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Do axon grows after cutting of some of its part to near original place?
Do axon restores after local damaging of some of its part?
I take https://class.coursera.org/neurobio-001/ classes and learn that axons are very long. So it is interesting if they able to restore connection to far places parts of body…
Well look at this picture from Junqueira histology book:
In an injured or cut peripheral nerve, segments of axons distal to the injury lose their support from the cell bodies and degenerate completely. The proximal segments can regenerate from their cut ends after a delay. The main changes that take place in an injured nerve fiber are shown in the picture above.
In the nerve segment distal to the injury the axon and myelin, but not the connective tissue, degenerate completely and are removed by macrophages. While these regressive changes take place, Schwann cells proliferate within the connective tissue sleeve, giving rise to rows of cells that serve as guides for the sprouting axons formed during the reparative phase.
The axon grows at the rate of 0.5-3 mm/day
Nerve Repair and Regeneration
Peripheral nerves have the ability to regenerate. The injured nerve fiber (axon) is very long and it has to regenerate and reach its target in a reasonable time so that the patient can have a good function (Figure 1). The nerve has protective layers of tissue surrounding it.
The epineurium surrounds the nerve itself. The perineurium is located around the fascicle (Figure 2). The endoneurium is located around the axon.
A motor neuron fiber’s axon transmits signals to a muscle or a gland. The neurons become stimulated at the dendrites (Figure 3). Neurons possess structures that allow for the transmission of impulses and are composed of two parts the receiving structures and the conducting structures. The receiving structures are the cell body and the dendrites. The conducting structures are the axon terminal and axon.
Signals from the brain are passed on to the muscles in the limbs by these motor neurons (Figure 4).
When a painful stimulus is applied to a sensory receptor in the skin (afferent), the information is transmitted to the central nervous system (CNS). Once the sensory signal has been received by the CNS, another signal is then sent from the brain (efferent) and passed along the motor neurons in order to move the muscles in response to the painful stimuli (Figure 5).
When the nerve is affected or cut, there will be no function of that nerve (Figure 6). When the axon is separated from the body, there will be degeneration of the axon and the degeneration will stop at the synapse and will not travel to the next neuron. Regeneration of the peripheral nerve is possible and all events of regeneration occur around the axon when the nerve is cut. The proximal stump will regenerate and the distal stump will have Wallerian degeneration. Macrophagocytes dispose of the degenerated axon and myelin sheath.
Peripheral nerves have Schwann cells and endoneurium that helps in regeneration. Schwann cells grow into the cut area and join the two ends.
The entire axonal material is phagocytized from the site of the injury to the endplate. A new generated axon sprouts and grows to reestablish the connection for reaching its target (Figure 7).
The neuron is able to survive and regenerate after the axon has been cut with neuronal survival and Wallerian degeneration. The Wallerian degeneration typically arises from severe nerve injury such as axonotmesis or neurotmesis. The cell body increases in size with migration of the nucleus towards the cell periphery. The cell body enlarges for approximately 20 days and remains enlarged until axon regeneration is complete. In the proximal part of the nerve segment, degeneration can occur and it is proportionate to the severity of the injury. Degeneration extends proximally to the next node of ranvier. Wallerian degeneration is seen in the distal portion of the nerve fiber (Figure 8).
Axonal degeneration is followed by degradation of the myelin sheath and infiltration by macrophages. The macrophages are accompanied by Schwann cells which clear the debris from degeneration. Distally, you will find Schwann cells proliferate and the axon sprouts (finger-like growths) and advance (Figure 9). Using Schwann cells as a guide, these sprouts advance about 1 mm per day. Atrophy of the associated muscle can be seen during the process.
Axonal growth is seen and the connection is reestablished with the muscle appearing to be bigger and a bit healthier. When the axon fails to establish continuity, a neuroma formation will be seen with no regeneration of the axon distally. Atrophy of the associated muscles will be seen during the process (Figure 10).
There are three types of nerve injuries: Type I (neurapraxia), Type II (axonotmesis), and Type III (neurotmesis).
The prognosis is good with neurapraxia and it is the mildest form of nerve injury and the nerve remains intact (Figure 11).
This type of injury is severe. The axon is damaged and the surrounding connective tissue remains intact (Figure 12). There will be partial or complete recovery of the nerve and Wallerian degeneration occurs distal to the injury site. Recovery occurs 1 mm per day or 1 inch per month.
There will be no recovery with neurotmesis. Fibrillation is present and the injury usually requires surgery (Figure 13). Motor neuron until potential is usually absent. In neurotmesis there will be degradation and neuroma formation.
There are several factors that affect the success of recovery. If the gap between the proximal and distal stumps is too wide or scar tissue has formed, surgery can help to guide the sprouts to the tube. Some of the factors that are favorable for nerve recovery after repair include younger age of the patient, distal injury, no significant delay in repair, sharp cuts (better than a crush), vascularity is preserved (Figure 14), and favorable orientation of the nerve in epineural repair.
For more information on nerves, follow the links below:
Answers to this Paper must be written on the paper provided separately.
You will not be allowed to write during the first 15 minutes.
This time is to be spent in reading the Question Paper.
The time given at the head of this paper is the time allowed for writing the answers.
Attempt all questions from Section I and any four questions from Section II.
The intended marks for questions or parts of questions are given in brackets [ ].
ICSE Biology 2014 (Solved)
Section -1 (40 Marks)
(Attempt All questions from this section
(a) Name the following :
(i) The part of the brain associated with memory.
(ii) The ear ossicle which is attached to the tympanum.
(iii) The type of gene, which in the presence of a contrasting allele is not expressed.
(iv) The hormone secreted by islets of langerhans.
(v) The process of conversion of ADP into ATP during photosynthesis. 
(b) State the main function of the following :
(i) Cerebrospinal fluid
(ii) Eustachian tube
(iii) Suspensory ligament of the eye
(iv) Sperm duct
(v) Lenticels. 
(c) Copy and complete the following by filling in the blanks 1 to 5 with appropriate words:
The human female gonads are ovaries. A maturing egg in the ovary is present in a sac of cells called ……… (1). As the egg grows larger, the follicle enlarges and gets filled with a fluid and is now called the ……… (2) follice. The process of releasing the egg from the ovary is called ……… (3). The ovum is picked up by the oviducal funnel and fertilization takes place in the ……… (4). In about a week the blastocyst gets fixed in the endometrium of the uterus and this process is called …….. (5). 
(d) Given below are six sets with four terms each. In each set one term is odd and cannot be grouped in the same category to which the other three belong. Identify the odd one in each set and name the category to which the remaining three belong. The first one has been done as an example.
Example: Calyx, Corolla, Stamens, Midrib
Odd term: midrib
Category : parts of a flower.
(i) Haemoglobin, Glucagon, Iodopsin, Rhodopsin.
(ii) Urethra, Uterus, Urinary bladder, Ureter.
(iii) Transpiration, Photosynthesis, Phagocytosis, Guttation.
(iv) Cyton, Photon, Axon, Dendron.
(v) Oxytocin, Insulin, Prolactin, Progesterone. 
(e) The figure given below represents an experimental set up with a weighing machine to demonstrate a particular process in plants. The experimental set up was placed in bright sunlight. Study the diagram and answer the following questions:
(i) Name the process intended for study.
(ii) Define the above mentioned process.
(iii) When the weight of the test tube (A & B) is taken before and after the experiment, what is observed ? Give reasons to justify your observation in A &B.
(iv) What is the purpose of keeping the test tube B in the experimental set up ? 
(f) Match the items given in Column A with the most appropriate ones in Column B and rewrite the correct matching pairs from Column A and Column B :
|Column A||Column B|
|(1) Pituitary gland||(a) Testosterone|
|(2) Sulphur dioxide||(b) Calcium|
|(3) Seminiferous tubules||(c) Growth hormone|
|(4) Clotting of blood||(d) Acid rain|
|(5) Guttation||(e) Sperms|
|(f) Global warming|
(g) Choose the correct answer from the four options given below :
(i) Cretinism and Myxoedema are due to :
(A) Hyper secretion of thyroxin (B) Hyper secretion of growth hormone (C) Hyposecretion of thyroxin (D) Hyposecretion of growth hormone.
(ii) Which of the following is not a natural reflex action ?
(A) Knee-jerk (B) Blinking of eyes due to strong light (C) Salivation at the sight of food (D) Sneezing when any irritant enters the nose.
(iii) After mitotic cell division, a female human cell will have :
(A) 44 + xx chromosome. (B) 44 + xy chromosome (C) 22 + x chromosome (D) 22 + y chromosome.
(iv) The antibiotic penicillin is obtained from :
(A) Protozoan (B) Bacteria (C) Virus (D) Fungus
(v) The site of maturation of human sperms is the :
(A) Seminiferous tubule (B) Interstitial cells (C) Epididymis (D) Prostate gland. 
(h) State the exact location of the following :
(i) Tricuspid value
(iii) Yellow spot
(iv) Seminal vesicle
(v) Adrenal gland 
Answer : 1
(a) (i) Cerebrum
(iii) Recessive gene
(iv) Insulin, Glucagon
(b) (i) Provide mechanical protection to brain or to provide nourishment to brain.
(ii) Maintain/Equalize air pressure on either sides of the ear drum.
(iii) Hold the lens in position.
(iv) Transport sperm from the epididymis to penis for discharge.
(v) To facilitate transpiration in older stem.
(c) The human female gonads are ovaries. A maturing egg in the ovary is present in a sac of cells called ovarian follicle (1). As the egg grows larger, the follicle enlarges and gets filled with a fluid and is now called the Graafian (2) follicle. The process of releasing the egg from the ovary is called ovulation (3). The ovum is picked up by the oviducal funnel and fertilization takes place in the oviduct (4). In about a week the blastocyst gets fixed in the endometrium of the uterus and this process is called implantation (5).
(d) (i) Odd term: Glucagon
(ii) Odd term: Uterus
Category: Parts of excretory system
(iii) Odd term: Phagocytosis
Category: Processes in plants
(iv) Odd term: Photon
Category: Parts of a neuron.
(v) Odd term: Insulin
Category: Female reproductive/sex hormona.
(e) (i) Transpiration.
(ii) It is the process in which water is lost in the form of vapour from the aerial parts of the plant.
(iii) After the experiment, we observe test tube A is raised up i.e., a loss of weight. In test tube B, the weight remains unchanged.
Reason: In test tube A, loses weight due to the plant transpires and loses water. In B there is no plant so there is no transpiration and the oil on the surface prevents direct evaporation and so weight remains unchanged.
(iv) As a control experiment.
|Column A||Column B|
|(1) Pituitary gland||(c) Growth hormone|
|(2) Sulphur dioxide||(d) Acid rain|
|(3) Seminiferous tubules||(e) Sperms|
|(4) Clotting of blood||(b) Calcium|
|(5) Guttation||(h) Hydathodes|
(g) (i) (C) Hyposecretion of thyroxin
(ii) (C) Salivation at the sight of food
(iii) (A) 44 + xx chromosome.
(iv) (D) Fungus
(v) (C) Epididymis
(h) (i) Tricuspid value: Between right auricle and right ventricle.
(ii) Amnion: Arouhd the foetus in the uterus.
(iii) Yellow spot: Exactly behind the lens on the retina of the eye.
(iv) Seminal vesicle: Between urinary bladder and rectum in male.
(v) Adrenal gland: Above each kidney fitted like a cap.
ICSE Biology 2014 (Solved)
SECTION-II (40 Marks)
(Attempt any Four questions from this Section.)
(a) Differentiate between the following pairs on the basis of what is mentioned within brackets:
(i) Spinal nerves and Cranial nerves (Number of nerves)
(ii) Near vision and Distant Vision (shape of the eye lens)
(iii) Corpus callosum and Corpus luteum. (function)
(iv) Turgor pressure and wall pressure. (Explain)
(v) Disinfectant and Antiseptic (Definition) 
(b) The diagram below represents the simplified pathway of the circulation of blood. Study the same and answer the questions that follow :
(i) Name the blood vessels labelled 1 and 2.
(ii) State the function of blood vessels labelled 5 and 8.
(iii) What is the importance of the blood vessel labelled 6 ?
(iv) Which blood vessel will contain a high amount of glucose and amino acids after a meal ?
(v) Draw a diagram of the different blood cells as seen in a smear of human blood. 
(a) (i) Spinal nerves: 31 pairs.
Cranial nerves: 12 pairs
(ii) Near vision: More convex/too curved.
Distant vision: Less convex/too flat.
(iii) Corpus callosum: Connect the left and right cerebral hemispheres.
Corpus luteum: Secrete female sex hormones Oesterogen and progesterone.
(iv) Turgor pressure: The pressure exerted by cell contents of a turgid cell on the cell wall.
Wall pressure: The pressure exerted by the wall of a turgid cell on the cell contents.
(v) Disinfectant: These are chemicals of strong concentration applied on spots and areas to kill germs.
Antiseptic: These are chemicals of mild concentration applied on the body to kill germs.
(b) (i) (1) Anterior/Superior venacava (2) Dorsal aorta
(ii) Function of 5: Supply oxygenated blood to liver.
Function of 8: Cajry deoxygenated blood from posterior parts of the body to the right auricle of heart.
(iii) Importance of the blood vessel labelled 6: Blood vessel 6 is called Hepatic portal vein. It carries deoxygenated blood from intestine to liver. This blood contains excess glucose, some toxic substances etc. which are sent to liver where they are detoxified and the excess glucose is converted to glycogen and stored. This prevents these substances from directly entering the heart and damaging the heart.
(iv) Blood Vessel-6
(a) A candidate in order to study the process of osmosis has taken 3 potato cubes and put them in 3 different beakers containing 3 different solutions. After 24 hours, in the first beaker the potato cube increased in size, in the second beaker the potato cube decreased in size and in the third beaker there was no change in the size of the potato cube. The following diagram shows the result of the same experiment:
(i) Give the technical terms of the solutions used in beakers, 1, 2, and 3.
(ii) In beaker 3 the size of the potato cube remains the same. Explain the reason in brief.
(iii) Write the specific feature of the cell sap of root hairs which helps in absorption of water.
(iv) What is osmosis ?
(v) How does a cell wall and a cell membrane differ in their permeability ? 
(b) A potted plant was taken in order to prove a factor necessary for photosynthesis. The potted plant was kept in the dark for 24 hours. One of the leaves was covered with black paper in the centre. The potted plant was then placed in sunlight for a few hours.
(i) What aspect of photosynthesis was being tested ?
(ii) Why was the plant placed in the dark before beginning the experiment ?
(iii) During the starch test why was the leaf:
(1) boiled in water.
(2) boiled in methylated spirit.
(iv) Write a balanced chemical equation to represent the process of photo-synthesis.
(v) Draw a neat diagram of a chloroplast and label its parts. 
(a) (i) (1) Hypotonic solution.
(2) Hypertonic solution.
(3) Isotonic solution.
(ii) In beaker 3, the concentration of potato cube and the medium is same. So there is no osmosis taking place therefore the size of cube remains same.
(iii) The concentration of cell sap is higher in the root hair as compared to soil water due to endosmoses is takes place facilitating absorption of water.
(iv) Osmosis is a process of flow of solvent molecules from lower concentration to higher concentration through a semipermeable membrane.
(v) Cell wall is freely permeable and cell membrane is semi-permeable.
(b) (i) Sunlight is necessary for photosynthesis. (ii) To make the leaves free from starch. (iii) 1. To kill the cells. 2. To remove the chlorophyll. (iv) (v)
(a) The diagram given below is a representation of a certain phenomenon pertaining to the nervous system. Study the diagram and answer the following questions :
(i) Name the phenomenon that is being depicted.
(ii) Give the technical term for the point of contact between the two nerve cells.
(iii) Name the parts 1, 2, 3 and 4.
(iv) Write the functions of parts 5 and 6.
(v) How does the arrangement of neurons in the spinal cord differ from that of the brain ? 
(b) Give scientific reasons for the following statements :
(i) Use of C.F.C is banned in many countries.
(ii) We cannot distinguish colours in moonlight.
(iii) Balsam plants wilt during midday even if the soil is well watered.
(iv) Carbon monoxide is highly dangerous when inhaled.
(v) A person after consuming alcohol walks clumsily. 
(a) (i) Reflex action.
(iii) 1. Sensory/Afferent neuron.
2. Dorsal ganglion/Dorsal root.
3. White matter
4. Grey matter
(iv) Function of 5 (Synape): Transmit the sensory impulse from sensory neuron to the motor neuron.
Function of 6 (Motor neuron/Efferent neuron): Transmit the command to the effectors (muscle or glands).
(v) In Brain: Gray matter on the outerside and white matter on inner side.
In Spinal cord: White matter on the outerside and Gray matter on inner side.
(b) (i) Chlorifluorocarbons (CFC) are one of the major cause for ozone depletion.
(ii) Moonlight is dimlight during which cone cells of our eye do not function well therefore colour is not perceieved. It is only red cells that function in moonlight.
(iii) It is a herbaceous plant and loses too much of water by exessive transpiration. The rate of transpiration is more than the rate of absorption. So they with weak stem droops and wilts.
(iv) Carbon monoxide has great affinity with haemoglobin of our blood. It mixes with haemoglobin almost 300 times more than that with oxygen. It cuts off the supply of oxygen due to which it is fatal.
(v) Alcohol affects the cerebellum part of the brain which is responsible for muscular co-ordination. So after consuming alcohol due to lack of muscular balance and co-ordination, the person walks clumisly.
(a) Given below is a diagram representing a stage during mitotic cell division. Study it carefully and answer the questions that follow :
(i) Is it a plant cell or an animal cell ? Give a reason to support your answer.
(ii) Identify the stage shown.
(iii) Name the stage that follows the one shown here. How is that stage identified ?
(iv) How will you differentiate between mitosis and meiosis on the basis of the chromosome number in the daughter cells ?
(v) Draw a duplicated chromosome and label its parts. 
(b) (i) Name the disease for which the following of vaccines are given :
(1) Salk’s Vaccine.
(ii) Give one example of each of the following :
(1) A water pollutant.
(2) An aquatic plant used in the lab to demonstate O2 liberation during photosynthesis.
(3) An antibiotic.
(4) A nitrogenous base in DNA.
(iii) Expand the following biological abbreviations :
(1) ATP (2) TSH (3) DPT (4) DNA 
(a) (i) Plant cell. Because Cell wall present and Centrioles absent.
(iii) Metaphase: The chromosomes will be arranged at the equator attached to the spindle fibre.
(iv) In Mitosis : The chromosome number in daughter cell is same as that of the mother cell i.e., diploid mother cell gives rise to 2 diploid daughter cells.
In Meiosis : The chromosome number is halved in the daughter cells i.e., the diploid mother cell gives rise to four haploid daughter cells.
(b) (i) 1. Poliomyelitis
(ii) 1. Chemicals like Mercury from Industries.
(iii) 1. ATP: Adenosine triphosphate.
2. TSH: Thyroid stimulating hormone.
3. DPT: Diphtheria Pertussis Tetanus.
4. DNA: Deoxyribonucleic acid.
(a) The given diagram represents a nephron and its blood supply. Study the diagram and answer the following questions :
(i) Label parts 1, 2, 3 and 4.
(ii) State the reason for the high hydrostatic pressure in the glomerulus.
(iii) Name the blood vessel which contains the least amount of urea in this diagram.
(iv) Name the two main stages of urine formation.
(v) Name the part of the nephron which lies in the renal medulla. 
(b) Briefly explain the following terms:
(i) monohybrid cross.
(ii) Biomedical waste
(iii) Innate immunity.
(v) Hormones. 
(a) (i) 1. Collecting duct.
2. Distal convoluted tubule.
3. Loop of Henle.
4. Bowman’s capsule.
(ii) The afferent arteriole splits into many fine branches due to which the volume of capillaries reduce thus raising the hydrostatic pressure in the glomerulus.
(iii) Blood vessel 6-Efferent arteriole that connects to renal vein.
(iv) 1. Ultrafiltration.
2. Selective Reabsorption.
(v) Loop of Henle.
(b) (i) Monohybrid Cross : A cross between two parents taking the alternative traits of one single character. For example, a cross between tall and dwarf pea plants.
(ii) Wastes containing dressings, amputated body parts, used surgical instruments etc. from hospitals, that spread diseases.
(iii) Innate immunity is the immunity that a person inherits from his parents i.e., the person is bom with it.
(iv) The process by which white blood cells squeeze out through the walls of capillaries to reach the site of infection.
(v) Hormones: According to Selye (1948), “Hormones are the physiological organic compounds produced by certain cells for the sole purpose of directing the activities to distant parts of the same origins.”
(a) (i) State any two harmful effects of noise pollution on human health.
(ii) Categorize the following activities as per the functions of the Red Cross Society and the WHO :
(1) To suggest quarantine measures to prevent spread of disease.
(2) Humanitarian services to victim of war.
(3) To educate people in accident prevention.
(4) To promote projects for research on disease.
(iii) Write any two major reasons for the population explosion in India.
(iv) State Mendel’s Law of segregation. 
(b) Give technical terms for the following :
(i) A method of contraception in which the sperm duct is cut and ligated.
(ii) Statistical study of human population.
(iii) The protective covering of the heart.
(iv) A sudden heritable change in the gene.
(v) Repeated units of DNA molecule.
(vi) The fluid portion of blood.
(vii) The nerve that transmits impulses from the ear to the brain.
(viii) Group of hormones which influence other endocrine glands to produce hormones.
(ix) Thin walled sac of skin that covers the testes.
(x) The permanent stoppage of the menstrual cycle in a woman aged 50 years. 
(a) (i) Two harmful effects of noise pollution:
1. Cause hearing disorder.
2. Cause high blood pressure.
(ii) 1. WHO
2. Red Cross
3. Red Cross
(iii) 1. Desire for a male child.
2. Illiteracy and Lack of awareness about birth control measures.
(v) This law states that in a monohybrid cross, the contrasting characters or factors separate/or segregate from each other at the time of gamete formation.
(b) (i) Vasectomy
(vii) Auditory nerve
(viii) Tropic hormones
Figure 2 Regulating the fate of the proximal tip of injured neurons. (a) After axotomy, neurons with high regenerative capacity can regenerate and rebuild a functional growth cone at their tip. This process is characterized by an organized microtubule cytoskeleton and the organized trafficking of mitochondria and anterogradely transported vesicles. (b) Conversely, injured adult CNS neurons stall at the site of injury and form a retraction bulb at their severed tip. This bulbous structure shows disorganized microtubules, which is associated with the accumulation of mitochondria and anterogradely transported vesicles. (c) Pharmaco-logical microtubule stabilization promotes microtubule protrusion in the leading edge of the severed axon tip and rescues the formation of retraction bulbs. Together, these effects promote axons to regenerate and improve gait behavior after injury.
Study finds a key to nerve regeneration
Researchers at the University of Wisconsin–Madison have found a switch that redirects helper cells in the peripheral nervous system into “repair” mode, a form that restores damaged axons.
Axons are long fibers on neurons that transmit nerve impulses. The peripheral nervous system, the signaling network outside the brain and spinal cord, has some ability to regenerate destroyed axons, but the repair is slow and often insufficient.
The new study suggests tactics that might trigger or accelerate this natural regrowth and assist recovery after physical injury, says John Svaren, a professor of comparative biosciences at the UW–Madison School of Veterinary Medicine. The finding may also apply to genetic abnormalities such as Charcot-Marie-Tooth disease or nerve damage from diabetes.
Svaren, senior author of a report published Aug. 30 in The Journal of Neuroscience, studied how Schwann cells, which hug axons in the peripheral nervous system, transform themselves to play a much more active and “intelligent” role after injury.
Schwann cells create the insulating myelin sheath that speeds transmission of nerve impulses. In the repair mode, Schwann cells form a fix-up crew that adds house cleaning and stimulation of nerve regrowth to the usual insulating job.
Svaren and his graduate student, Joseph Ma, compared the activation of genes in Schwann cells in mice with intact or cut axons. “We saw a set of latent genes becoming active, but only after injury,” says Svaren, “and these started a program that places the Schwann cells in a repair mode where they perform several jobs that the axon needs to regrow.”
In the repair mode, but not in the normal one, Schwann cells start cleaning house, helping to dissolve myelin, which is essential for proper functioning but ironically deters regeneration after injury. “If you invite Schwann cells to a party,” says Svaren, “they will clean up the bottles and wash your dishes before they leave the house.”
This cleanup must happen within days of the injury, says Svaren, who directs the cellular and molecular neuroscience core at the Waisman Center on the UW–Madison campus.
The Schwann cells also secrete signals that summon blood cells to aid the cleanup, and they map out a pathway for the axon to regrow. Finally, they return to the insulator role to grow a replacement myelin sheath on the regenerated axon.
Supportive Schwann cells (green) surround the conductive axon (purple) of a neuron in the peripheral nervous system in this artificially colored image. A new study by John Svaren shows that Schwann cells not only make the insulating myelin (black), but also are active players in axon repair after damage. Image: John Svaren
Unexpectedly, the Schwann’s transition into the repair form did not entail a reversion to a more primitive form, but rather was based on a change in the regulation of its genes. “Almost every other nervous-system injury response, especially in the brain, is thought to require stem cells to repopulate the cells, but there are no stem cells here,” Svaren says. “The Schwann cells are reprogramming themselves to set up the injury-repair program. We are starting to see them as active players with dual roles in protecting and regenerating the axon, and we are exploring which factors determine the initiation and efficacy of the injury program.”
After the human genome was deciphered, epigenetics — the study of gene regulation — has moved to the forefront with the realization that genes don’t matter much until they are switched on, and that genetic switches are the fundamental reason why a skin cell doesn’t look like a nerve cell, and a nerve cells functions differently than a white blood cell.
In epigenetics, as elsewhere in biology, processes are often regulated through a balance between “stop” and “go” signals. In the Schwann cell transition, Svaren and Ma identified a system called PRC2 that usually silences the repair program. “This pathway amounts to an on-off switch that is normally off,” Svaren says, “and we want to know how to turn it on to initiate the repair process.”
The new study suggests tactics that might trigger or accelerate this natural regrowth and assist recovery after physical injury.
The nature of the top-level gene-silencing system suggested drugs that might remove the silencing mark from the genes in question, and Svaren says he’s identified an enzyme that may “remove the brakes” and deliberately activate the repair program when needed in response to injury.
Even if the drug tests are promising, years of experiments will be necessary before the system can be tested in people. Furthermore, as Svaren acknowledges, “many factors determine how well an axon can regenerate. I am not saying this single pathway could lead to a cure-all, but we do hope it is an important factor.”
Svaren says it’s not clear how the current finding on peripheral nerves relates to damage to the brain and spinal cord, where a different type of cell cares for neurons. There are some similarities, however. In multiple sclerosis, for example, cleanup must precede the replacement of damaged myelin.
Ultimately, the study could open a new door on regeneration, even beyond one key sector of the nervous system. “We have thought of the Schwann cell as a static entity that was just there to make myelin, but they have this latent program, where they become the first responders and initiate many actions that are required for the axon to regenerate,” Svaren says.
The assembly of a new growth cone is a prerequisite for axon regeneration after injury. Creation of a new growth cone involves multiple processes, including calcium signalling, restructuring of the cytoskeleton, transport of materials, local translation of messenger RNAs and the insertion of new membrane and cell surface molecules. In axons that have an intrinsic ability to regenerate, these processes are executed in a timely fashion. However, in axons that lack regenerative capacity, such as those of the mammalian CNS, several of the steps that are required for regeneration fail, and these axons do not begin the growth process. Identification of the points of failure can suggest targets for promoting regeneration.
Expression of Slits in diencephalon
To determine whether the Slits may be involved in the controlling the pathfinding and innervation patterns of RGC axons within the diencephalon, we examined the expression patterns of the mammalian slit homologs slit1, slit2, and slit3, relative to the developing RGC axonal pathway. In situhybridizations were performed on coronal sections of E15 and E17 rat brains, ages when RGC axons grow over the diencephalon and a repellent activity for retinal axons is released by the hypothalamus and epithalamus (Tuttle et al., 1998).
At E15, slit1 is strongly expressed in the ventromedial part of ventral thalamus and throughout much of the hypothalamus, with particularly high levels in the dorsal two-thirds (Fig.2A). Slit2is highly expressed in medial ventral thalamus, as well as in discrete areas within the dorsal and ventral regions of hypothalamus (Fig.2C). In addition, slit1 is expressed weakly (Fig.2A) and slit2 is expressed strongly (Fig.2C) in epithalamus and just lateral to the dorsal thalamic ventricular zone. Neither slit1 (Fig. 2A) nor slit2 (Fig. 2B) are expressed in the lateral aspect of dorsal thalamus, a target of RGC axons.
Expression of the slits in embryonic rat diencephalon. Coronal sections through the diencephalon of E15 (A, C, E) and E17 (B, D, F) rat brains showing slit1 (A,B), slit2 (C,D), and slit3 (E,F) expression detected with S 35 -labeled riboprobes. Dorsal is up. Sections were stained with bisbenzimide. Each photo is a single exposure using both dark-field and UV fluorescence illumination.A, At E15, slit1 is expressed in the ventromedial part of ventral thalamus, as well as throughout the dorsal two-thirds of hypothalamus. slit1 expression is also detected in medial dorsal thalamus and epithalamus. B, At E17, slit1 continues to be expressed throughout most of hypothalamus, as well as in medial ventral and dorsal thalamus, and epithalamus. C, At E15, slit2 is highly expressed in medial dorsal thalamus and at lower levels in epithalamus, medial ventral thalamus, and in distinct parts of dorsal and ventral hypothalamus. D, At E17, slit2 is most highly expressed in the dorsal thalamic, epithalamic, and ventral hypothalamic ventricular zones, as well as throughout ventral hypothalamus. In contrast, slit3 is expressed at low or nondetectable levels in diencephalon at both E15 (E) and E17 (F).Arrowheads mark the optic tract. Scale bars, 200 μm.
At E17, both slit1 (Fig. 2B) andslit2 (Fig. 2D) continue to be highly expressed within the hypothalamus, with slit2 expression highest in the ventral half. At this age, a small wedge ofslit1 expression is present in the lateral aspect of dorsal thalamus (Fig. 2B). In addition, slit1 is expressed strongly in epithalamus and in a thin band at the midline of dorsal thalamus slit2 expression is high in the epithalamic and dorsal thalamic ventricular zones. In contrast, at both E15 (Fig.2E) and E17 (Fig. 2F),slit3 expression in the diencephalon is very low (e.g., ventral hypothalamus and dorsal thalamus, except its lateral aspect) or nondetectable relative to slit1 and slit2.
These expression patterns of the Slits correlate with the fasciculation and innervation patterns of RGC axons within the diencephalon (for description, see Fig. 1). In summary, at the levels of the diencephalon over which the optic tract courses, we find that the combined expression of the Slits is high in the hypothalamus (high fasciculation, restricted sparse innervation), declines to lower levels in the lateral part of ventral thalamus (tract begins to defasciculate, restricted modest innervation), declines further to nondetectable levels throughout most of the lateral part of dorsal thalamus (tract is defasciculated, heavy innervation), and then increases to high levels in the epithalamus (high fasciculation and tract turns caudally, no innervation). These findings are consistent with a role for Slit1 and/or Slit2 as diencephalic repellents for RGC axons.
Expression of Slit receptors in retina
If slit1 and slit2 act as repellents for RGC axons, we would expect that robo1 and/or robo2, receptors for the Slits (Brose et al., 1999 Yuan et al., 1999), would be expressed by RGCs. To test this possibility, in situhybridizations were performed on sections through E13, E15, and E17 rat retinas, ages that cover the majority of the period of RGC axon growth.
At all ages examined, robo1 is expressed most strongly in the retinal marginal zone (Fig.3A–C). In addition, beginning at E15, scattered cells in the RGC layer in central retina are well labeled (Fig. 3B,G). By E17,robo1 expression is present at low levels throughout the retina, with punctate dense labeling in the forming RGC layer, indicative of scattered highly expressing cells (Fig. 3C).robo2 is expressed in central retina at E13, with especially high levels on the vitreal side, the location of the forming RGC layer (Fig. 3E,D). Expression ofrobo2 spreads peripherally such that at E17 robo2is expressed throughout the retina, again with highest expression in the forming RGC layer (Fig.3F,H).
Expression of the Slit receptors,robo1 and robo2, in embryonic rat retina. Coronal sections of E13 (A, D), E15 (B, B′, E,E′), and E17 (C, F) rat retinas showing robo1 (A–C) and robo2 (D–F) expression detected with S 35 -labeled riboprobes. Dorsal isup. The sections are counterstained with bisbenzimide. Each photo is a single exposure using both dark-field and UV fluorescence illumination. B′ and E′ are higher power views of the regions marked with an arrowin B and E, respectively. At 13 (A), E15 (B, B′), and E17 (C), robo1 is expressed in the retinal marginal zone (arrowheads). Scattered cells that appear to be highly expressing slit1 are detected in the ganglion cell layer in central retina at E15 (arrows in B, B′) and at E17 (arrow in C). At E13 (D) and E15 (E,E′), robo2 is expressed in central retina, with highest levels in the ganglion cell layer (arrows). It is also highly expressed in the epithelium at E13 (D, arrowhead). At E17,robo2 is expressed throughout the retina, with highest levels in the ganglion cell layer (arrow inF). OpN, Optic nerve. Scale bars, 200 μm.
These data demonstrate that, at the time RGC axons are extending over the diencephalon, robo2, and to a lesser extentrobo1, receptors for Slit1 and Slit2, are expressed in the RGC layer. Given the high, uniform expression of robo2 in the RGC layer, we conclude that most if not all RGCs express it. However, because only a small proportion of cells in the RGC layer highly express robo1, it is difficult to be certain that they are RGCs because a sizeable proportion of cells in the adult RGC layer are displaced amacrine cells (Jeon et al., 1998). In summary, our findings suggest that Slit1 and/or Slit2, acting predominantly through Robo2, may act as diencephalic repellents for RGC axons in vivo.
Expression of Slits in retina
We also examined the expression of slit1,slit2, and slit3 within the retina at E13, E15, and E17. At all ages examined, both slit1 (Fig.4A–C) andslit2 (Fig. 4D–F) are most highly expressed in the RGC layer. Expression is first detected at E13 in central retina but spreads peripherally over time, apparently following the central to peripheral gradient of the generation of RGCs (Morest, 1970). In addition, a domain of high slit2 expression surrounds RGC axons coursing through the optic nerve (Fig.4E,F). In contrast,slit3 (Fig. 4G–I) is not expressed to any significant degree in the retina at any of the ages examined. At E17,slit1 exhibits a graded, high ventral to low dorsal expression pattern. These data suggest that in vivo, Slit1 and Slit2, acting predominantly through Robo2, and to a lesser extent through Robo1, may be involved in intraretinal development. In addition, if both Robo and Slit proteins are present on RGC axons, they might modulate interactions between RGC axons.
Expression of Slits in embryonic rat retina. Coronal sections of E13 (A, D,G), E15 (B, E,H), and E17 (C, F,I) rat retinas showing slit1(A–C), slit2(D–F), and slit3(G–I) expression detected with S 35 -labeled riboprobes. Dorsal is up. The sections are counterstained with bisbenzimide. Each photo is a single exposure using both dark-field and UV fluorescence illumination. At E13 (A, D) and E15 (B,E), slit1 (A,B) and slit2 (D,E) expression is highest in the ganglion cell layer in central retina (arrows), but by E17, bothslit1 (C) and slit2(F) are expressed throughout the RGC layer (arrows). Note that slit1 expression is more restricted to the ganglion cell layer than slit2expression. Arrowheads in E andF indicate expression of slit2 at the optic disk and bounding the optic nerve (OpN).slit2 expression at E17 shows a high ventral to low dorsal graded pattern (C). slit3expression is not detected in retina at E13 (G), E15 (H), or E17 (I). Scale bars, 200 μm.
Slit2 biases and inhibits retinal axon growth in collagen gels
To determine the effects of Slit2 on RGC axon growth, we cocultured in three-dimensional collagen gels explants of retina at a distance from aggregates of 293T cells transiently transfected withslit2-myc cDNA or with vector cDNA as a control. Similar analyses were not done for Slit1 because we have not been able to produce sufficient levels of Slit1 protein by transfection. Explants of retina were prepared from E15 rat embryos, an age when RGC axons are extending over the diencephalon in vivo and are responsive to the hypothalamic and epithalamic repellent activities in vitro (Tuttle et al., 1998).
Axon outgrowth from retinal explants is robust when cocultured with mock-transfected cells (Fig.5A–D), whereas when cocultured with slit2-transfected cells (Fig.5E–H), outgrowth is substantially decreased. Overall, axon growth appears to be biased away from the cells, and often bundles of axons originate on the explant side facing theslit2-transfected cells (Fig. 5G). We quantified several features of axon outgrowth in the cocultures, including the bias in outgrowth, the length of axon bundles, and the total number of axon bundles, using the scheme presented in Figure6A. When retina is cocultured with mock-transfected cells (n = 18), 35% more axon bundles extend from the side facing toward the cells compared with the side away from them (Fig. 6B). In contrast, when retina is cocultured with slit2-transfected cells (n = 20), 30% fewer axon bundles emanate from the side facing toward the cells (Fig. 6B). Comparison between the two types of cocultures reveals that the ratio of toward to away is decreased by ∼50% in the Slit2 cocultures. Thus, Slit2 substantially alters the distribution of axon outgrowth from retinal explants, resulting in a biased outgrowth away from the source of Slit2. In addition, Slit2 results in a decrease in the length of retinal axon bundles. In cocultures with mock-transfected cells, axon bundles are the same length on the explant sides toward and away from the cells, whereas in the Slit2 cocultures, they are 35% shorter on the side toward the slit2-transfected cells compared with the away side (Fig. 6C). This decrease in the length of axon bundles suggests that Slit2 slows the rate of retinal axon extension.
Axon outgrowth from retinal explants is biased away from, and inhibited by, slit2-transfected cells. Explants from E15 rat retinas were cocultured for 1–1.5 d in collagen gels at a distance from aggregates of 293T cells transfected with humanslit2-myc (Slit2) or, as a control, with the parental plasmid (Mock). Cocultures were immunostained with an anti-β-tubulin antibody (see Materials and Methods) and photographed under fluorescence illumination. The 293T cells are to the bottom. Shown are a representative series of explants to show the range and bias of axon outgrowth.A–D, When cocultured with mock-transfected cells, retinal axon outgrowth is robust and exhibits a modest bias toward the cells. All 18 explants had outgrowth in the mock cocultures.E–H, In contrast, when cocultured withslit2-transfected cells, retinal axon outgrowth is substantially decreased and is biased away from the cells. Five of 20 explants in the Slit2 cocultures had no outgrowth (data not shown). Thearrow in G marks axon bundles that arise from the side of the explant facing theslit2-transfected cells but extend away for them. Scale bar, 200 μm.
Quantification of effects of Slit2 on biasing and inhibiting retinal axon outgrowth in vitro.A, Quantitation scheme. Cocultures were labeled with an anti-β-tubulin antibody, and the number and length of axon bundles were quantified in the hemiretina sector facing toward or away from the 293T cells. Quantitation was done blind to transfected cell type on 18 cocultures with mock-transfected 293T cells (575 axon bundles) and 20 cocultures with slit2-transfected 293T cells (92 axon bundles). B, Axon outgrowth is biased away fromslit2-transfected cells. The ratio of the number of axon bundles extending from the explant side facing the 293T cells compared with the side facing away from the cells is decreased by ∼50% in the retina Slit2 compared with the retina mock cocultures (p < 0.04 Student's ttest). C, Axon length is decreased by Slit2. The ratio of the length of axon bundles on the side of the explant facing toward compared with the side facing away from the cells is decreased by ∼35% in the retina Slit2 compared with the retina mock cocultures (p < 0.05 Student's ttest). D, Slit2 decreases overall axon outgrowth. The total number of axon bundles extending from retinal explants is decreased by 84% in the retina Slit2 compared with the retina mock cocultures (p < 4 × 10 −9 Student's t test).
The overall axon outgrowth from retinal explants is also diminished in the presence of slit2-transfected cells. Counts of the total number of axon bundles emanating from retinal explants in the cocultures shows that the number is decreased by 84% in the cocultures with slit2-transfected cells compared with mock-transfected cells (Fig. 6D). Thus, Slit2 is a potent inhibitor of retinal axon growth in vitro. The growth inhibition of Slit2 appears to be concentration-dependent because, on the explant side facing the slit2-transfected cells in which the amount of Slit2 protein should be greater, fewer axon fascicles emerge (Fig.6B) and they are shorter (Fig. 6C).
Although retinal axon outgrowth is fasciculated in both sets of cocultures, the axon bundles generally appear to be denser, that is more tightly fasciculated, in the presence of Slit2 (Fig. 5). To assess the degree of fasciculation, we digitally measured the optical density of the axon bundles immunostained using an anti-β-tubulin antibody, with the rationale being that more tightly fasciculated axon bundles should exhibit a greater optical density (see Materials and Methods). Retinal explants cocultured with mock-transfected cells had an average pixel value of 100 ± 1.5 (on a scale of 0 to 256), whereas those cocultured with slit2-transfected cells had an average pixel value of 114.7 ± 5.9. This difference was highly significant (p < 0.005 Student's t test). We therefore conclude that retinal axons are more tightly fasciculated in the presence of Slit2.
The findings described above demonstrate that Slit2 inhibits retinal axon growth and alters the distribution of outgrowth from retinal explants, resulting in a biased growth away from the source of Slit2. To determine whether Slit2 also has a directional affect on retinal axon growth, especially whether it repels retinal axons, we measured the angle of deviation of axons away from slit2-transfected cells (Fig. 7A). We found no significant difference in axon turning when retinal explants are cocultured with slit2-transfected compared with mock-transfected cells (Fig. 7B). Thus, although Slit2 biases and inhibits retinal axon growth in vitro, we are lacking formal criteria that Slit2 is also a chemorepellent for retinal axons.
Quantitation of the effect of Slit2 on the directional growth of retinal axons in vitro.A, Quantitation scheme. Quantitation was done blind to transfected cell type on 13 randomly selected cocultures of each type (those with no outgrowth were not used) 575 axon bundles were analyzed in the cocultures with mock-transfected cells, and 32 axon bundles were analyzed in the slit2-transfected cell cocultures. The axons angle of deviation away from the 293T cells was measured in the “toward” hemiretina sector as follows: a line (Gx), representing the expected direction of growth, was drawn through the center of the explant and the base of the axon bundle. A second line (Ga), representing the actual direction of growth, was then drawn through the base and the tip of the axon bundle. The absolute value of the angle between the base line (thick dashed line) and Ga (AGa) was then subtracted from the absolute value of the angle between the baseline and Gx (AGx). The difference is negative when the bundle extends away from the 293T cells and positive when it extends toward them. B, Retinal axons are not repelled by Slit2 in collagen gel cocultures. No significant difference is found in the angle of deviation of axon bundles away from the 293T cells between the retina mock and the retina Slit2 cocultures (p = 0.22 Student's ttest).
CTE is a disease of the brain. To really understand the science of what’s going on, you'll need some background on what the brain is like when it is healthy. A good place to start is by looking at our brain cells, or neurons.
If you’ve ever heard someone talking about how brains are wired, or if you’ve heard someone talking about getting their brains firing, they were talking about their neurons.
Neurons are the basic building blocks of the brain. About 90 billion neurons form trillions of connections, creating a complex network that allows us to interpret and react to our environment.
Every neuron has three main parts: the cell body, the axon, and the axon terminal. We’ll focus mainly on the axon, which is a long and skinny structure that behaves a lot like a wire in an electrical circuit. Neurons communicate with one another by sending electrical signals down their axons and off to adjacent cells.
Problems with the neuron
The axon’s long and spindly shape helps the neuron reach far away cells in different parts of the brain, but there are two problems that come with that shape:
1. It makes the axons fragile, and prone to injury during concussion.
Things tend to break at their weakest point, and the axon is very often the weak point for the neuron. After a concussion, damage to axons is much more common than damage to other parts of the cell. A damaged axon has more trouble sending its signals, interfering with the brain’s ability to do its job.
2. It makes it difficult for the cells to distribute chemicals and materials to all areas of the cell.
Almost everything the cell needs to function is made in the cell body, but a lot of that stuff needs to be used along the axon or at the axon terminal. To get everything where it needs to go, the cell needs a transportation system.
Microtubules: a fragile transportation system
To help distribute molecules and materials throughout the cell, neurons have a special transportation system, made up of tiny tubes called microtubules. These tubes run the length of the cell, helping materials from one end make it down to the other end.
To continue with our example, if the axon were as big as a regular wire, each microtubule would only be as wide as a single strand of hair.
Remember: axons are the weakest point of the neuron, making them the first thing to break during a concussion. Microtubules are much smaller and weaker than the axons, making them vulnerable not only to concussion, but also smaller impacts that may leave the axons intact.
Since these tubes are so small, they need help supporting their structure. A special protein called tau helps keep everything together by sticking to the tubes outside. In healthy brains, this is where the story ends: tau supports the microtubules, microtubules help the cells function, and the brain operates normally.
In diseased brains, however, the same protein that helped keep everything together can actually cause things to fall apart.
Tau proteins going haywire
If the microtubules are injured or break down, tau proteins can misfold, detach, and float freely inside the cell. Once proteins start misfolding, even without additional trauma they can cause other tau proteins within the same cell to misfold and malfunction, impairing cell function and eventually killing the cell. The misfolding tau appears to spread to connected cells when they cause those cells to malfunction as well through what is called prion-like spread.
Scientists are still trying to understand why this process leads to CTE in some people and not others. What scientists do know is that the tau in CTE spreads in a distinctive pattern that is unique to CTE. Scientists also believe that the slow spread of misfolding is likely one reason it takes so long for symptoms to show up. The slow spread also provides opportunities for effective treatment to slow or stop the disease.
Future directions of CTE research
One of the biggest questions in CTE research today is: How can we diagnose CTE in a living person? Once this is possible, we can begin evaluating potential treatments and therapies to help people who are suffering from the symptoms of CTE.
Scientists are working hard to develop such a test, and there have been promising findings using a variety of special techniques. Some of the most exciting lines of research are trying to diagnose CTE using:
Positron Emission Tomography (PET scans): Researchers first inject a tracing chemical that binds to the tau proteins in CTE, then use a special brain scanner to trace where the chemical settles in the brain. With a tracer chemical that binds to CTE tau (and only CTE tau), this technique could show us the tell-tale distribution of tau tangles while someone is still alive. Several research groups have developed such a chemical, and early studies in athletes are already underway. CLF is currently recruiting former NFL players for the FIND-CTE Study using a new tracer.
Fluid based biomarkers: New techniques in biochemistry have allowed researchers to develop extremely sensitive tests able to detect proteins and substances in the blood at extremely low levels. Researchers using these tests are looking for evidence of abnormal tau and other indicators in the blood of athletes at risk for CTE. Normally these indicators would be caught by a robust barrier between the bloodstream and the brain (called the blood brain barrier), but repeated concussions and subconcussive blows that cause CTE can also damage this barrier, allowing clues to slip out of the brain. Take a look at the DIAGNOSE CTE Research Project to learn more.
Another major field of inquiry is understanding risk factors for CTE and CTE progression – why do some people get CTE while most do not, and why do some people appear to have worse symptoms associated with CTE?
Genetics play a role in every major neurodegenerative disease. Together with our collaborators at the BU CTE Center, directed by Dr. Ann McKee (support Dr. McKee’s research here), we published the first CTE genetics study, which found that among those diagnosed with CTE, a variant of TMEM106B was associated with a 2.5 times greater risk of dementia. However, they did not find an association with developing CTE pathology, supporting the hypothesis that brain trauma exposure is the primary risk factor for CTE.
As the VA-BU-CLF Brain Bank grows, our ability to detect the influence of genetics on CTE pathology and symptoms will grow exponentially. Understanding the genetics of CTE will provide insights into why CTE occurs and how it progresses, creating better targets for interventions and treatment. You can support that effort by joining the CLF Research Registry. While the science isn't there yet, in the future, genetic profiles may help us identify children who should not be exposed to contact sports.
Return of Periodical Cicadas in 2021: Biology, Plant Injury and Management
Natural events often occur in predictable cycles. In temperate North America, we are accustomed to the annual production of the leaves, flowers and seeds of our deciduous oaks and maples. Agave americana, the giant agave native to Mexico and Texas, is commonly known as the century plant due to its enormous periodic bloom of a decade or two. Even celestial events occur with clockwork predictability, like the visit of Halley’s comet every 75 years. If you live in the eastern United States, get ready.
In the spring of 2021, trillions of periodical cicadas are expected to emerge in parts of the following states: Delaware, Georgia, Illinois, Indiana, Kentucky, Maryland, Michigan, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Tennessee, Virginia and West Virginia. They will be a source of wonder and consternation as they emerge from the earth and lay eggs in treetops. (Photo 1)
What are periodical cicadas?
Taxonomically, periodical cicadas are members of a large clan of insects known as Hemiptera, with piercing-sucking mouthparts and gradual metamorphosis, meaning juveniles are called nymphs rather than larvae. During development, there is no pupal stage. Other familiar members of this clan and close relatives of cicadas include leafhoppers, spittle bugs and lanternflies. Periodical cicadas differ from their relatives, annual and dog-day cicadas, which appear yearly in summer and autumn throughout North America and much of the world.
By virtue of their visits in cycles of 13 or 17 years in distinct locations, periodical cicadas are unique in the animal realm. These regional, periodic visits are called broods, and there are three broods of 13-year cicadas and 12 broods of 17-year cicadas. Scientists classify the different broods using Roman numerals. Periodical cicadas emerging in 2021 are known as Brood X, with the X, of course, adding an element of consternation that will be pondered by many and exploited by the media. A common misconception regarding periodical cicadas is that they are but a single species. They are not. There are four species of 13-year cicadas, which go by the names of Magicicada neotredecim, M. tredecim, M. tredecassini and M. tredecula, and three species of 17-year cicadas, called M. septendecim, M. cassini and M. septendecula.
While Native Americans were fully aware of periodical cicadas by the time the first colonists landed on the New World’s shores, colonial Europeans had never experienced a massive appearance of large, boisterous insects emerging from the earth and flying to treetops. In 1633, William Bradford, the first governor of Massachusetts, wrote, “All the month of May, there was such a quantity of a great sort of flyes like for bigness to wasps or bumblebees, which came out of holes in the ground … and ate green things, and made such a constant yelling noise as made all the woods ring of them, and ready to deaf the hearers.”
For immigrants escaping persecution in parts of Europe, this vast, disturbing natural event awakened long-forgotten fears of the eighth biblical plague, the plague of locusts. Throughout the colonies, the name locust soon became attached to periodical cicadas. Of course, we know locusts are grasshoppers, chewing insects of the Orthoptera clan that sometimes appear in astounding numbers, consuming everything plantlike in their path. However, journalists and a misinformed public continue to refer to periodical cicadas as locusts.
Seventeen years underground, and then what?
As you read this article, there are literally trillions of cicadas in subterranean galleries a foot or more beneath the soil’s surface. Densities of periodical cicadas can be staggering, with some areas harboring as many 1.4 million nymphs per acre (3.5 million per hectare). (Photo 2) Brood X nymphs entered the soil in the summer of 2004 after hatching from eggs deposited by their mothers in small branches in the treetops. After burrowing into the soil, they feed on small roots of several different species of deciduous trees, but they also may feed on rootlets of gymnosperms and herbaceous plants, including grasses. Nymphs and adults pierce xylem elements with their sucking mouthparts and consume xylem fluid. Hatchling cicadas, known as first-instar nymphs, shed their exoskeletons four times, developing into fifth-instar nymphs by their 17th year, when they emerge from the soil.
Photo 2 In some areas, cicadas will reach densities even greater than those in the once square foot depicted here, translating to more than a million per acre.
Environmental cues linked to development and the exact timing of emergence are not fully understood, but the nutritional quality of plants consumed, soil temperatures and day length are all believed to play a role. When soil temperatures reach about 64 F, the massive synchronous emergence of cicada nymphs from their galleries will begin and last for only a matter of days. In the spring of 2020, at locations in Maryland, Virginia, the District of Columbia, Kentucky and Ohio, early-rising periodical cicadas of Brood X emerged between April 19 and June 14 (Raupp et al. 2020). Synchrony is critical for periodical cicadas. Their bizarre strategy for survival is to simply overwhelm hungry predators by filling all of their bellies and leaving yet enough cicadas to survive and perpetuate their species. This strange survival scheme is called predator satiation. It has proven successful for hundreds of thousands of years.
The bulk of cicadas emerge at dusk and move from the soil to vertical structures including trees, underlying vegetation and human-made structures such as buildings and lawn furniture. After shedding their last nymphal skin, adults expand their wings before their exoskeleton hardens. In the first 24 hours, the toll on emerging cicadas will be vast, but those that survive move to the treetops to mature. After several days, with wings and acoustic organs functional, males fly, aggregate in clusters of trees and begin an ear-splitting chorus designed to attract other members of their species. Membranes on both sides of their abdomen, called tymbal organs, vibrate to produce a variety of calls that can approach 100 decibels, an intensity slightly lower than that of a leaf blower or chain saw.
Once members of the same species are assembled, males use courtship calls to woo potential mates. If a female likes the male’s performance, she signifies her willingness to mate with an audible flick of her wings. Inseminated females eventually move to small branches on favored trees to lay eggs. Using a rigid appendage on the abdomen called an ovipositor, the cicada cuts slivers into twigs and deposits batches of 20 to 30 eggs into each of these egg nests. (Photo 3) Individual females may lay up to 600 eggs during the course of a lifetime. In the relative safety of the egg nest, eggs develop for six to 10 weeks, after which time tiny cicada nymphs drop from the canopy to the ground.Photo 3 Trees are injured when females slice branches and deposit eggs into the wood with an egg-laying appendage called an ovipositor.
Within a few minutes, they burrow into the soil, where they locate roots of plants and begin feeding for the next 17 years.
What injury do cicadas cause?
Photo 4 Small branches may have dozens of egg nests, causing them to flag and often break. Photo by Paula Shrewsbury.
Injury caused by xylem-feeding of adult cicadas is inconsequential. The real insult to woody plants comes from wounds caused when cicadas slice branches to insert eggs. This injury causes the tips of many branches to wither and die just distal to the sites of egg laying. These dead terminals droop, and the injury is called flagging. Eventually, dead terminals may break entirely and drop, littering the ground below with branches. Branches that do not break and drop may eventually enclose the ovipositional wound, but the wound site may be structurally deficient and may break at a later time. Concern also exists that egg-laying wounds may be entry points for pathogens to colonize plants. (Photos 4 & 5)
Photo 5 Recently transplanted trees, like this young oak, may be severely injured by cicadas and may not survive.
With respect to the types of plants used for oviposition, the bad news is that periodical cicadas are broad generalists. An important study conducted by Miller and Crowley (1998) at the Morton Arboretum of 140 genera of woody plants revealed that more than half sustained injury caused by ovipositing females of Brood VIII. Some of the most heavily attacked, and those experiencing the greatest twig breakage, included Acer, Amelanchier, Carpinus, Castanea, Cercidphyllum, Cercis, Chionanthus, Fagus Quercus, Myrica, Ostrya, Prunus, Quercus and Weigela. Several genera sustained no injury despite being surrounded by trees that were attacked. They included Rhus, Asimina, Berberis, Gymnocladis, Viburnum, Euonymus, Maclura, Abies, Larix, Picea, Pinus, Pseudotsuga and Phellodendron.
A more recent account of 42 common woody-plant species added several new genera to the list, and found that all but 10 were used as ovipositional hosts for Brood X cicadas in Delaware. This study found that native and non-native woody plants were equally likely to be used for oviposition by cicadas, but alien plants, those with no other known congener in the United States, were less likely to be used for oviposition (Brown and Zuefle 2009). (Photo 6)
Photo 6 On established trees, many branches will flag and break off where cicadas are abundant.
Several other factors besides taxonomic identity of a plant affect the use of a plant as an egg-laying host for cicadas. Small, bushy plants tend to receive fewer egg nests than those having simpler structure with longer branches. Several studies revealed trees near forest edges and branches with sunny exposures sustain more cicada injury. This places nursery stock, orchards and recently transplanted saplings in commercial and residential landscapes at elevated risk, particularly if there are established trees nearby with a history of supporting cicadas.
While flagging and limb breakage occur in the short term, there is little evidence that cicadas pose a long-term threat to the vitality of trees, especially older established ones (Miller and Croft 1998). A study of early successional trees found no clear effect of cicada ovipostion on growth rates or radial growth of trees attacked by cicadas (Clay et al. 2009).
Are there natural agents limiting cicada populations?
As mentioned previously, periodical cicadas evolved the strange predator-
satiation strategy as a means of survival in the face of intense pressure from so many creatures anxious to eat them. Starlings, grackles, robins, blue jays, blackbirds, sparrows, titmice, vireos, gulls, terns and several other feathered reptiles eat cicadas. Snakes, turtles and fish consume them. Skunks, squirrels, mice and other small mammals eat cicada adults and nymphs. Many predatory arthropods, including spiders, centipedes, opilionids, ants, stink bugs, assassin bugs and flies, have been observed feeding on various life stages of cicadas. A specialized fungus, Massospora cicadina, infects and kills large numbers of cicadas in each brood and, in a fascinating twist, becomes a sexually transmitted disease in cicada populations.
Cats and dogs will consume large numbers of cicadas in 2021. Cicadas in general, and periodical cicadas specifically, were and are important sources of protein for indigenous people, including Native Americans.
In addition to death due to biotic agents such as predators and disease, abiotic factors, including extreme weather conditions such as thunderstorms, doom many. Human activity such as deforestation, agriculture and urbanization with attendant proliferation of impervious surfaces is responsible for local extirpation of cicada populations. In recorded history, two broods of cicadas have disappeared, Broods XI and XXI.
Preventing cicada injury to trees
While a typical knee-jerk reaction might be to treat trees with insecticides, several scientific studies show this may not be the best way to go. Protecting trees from cicada injury is of the utmost importance to fruit growers, where injury to highly susceptible trees such as apples, peaches and cherries directly impacts yields and profits. Important data collected in a commercial orchard clearly demonstrated the efficacy of using netting rather than insecticides to protect trees from egg-laying cicadas. Trees netted with 1.0-cm mesh sustained virtually no damage, whereas trees treated several times with potent carbamate and synthetic pyrethroid insecticides received eight to 25 times more injury from cicadas. (Chart 1)
Chart 1 A comparison of different control tactics clearly shows that trees protected with 1.0-cm mesh netting received far less cicada injury, measured as number of egg scars, than trees treated with insecticides or enclosed in netting with larger mesh sizes. Data plotted from Hogmire et al. (1990).
Mesh size does matter. While 1.0-cm mesh performed well, when mesh size increased to 2.5 cm, cicada damage was as severe as that of untreated trees (Hogmire et al. 1990). Another important finding of this study was that netting proved to be only slightly more expensive than insecticide applications. A second trial with active ingredients listed by the Organic Materials Review Institute (OMRI) for use in the production of organic crops found six applications of emulsions of kaolin clay, neem and karanja oils to be ineffective in reducing the number of egg nests, while fabric netting provided complete protection from cicadas (Frank 2020). Cicadas actively move about and lay eggs for a period of several weeks, necessitating repeated applications of contact insecticides as new cicadas arrive.
Do soil injections of neonicotinoids provide longer-lasting protection to small trees compared to exclusionary nets? Our research demonstrated that soil drenches of imidacloprid applied to sapling Tilia were only about half as effective at preventing egg laying compared to 1.0-cm mesh nets (Ahern 2005). The material cost to enclose a 3-meter- (10-foot-) tall tree was $2.82 in 2005. Time to enclose a sapling was a matter of minutes. (Photo 7)
Photo 7 Small trees can be protected from cicada injury by enclosing them in netting.
Netting clearly provides superior protection and may be cost effective for small trees, but what about mature trees? Aforementioned studies indicate that the effects of cicada injury, while dramatic, likely have minimal negative effects on the long-term growth of trees. However, in addition to improving the short-term appearance of injured trees, careful sanitary pruning of damaged branches may enhance wound closure and reduce structural defects in branches as they mature.
How should we prepare for the impending arrival of Brood X?
For arborists, now is an excellent time to plan and discuss the upcoming appearance of Brood X with clients. Step one involves determining if cicadas will be present on your clients’ properties. Even though Brood X will appear in more than a dozen states, their distribution will be patchy, meaning in some areas vast numbers will emerge, but miles away few or none will be seen. If you are familiar with the cicada history of your clients, you may already know that cicadas emerged at their properties in 2004. If your business is new to an area or if you have expanded your client base to new locations, talk to your clients and see if they have knowledge of what happened in their landscape 17 years ago.
If cicadas are likely, inventory properties proactively to evaluate which trees are at greatest risk and discuss plans for protecting those trees. Several commercial vendors sell plastic netting suitable for protecting trees, but remember, mesh sizes larger than 1.0 cm may not prevent ovipositional injury. Suppliers can be found on the internet, and netting can be purchased in bulk. Some naturalists have expressed concerns about nesting birds becoming trapped in netted trees, so inspect trees prior to netting to avoid harming wildlife.
Urban foresters and planners should consider delaying planting woody plants in the spring of 2021 in areas known to support populations of periodical cicadas. If trees were planted in the fall of 2020 or in recent years past, consider protecting them.
Excellent information on all things related to cicadas can be found at the Cicada Mania website https://www.cicadamania.com/.
Get ready. Just as cherry trees bloom each spring and Halley’s comet stops by every 75 years, Brood X cicadas will return in 2021.
The Brain Is Made of Its Own Architects
In the 1940s, the Nobel prize–winning neurobiologist Roger Sperry performed some of the most important brain surgeries in the history of science. His patients were newts.
Sperry started by gently prying out newts’ eyes with a jeweler’s forceps. He rotated them 180 degrees and then pressed them back into their sockets. The newts had two days to recover before Sperry started the second half of the procedure. He sliced into the roof of each newt’s mouth and made a slit in the sheath surrounding the optic nerve, which relays signals from the eyes to the brain. He drew out the nerve, cut it in two, and tucked the two ragged ends back into their sheath.
If Sperry had performed this gruesome surgery on a person, his patient would have been left permanently blind. But newts have a remarkable capacity to regrow nerves. A month later Sperry’s subjects could see again .
Their vision, he wrote, “was not a blurred confusion.” When he dangled a lure in front of one of the newts, the creature responded with a quick lunge. It was a peculiar sort of lunge, though: The animal looked up when the lure was held below and down when it was dangled overhead. Sperry had turned the newt’s world upside down.
The experiment revealed that nerve cells, or neurons, possess a tremendous capacity for wiring themselves. Neurons grow branches known as dendrites for receiving signals, and sprout long outgrowths called axons to relay the signals to other neurons. Axons in particular can travel spectacular distances to reach astonishingly precise targets. They can snake through the brain’s dense thicket, pushing past billions of other neurons, in order to form tight connections, or synapses, with just the right partners.
The neurons in the eyes of Sperry’s newts regrew their axons, eventually linking up to neurons in the vision-processing region of the brain. Evidently the axons from the eyes were able to find the same parts of the brain that they had been linked to before the surgery. The only difference was that the post-operation eyes delivered inverted images, because the eyes had been rotated but the neuronal connections that they made unfolded as normal.
Six decades of research have made clear that Sperry’s newts were not unusual. All animals have nervous systems that wire themselves together with great precision. In humans this process starts in the womb, when the first neurons begin to develop. Their axons can go great distances, the longest ones extending all the way from the toes to the base of the spine. Even after our brains have developed, some neurons continue to wire themselves: Nerves heal from small injuries, and axons make new connections as we develop new skills.
When neurons fail to wire correctly, our bodies and brains go awry in many ways. About one in a thousand babies is born with a disorder called Duane syndrome , in which the nerves controlling the eye muscles send some of their axons to the wrong destinations. Axons that are supposed to grow into the muscle on the eye’s inner edge may end up on the outer edge instead. When people with this syndrome try to turn an eye inward, they send a message to the muscle on the inside edge to contract. But the same message also goes to the muscle on the outside edge. Both muscles pull at the same time, yanking the whole eye back into its socket.
Inside the brain, the results of bad wiring can be even more devastating. Normally, 200 million axons cross from each hemisphere of the brain to the opposite side. In a disorder called agenesis of the corpus callosum ( agenesis meaning “lack of development”), many axons cannot find their way out of their own hemisphere. Instead, their axons curl together into large bundles. People with this form of agenesis have trouble moving information from one hemisphere to the other. They end up with a lot of autism-like symptoms: They have a hard time understanding figurative language and inferring what other people are thinking, for example.
To better treat wiring disorders, scientists are trying to understand how neurons form circuits. But almost 70 years after Sperry’s newt surgery, the wiring question remains one of the deepest mysteries in neuroscience. One reason why is that the wiring problem is actually a series of problems, each of which our neurons may solve in several ways.
The first order of business for new nerve cells is finding where, among the 100 billion neurons of the nervous system, their partners are waiting. They do so by following a chemical trail. The tip of the axon, called a growth cone, senses chemicals drifting by. Responding to these cues, the axon grows like a vine toward attractive chemicals and away from repellent ones. The chemical cocktail has a different flavor from one part of the body (or brain) to the next.
The nervous system further directs these wandering axons by placing guide cells along their path. Some guide cells release navigational chemicals. Others become part of the path itself, as migrating axons grab the cells and climb them like ropes. Guide cells even babysit axons that arrive at a destination early, before a partner cell is available to connect. Without a viable partner the axon would die the guide cells form temporary synapses with the axons until the intended target is found.
The final stage of neural wiring is in many ways the most enigmatic. When an axon reaches the correct part of the brain, it needs to choose among the many neurons there. A few tricks that aid the process have been uncovered by University of Tokyo neuroscientist Akinao Nose , who has studied fly embryos. For a fly to be able to control its body, each muscle segment must be wired to a particular motor neuron. Nose wondered: How does the M12 neuron attach to the M12 muscle segment but not, say, to M13 next door?
In a paper published last year, Nose reported that the muscle cells advertise their differences. The muscle cells in the M13 segment are covered with a protein called Toll. M12 muscle cells are Toll-free. Nose hypothesized that the Toll proteins on M13 cells provide a signal that tells the M12 neuron to stay away. As a test, he and his colleagues modified the cells in the M12 muscle segment so that they manufactured Toll. Sure enough, the M12 neuron made fewer synapses on the Toll-studded M12 segment . When Nose shut down the Toll gene in M13 muscle cells, the M12 neuron started wiring itself to those cells instead.
Other signals prevent neurons from attaching to themselves. UCLA neuroscientist Larry Zipursky discovered this self-avoidance mechanism by studying a fly gene called DSCAM1 . When Zipursky shut down the gene, axon branches in individual neurons all took the same path. With the gene turned on, the axons took different paths toward other neurons. Apparently, DSCAM1 enabled neurons to distinguish their own axon branches from those of other neurons. Zipursky found that each neuron reads only certain portions of the DSCAM1 gene, producing specific proteins as a result. Since different neurons ignore different parts of the gene, DSCAM1 can produce more than 19,000 different proteins. With each neuron containing dozens of such proteins, the set of identity markers is essentially unique.
The team determined that DSCAM1 proteins on the surfaces of two axons will latch together if they match up—that is, if they are two parts of the same cell. The branches then undergo a chemical reaction that causes them to pull apart.
In the wake of Zipursky’s discovery, scientists are beginning to search for analogous identity proteins in humans and other mammals. A strong candidate is a group of proteins called protocadherins . Like DSCAM1 , these molecules sit on the surface of mammal neurons. Mammals carry dozens of protocadherin genes. When protocadherin proteins are expressed variably, there can be at least 12,000 combinations, or tags, in all.
When scientists genetically engineer mice without the genes, the animals end up with a range of neurological disorders. In the most severe cases, so many neurons die that the mice fetuses don’t survive till birth. Other protocadherin mutations are milder but just as intriguing. For instance, axons lose their way from the mouse’s nose to the brain. For now, though, such anomalies remain no more than tantalizing clues. Scientists have yet to prove that protocadherins help mammal neurons avoid self-wiring.
Back when Roger Sperry first twisted newt eyes and discovered how precisely neurons could wire themselves, he struggled to make sense of what he discovered. He decided that neurons had to be able to recognize their partners. “The cells and fibers of the brain and [spinal] cord must carry some kind of individual identification tags,” he wrote in 1963. Sperry could tell that the idea had serious problems: “The scheme requires literally millions, and possibly billions, of chemically differentiated neuron types.”
As it turns out, neurons do seem to have identification tags, but the job they perform is the precise opposite of what Sperry imagined: avoiding the wrong connections rather than seeking out the right ones. The latest research suggests that the strategy the neurons use is also not nearly as sophisticated as Sperry hypothesized. Biology is remarkably economical, it seems. A collection of shortcuts turns the challenge of wiring 100 trillion connections into a job so simple that even a bunch of wandering cells can do it.