctions) are direct connections between cells. No cleft or neurotransmitters involved. Allows rapid relay of impulses between cells. Important in nervous system of some animals (mostly invertebrates) and cardiac muscle cells. Used when speed is more important than subtlety, e.g., escape behavior.
Chemical synapse: Presynaptic element has neurotransmitters, usually contained in vesicles.
Postsynaptic membrane has receptors for neurotransmitters. Action potential arriving at bouton stimulates release of neurotransmitter. Calcium entry is stimulus for vesicle release (exocytosis).
Chemical transmission is slow, but allows for more subtlety in responses.
Neurotransmitters:
There may be more than 50 different chemical neurotransmitters used in the brain.
Acetylcholine (ACh): in neuromuscular junction and between neurons in CNS and PNS. Well-described neurotransmitter.
Otto Loewi's Experiment : Classic experiment which demonstrated that a chemical (now known to be acetylcholine) released by the vagus nerve ("vagusstoff") could inhibit the heart.
Chemically Regulated Gates of muscle endplate - Model for synapse.
ACh receptors are either nicotinic (nicotine binds to them) or muscarinic (muscarine binds to them).
Skeletal Muscle ACh receptors are nicotinic.
Endplate becomes permeable to Na and K at the same time. Membrane voltage goes toward 0 mV (graded potential; depolarization).
Action of ACh is stopped by Acetylcholinesterase (AChE) on postsynaptic side.
ACh produces "Endplate Potential" (EPP) in muscle -- will initiate an action potential in the muscle membrane and cause contraction.
ACh produces "Excitatory Postsynaptic Potential" or EPSP in Neuron. One EPSP may or may not initiate an action potential. Depends on number of EPSPs, sensitivity of neuron and where the EPSP is being generated. EPSP is due to the flux of both Na+ and K+ ions.
Some neurotransmitters inhibit post-synaptic cell. These transmitters act of receptors which allow K+ and Cl- through. Cell hyperpolarizes. Potential is called Inhibitory Postsynaptic Potential (IPSP).
Post-synaptic neuron integrates (sums up) incoming EPSPs and IPSPs. If net effect is enough to bring initial segment to threshold, an action potential will be generated. If not, no action potential produced.
Temporal and Spatial Summation
Temporal: Timing of EPSPs and IPSPs
Spatial: How close are excitatory and inhibitory synapses?
Presynaptic Inhibition: Direct inhibition of neurotransmitter release.
Other Neurotransmitters: 50 known or suspected neurotransmitters.
Monoamines or Biogenic Amines
(Nor)epinephrine (adrenalin), dopamine, and serotonin. Broken down by enzymes monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT). Pre-synaptic neurons also have reuptake mechanisms.
Monoamines are the "feel good" transmitters. Anti-depressants elevate the levels of monoamines. Common antidepressants are MAO inhibitors (MAOI) and tricyclics (Elavil - elevates norepinephrine and seronin levels by reuptake inhibition). Prozac increases levels of serotonin only and differs from MAOI and tricyclics. LSD inhibits serotonin synapses in reticular system/raphe of brain. Cocaine elevates dopamine by inhibiting reuptake of dopamine (blocks dopamine reuptake transporter). Cocaine also seems to act on serotonin and norepinephrine transporters. Dopamine is strongly linked to pleasure and reinforcement, thus making cocaine highly addictive. MDMA (Ecstasy) promotes serotonin release and blocks reuptake (sort of an instant Prozac), but can be toxic to neurons (at least in animal and cell culture experiments).
* Amphetamine, methamphetamine, ephedrine, and epinephrine are structurally very similar but differ in their ability to cross the blood-brain-barrier.
Amino Acids
Gamma-aminobutyric acid (GABA), glycine (inhibitory), aspartic acid, glutamic acid. Monosodium glutamate (MSG) - "drug for the tongue?" (We have taste receptors that are sensitive to glutamate). Glutamate can be toxic to neurons in high doses -- involved in brain damage due to stroke. Glutamate receptors: 5 general types. The NMDA receptor is of great interest because of its role in memory and synaptic plasticity. PCP (angel dust) acts on NMDA receptors and may be useful in treating stroke.
The GABA receptor complex is a chloride channel -- benzodiazepines and barbiturates bind to it.
Glutamate Receptor Blockers Used for treatment of stroke and Epilepsy.
GHB: Structurally similar to GABA, but may mimic dopamine. Initial euphoria followed by depression. Can be deadly when mixed with other depressants (alcohol, heroin)
Rohypnol : flunitrazepam. A "date-rape drug" . It is a benzodiazepine that produces sedation and amnesia.
Neuropeptides:
Endorphins and enkephalins (morphine-like). Involved in pain pathways. Opiates like codeine, heroin, etc. are pain killers. They depress neurons in thalamus.
Some recently identified neuropeptides are involved with hunger and satiety.
Neurohormones involved in control of appetite (leptin, NPY, orexin)
Obesity and eating/set point hypothesis
Opiate Receptors
Acupuncture may work via endorphins.
Clinical Conditions
Multiple Sclerosis (MS)- immune attack on myelinated neurons.
Amyotrophic lateral sclerosis (ALS). Lou Gehrig's disease. Motor neuron atrophy. Many possible causes: genetic and toxins. High incidence in Guam led to toxin hypothesis. Glutamate is involved. Recent drugs (glutamate blockers and growth factors) have shown promise in slowing progress of ALS.
Myasthenia gravis: immune attack on muscle endplate ACh receptors resulting in a block in synaptic transmission.
Anti-acetylcholinesterases are typically used for treatment.
(Note, one commonly used drug, pyridostigmine bromide, may be responsible for some of the "Gulf War Syndrome," as reported on "60 Minutes," 10/31/99. It had been discounted as a cause in 1996 (see Frontline Report on Gulf War Syndrome).
Parkinson's Disease: low dopamine in part of brain which controls fine control of muscles (substantia nigra). Tremors in muscles. L-Dopa therapy. L-Dopa is converted into dopamine. Fetal cell and adrenal cell transplant research is very promising.
Cause of Parkinson's Disease is not known, but environmental factors ( viruses, toxins, and especially pesticides) are suspected.
Early onset (before the age of 40) Parkinson's is probably genetic.
Drug-Induced Parkinson's Disease ("Case of the Frozen Addicts"): "In 1983 a group of heroin users attempted to synthesize Demerol and accidentally produced a compound called MPTP. MPTP crosses the blood brain barrier and is converted to MPP+ that selectively binds to and destroys dopamine receptors. These individuals essentially gave themselves instant Parkinson's disease.
Huntington's Chorea: genetic (autosomal dominant; CAG repeat). Production of mutant protein called "huntingtin" in the brain. The protein forms clumps in nuclei of neurons that may lead to their destruction. Decrease in many neurotransmitter systems, especially GABA (GABA is abundant in "spiny neurons" of the basal ganglia and these cells are preferentially lost in Huntinton's disease). Movements are "dance-like" (e.g., "chorea" as in "choreography" relates to dance) or writhing. Also known as Woody Guthrie's disease.