Neuronal response to injury:

overview of degeneration and regeneration

(and PNS vs CNS)

more ten bodies more neuronal

in CNS

5BBA2081

neuron dies
Iniwry in cell body
(& more cell bodies in CNS = more neuronal death)

In iury to axon might regenerate

7 regeneration
Tisane
injuryfrom

Cws neurons have a lower intrinsic Aline Spejo

een body

ability to regenerated thanANS t

inhibitory environment in Cws x


angenurn

cante release of caspase 3 which causes

All stimuli for apoptosis Objectives

apoptosis

□ To be aware of various sources of injury to the Nervous System.

□ To be able to describe the consequences of axotomy:

Chromatolysis;

Wallerian degeneration.

□ To be able to describe options of axonal regeneration:

Growth factors vs neurotoxic factors;

Permissive vs inhibitory substrates.

□ To understand some of the factors that underlie differences in the

regenerative capacity in PNS and CNS:

Glial differences;

Neurotrophins (growth factors);

Substrate differences;

Growth inhibitors.

* References in last page.

Sources of injury to the Nervous System

to spinel andGreg

□ Mechanical: traumatic injury (falls, vehicle-related

collisions, sports injuries, violence);

X receive enough 02
cells

□ Ischaemic: insufficient blood flow to the brain leads

us breadcut

to energy crisis (vessels compression or blockage,

e g fun untreated heart attack

extremely low blood pressure)

by body
in

body attacks healths ans attacked

CNSMylansheath

□ Auto-immune: Multiple Sclerosis, Myasthenia

Gravis, Guillain-Barré Syndrome, etc.

muscle peripheral mykin

in
dimmed to sensations

keepers
respond
attacked prehbtwo
aus u

muscles
Nd i
be Ap x waver effectively

3!


Sources of injury to the Nervous System

□ Infectious: bacteria, fungus, protozoa and virus

infections: Meningitis, Lyme disease, Encephalitis,

Neurosyphilis, Rabies, Toxoplasmosis, etc.

neurodegenerative

mostly

□ Genetic: Alzheimer’s Disease, Huntington’s Disease,

Epilepsy, Parkinson Disease, Charcot-Marie-

Tooth Disease, etc.

nn cause functional deficit proceeds as CNS Kogeuruse

4!


Does the Nervous System regenerates?

central dogma of neurosciencegracing

him

Purves,!D.!Neuroscience.!5ed.! “Everything may die, nothing may bebrain'recapable

regionsin

regenerated.” neurogenesis

butregenerationof

“It is for the science of the future to

Ns
v limited

change, if possible, this harsh decree.”

us v

Santiago Ramón y Cajal complex

begin

brenningu

diffneuro

au injure
neurons

in
convey

diff
usgs's

Why is regeneration limited relatedto

in the adult CNS?! diffpath

it Wsu

plastic neurons we

grew connecttothe

wrong neurons
5!


Regeneration or compensation?

Functional recovery after lesion can be achieved through

compensation of nutintact
regeneration

reorganization circuits.

corticospinal

neurons

beenbodies
no
or v little rgua

in cortex afterCNSinjury

brain

W

send

corticospinal thwyn alternative

neuronsalso
connectedto spinal
pathway

amnemann
there

d cord

nnectionnormally
do
not

v strong motu
to Kandel,!ER.!Principles!of!Neural!Science.!5ed.!

neurons

alternativepathway
arms

connection gets stronger

in case of

injury 6!


Types of Neuronal Regeneration

nuance
Generation of new cells: NEUROGENESIS on of mu
cream ans

v limited

in

happensonly

populations areasof
neurogenesis
specific veg

ofstemcells offpar

I
hat

can

create

burn

Ms

particular

intissue
site

hire Lei et al., 2019. Front. Neurosci.
may

allfactors

needed

for □ Rare and limited to certain brain regions;

navalWhehpement

tr □ Tissue must retain a population of multipotent neural stem cells;

has
urn □ Stem cells must be in a distinct region appropriate for genesis and differentiation;

migrate

□ Regenerating tissue with capacity to recapitulate the migration, outgrowth, and
a V location

synapse formation processes.

location it
Nein

has

to make new
 Wwweur

Types of Neuronal Regeneration

Axon regrowth whencut regeneration

canola

usuallyin injuries

f equine

Axotomy: transection of axons

Proximal Distal divide neuron in 2

segment segment Istump

smannened xhave
contact

tocutbody ween
body

PNS

regent

□ Nerve injury:
Nerve cut possible

projecting axons from

sensory and motor

neurons are severed;

□ Robust regeneration.

Nerve crush

Types of Neuronal Regeneration

Axon regrowth

CNS

□ Brain or spinal cord injury;

□ Significant cell death; muchmm Ann

□ Very poor regeneration. to

annsinjury
beinjurydirely

to aabody

has
sincecns
Purves, D. Neuroscience. 5ed.

lotsof au immunohistochemistry

bodie ofspinalcord

Ime
Anderson MA et al., 2018. Nature.

v limited

regeneration

PNS vs CNS regeneration

PNS receives

resenting
fans

tegenerhing

doesn't

NS

cutpenerve CNSnerve

to somedegree Aregeryreute

less intrinsic ability of

implanted nns
nerve

implantedgraft
anynerve intoonsinium
CNS nomen to hgenerk
into Inhibitory environment

PNsiniury

I and deficient neuronal

intrinsic growth ability

9N nerveX contribute to decreased

hegenratein regeneration in the

CNS
CNS.

CNS environment less generation of

cops nerve PNS

in

have inhibitors
block
Kandel, ER. Principles of Neural Science. 5ed.
 foul red pan genefin in Ns

PNS here p
axonal regeneration

Responses to axotomy

Kandel, ER. Principles of Neural Science. 5ed.


Cell death N distancefwm cell body

Responses to axotomy

bu of

injury Neuronal Death

Spinalcordof her

Spinal motor neurons before proximal lesion

□ Lesion proximity to the cell body relates to the

extension of neuronal death;

□ CNS injury leads to greater neuronal death.

m mn
Spinal motor neurons after proximal lesion

imenior

3 s

weeks

after

ourhee injur
neutral

no z
death

much
musclepreaue

growthforever survival
neuronal less
inIinvennnim importantan

m.mn arm
IkoEFqmum interns

noox neuronal
werebody death Gfs retrograded throughaxontill they reachourbody

inside

spinal
cord annibute to survivalofcell


Responses to axotomy

Neuronal Death

at nicrosis as

directresult of injury

Apoptosis

□ Growth factor deprivation;

□ DNA damage;

extracellularcart
□ Hypoxia; theceil

goesinside
activatecatdependent create
proteases

□ Cellular stress (oxygen free

oxygenrevenue
species
causes

radicals, glutamatergic apoptosis

lotsofcursteared unncauses
cysteine-aspartic acid protease

excitotoxicity); cans course apoptosis

her arms
□ Inflammation. onramp in

inurement

gunmanexatany

keeps murang
conskeepshaving
Purves, D. Neuroscience. 5ed.

ut activity
bursts
toxicity

Responses to axotomy

Inflammation

Astrocytes microglia prefirelate

resident 4KNP becomereactive reactivegliosis Inflammatory

cells infiltration

causes BBDB to

A shape lesion

fen
Urns

break

infledrate

periphery arts f

crews produce

immune inflammation

s re

cytokines helps tissue

nut modelling

dual effect cleardebrisof

lesion
Crea

Reactive gliosisequine i otherto

harmfulthings

thetissue

Responses to axotomy Chronic

inflammation

Inflammation in the CNS

PNS
infiltration of
macrophages

macrophages

infletrate

b macrophages

x stimulates
eglin macrophages

stay
teared more
stay

muro
f

Macrophage /
chronic

Microglia

informant
marker

further

cen

death


Responses to axotomy Degnanon

of dinar

Wallerian degeneration breakdenof segment

membrane cytoskeleton

1mykinofdistal
process

stump active

Kandel, ER. Principles of Neural Science. 5ed.

electronmicroscopy
crosssection ofnerve

□ Process by which the distal infact atons neutny TYWYN

axon

portion of a damaged axon

segment degenerates;

□ Membrane, cytoskeleton and axon aterdeserving

as ofcuts in aapio.tn

myelin are degraded; waver

□ Actively regulated response.

Kandel, ER. Principles

of Neural Science. 5ed.

Responses to axotomy

Myelin clearance

Kandel, ER. Principles of Neural Science. 5ed.

bcmyelinhasto be cleared

□ Schwann cells: break the myelin, engulf it and secrete factors that recruit
wenn periphery

macrophages from blood stream; macro pwagocytuse dubrit

mm

if mykinnutremoved it'llinhibitaxon
regeneration

□ Resident microglia and blood-derived macrophages removal of myelin

debris; most
dieafteriniuvy

f oligodendrocytes
debrisfrom my
□ Slow and inefficient in the CNS: Schwann cells
Lein not cleared
are absent

(oligodendrocytes), mm only microglia (BBB). debris centime

to

punt
axon

gram


Responses to axotomy

Chromatolysis

tht
automniled

aw

Morgmroligial characteristics
both

of
ceu undergai Kandel, ER. Principles of Neural Science. 5ed.
Nissil I
our
Bf.kamafeemfhwaegqo7amfimen.ms the target.scenaoesbacktonormmeromm

□ Cell body swells; µpg

fromCentre
□ Nucleus moves hpruritus position;
to an eccentric

□ Rough endoplasmic reticulum becomes

fragmented - dissolution of Nissl bodies.

□ More common in the CNS;

□ Leads to neuronal death.

remnant

of.ir http://vanat.cvm.umn.edu/neurHistAtls/pages/neuron8.html

Yammerer

aka
posit
pedier
 W

Responses to axotomy

Transynaptic changes after axotomy

schwanncerts
pruss
detached funceu
Ng
nonecytes body
input

microglia

y
grow

d
prolongation
y

hysically

detach

ynupsing

in ceu it'd'velost

body if axonregenerates
connections
Kandel, ER. Principles of Neural Science. 5ed.
lots of

transmission metablon'm redirected to
neuronxsynaps axon

nopoint inmakingit fine make organs for
regeneration

□ Postsynaptic: disruption of major inputs to a cell may lead to target
poof

syruphunky atrophy (muscle).

nerve hat's the main innervation
eg cut

muscle receive inputgmusle atrophy

muscle
innervate □ Presynaptic: synaptic stripping

other nerves

if
PNS Schwann cells
X atrophy CNS astrocytes and microglia
muscle

Depresses synaptic activity and can impair functional recovery.

Responses to axotomy

Transynaptic changes after axotomy

immunohistochemistry of spinal cord

neuron

of neuron

perp
I am
ro

of ii

is f

www.t www.rffinednelrwn

µdY

Synapse marker

Regeneration

marker

had atm

cute


Responses to axotomy

Transynaptic changes after axotomy

all
cutting a cell in MNS will affect brain bc they're

connected

Towardscellbody Towards the end

Retrograde Enterograde Anterograde

Degeneration Degeneration

Rapid degeneration

maytakeuptoyearsCuslow
degeneration


Schwann cell

Aton Biingner
Responses to axotomy cen has to hem

moneexpenion fibronectin

fpowinprapikhingqeguyrd.MY Wilmer Axon regeneration q.bmiinh.IT warm

wobwimi laminin CD
4 inappropriate

autinfNtAMjUg cnn.renhlupp.az
N Cadherin
GANGEowe
Regenerating neurons:

gGrant

BDNF

□ Increased expression ofresponsiveto

a class of GFs.
Ears beare(Trk
neurotrophin receptors
more
and our

i42
p75);
i upregulation of certain genes which
increase plushub 2modify traffic of
someproteins
□ Modification of gene expression
and protein trafficking in the cell
body to promote axon-growth (actin,are9
one
1
tubulin, GAP-43, etc); components
sunroof
cnn.mn
upregulate Aplasma tf i e
refer
ater
□ Cell intrinsic growth programsLaws
are deficient ininner
various CNS
populations.
but in PNS ceil turnon
4 2
 Responses to axotomy

Axon regeneration

Intrinsic Growth Program

Promotes Regeneration:
benot
enough stimuliler
□ Conditioning lesions: cur to switchon
prior injury activates axonal up
growth program. peripheralinjury
days later
sentry
neuron
madecennellerr
d
to dublicated regenerate
sensorycell has incur
axon cam brunch
pleapteral axon ofaxon no
brunch een upregulates
gem andprotein
nessacing fr
negation
car
prepared

days
Kandel, ER. Principles of Neural Science. 5ed. later he ngenule
 Responses to axotomy

Axon regeneration
2 Arrange
I icthemselvesincolumn
Schwann cells:

□ Bands of Büngner;

□ Secretion of laminin, fibronectin

mm
and collagens growth mm
permissive
mm molecules;
submulesfor
axongrowth toguideaxon
Zhiguo C. et al., 2012. Stem cells.
□ Increased cell surface adhesion
molecules expression (N-CAM, LI,
N-cadherin); soaxonscanadhere Mere atom
cells
µ Schwann
makeh
whenguided grownornewhep
□ Increased secretion of
neurotrophins, along with
macrophages (NGF, BDNF, IGF,
mmmm
CNTF, GDNF) to promote neuronal
mmmm
survival, axon regeneration and
guidance.
 Responses to axotomy

Axon regeneration
Schwann cells:

□ Bands of Büngner;
CNS glia – oligodendrocytes,
□ Secretion of laminin, fibronectin astrocytes and microglia:
and collagens growth permissive
molecules; □ Growth factors not expressed
in temporal or spatial
□ Increased cell surface adhesion gradients supportive of
molecules expression (N-CAM, LI, regeneration;
N-cadherin);
□ Express and/or secrete growth
□ Increased secretion of inhibitory molecules.
neurotrophins, along with
macrophages (NGF, BDNF, IGF,
CNTF, GDNF) to promote neuronal
survival, axon regeneration and
guidance.
 Responses to axotomy

Axon regeneration inhibitors

Glial scar

CNS Glial cells (especially astrocytes) create a cavity to seal

off the injury epicentre and secrete chemorepellent
mmmm matrix
(semaphorin 3A, ephrins, Slit) and growth-inhibiting
mmmm
components (tenascin and chondroitin sulfate proteoglycan).
ni II iiiion

glialscar
tosealoff
lesion
region of glutamate
radicals
02 healthy
Xaffeettissue
ie to
d thermal

Bartus, K. et al., 2014. The Journal of Neuroscience. but is a physical Neurons Astrocytes
as
barrier secrete new
nmiifm
asmmtesinhiyitffeyqgemorepgrYI.fm

which argot
inhibit
 Responses to axotomy

Axon regeneration inhibitors

Glial scar

CNS Glial cells (especially astrocytes) create a cavity to seal

off the injury epicentre and secrete chemorepellent
(semaphorin 3A, ephrins, Slit) and growth-inhibiting matrix
components (tenascin and chondroitin sulfate proteoglycan).

highlyinhibit

Axons Glial Scar

glial scar axons stop here

 Responses to axotomy

Axon regeneration inhibitors

CNS myelin
v inhibitory
Incomplete myelin clearance in the
ur
CNS:
□ Oligodendrocytes have little or no
ability to dispose myelin (vs
Schwann cells); myelindebn
remains
w
□ BBB prevents the entry of slager
inhibit
macrophages microglia;axon toargue
www mn
Y w
□ Chronic inflammation - our
om
inflammation is not resolved and
BBB
Kandel, ER. Principles of Neural Science. 5ed. cytokines are produced.
t care
u
chew
infront
 Responses to axotomy

Axon regeneration inhibitors

inhibitory
inhibited in ur

havein the
r
receptors
axontrying
to
regenerate
a
activate a
inhibits
pathwaythat Kandel, ER. Principles of Neural Science. 5ed.
axongrowth
 Responses to axotomy

Axon regeneration - guidance

□ Distal stump have endoneurium, Schwann cells basal
lamina and neurillema f ming a egene a i n be
ummm
guiding regenerating axons after PNS lesion. Tecate
connective tissue gumneling distal stump x defeated

Saladin, Kenneth. Anatomy and Physiology: The unity

of form and function. McGraw Hill Publisher
 Responses to axotomy

Axon regeneration - guidance

Nerve cut
axon needs to be sutured together

Purves, D. Neuroscience. 5ed.

Nerve crush
intact connective tissue axon has pathey

to Cullen find target a case reshot

 Responses to axotomy

Axon regeneration - guidance

big gapto create

suture a tube pathway
PNS regeneration
strategies
suture
 Responses to axotomy

Axon regeneration - guidance

nerve graft

i
r r

off
t
t
rural
nerveondamagedarea

thenexercise

PNS regeneration
strategies
Purves, D. Neuroscience. 5ed.
 Responses to axotomy

Axon regeneration - remyelination

Cmsseason
TNG

Idegemutive
Yagasaki, Y et al., 2013. PLOS ONE.
e atens
negenated
a
ater shower
axons n
bei
t my
Schwann cells have excellent remyelination (repair) capacity.
Oligodendrocytes in the CNS die after injury and are not
sunt
mower
s
good regenerators.
not
perfect
References:

Principles of Neural Science. Eric R. Kandel,; James H. Schwartz; Thomas M. Jessell; Steven A. Siegelbaum
and A. J. Hudspeth. Fifth Edition. 2013. McGraw Hill Professional. Chapter 57: Repairing the Damaged Brain.
Neuroscience. Dale Purves, George Augustine, David Fitzpatrick, William Hall, Anthony-Samuel Lamantia,
Leonard White. 5th Edition. 2012. Sinauer Associates, Inc.: Sunderland, MA. Chapter 25: Repair and Regeneration
in the Nervous System.
Giger RJ, Hollis ER 2nd, Tuszynski MH. Guidance molecules in axon regeneration. Cold Spring Harb
Perspect Biol. 2010. (http://www.ncbi.nlm.nih.gov/pubmed/20519341)

Additional References:

Huebner EA, Strittmatter SM. Axon regeneration in the peripheral and central nervous systems. Results Probl
Cell Differ.2009;48:339-51. (http://www.ncbi.nlm.nih.gov/pubmed/19582408)
Gaudet AD, Popovich PG, Ramer MS. Wallerian degeneration: gaining perspective on inflammatory events
after peripheral nerve injury. J Neuroinflammation. 2011. 30;8:110. (http://www.ncbi.nlm.nih.gov/pubmed/21878126)
Vargas ME, Barres BA. Why is Wallerian degeneration in the CNS so slow? AnnuRev Neurosci. 2007;30:153-
79. (http://www.ncbi.nlm.nih.gov/pubmed/17506644)
McIlwain DL, Hoke VB. The role of the cytoskeleton in cell body enlargement, increased nuclear eccentricity
and chromatolysis in axotomized spinal motorneurons. BMC Neurosci. 2005 Mar 17;6:19.
(http://www.ncbi.nlm.nih.gov/pubmed/15774011)
Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J. Functional regeneration beyond the glial scar.
Exp Neurol. 2014 Mar;253:197-207. (http://www.ncbi.nlm.nih.gov/pubmed/24424280)
Ramer LM, Ramer MS, Bradbury EJ. Restoring function after spinal cord injury: towards clinical translation of
experimental strategies. Lancet Neurol. 2014Dec;13(12):1241-56. (http://www.ncbi.nlm.nih.gov/pubmed/25453463)
Perry VH, Brown MC, Gordon S. The macrophage response to central and peripheral nerve injury. A possible
role for macrophages in regeneration. J ExpMed. 1987 Apr 1;165(4):1218-23.
(http://www.ncbi.nlm.nih.gov/pubmed/3559478).