Download CNS Neurotransmitter Pathways

CNS Neurotransmitter
Pathways
Dr. G. R. Leichnetz
CNS Neurotransmitters
Classical (Simple) Neurotransmitters
Ionotropic- excitatory, inhibitoryact through ion channels
Metabotropic- neuromodulatoryact through G proteins,
second messengers
Neuropeptides
Simple neurotransmitters are synthesized in the axon
terminal, whereas neuropeptides are synthesized in the
cell body. They are co-released. Recovery takes longer
for neuropeptides to be replaced in the terminal. Raw
materials reach the terminal via anterograde axonal
transport along microtubules, and byproducts of
synthesis travel back to the cell body via retrograde
transport.
Principal CNS Neurotransmitters
Glutamate- excitatory- approx. 40%
GABA
- inhibitory- approx 40 %
(hard-wired, information-processing systems)
Acetylcholine
Norepinephrine
Dopamine
Serotonin
(affect background activity of the brain, EEG)
GLUTAMATERGIC SYSTEMS
Pyramidal cells of the cerebral
cortex are glutamatergic.
They give rise to associational,
commissural, and projectional
(corticofugal) fibers.
III
All cortical efferents
(corticofugals):
corticospinals,
corticobulbars
corticostriates
corticopontines
corticothalamics
are glutamatergic
(excitatory).
V
Corticofugal Projections
Associational
Commissural
Corticostriate
Corticopontine
Cortico
-spinal
Corticobulbar
Corticothalamic
Associational fibers (intrahemispheric)- cortico-cortical
fibers interconnect cortical regions within the same
hemisphere; originate from layer III pyramidal cells and
are glutamatergic.
Commissural fibers (interhemispheric)- cortico-cortical
fibers interconnect cortical regions in opposite
hemispheres; originate from layer III pyramidal cells and
are glutamatergic.
Corticofugal projections (cortical efferents) that descend
through the internal capsule originate from lamina V
pyramidal cells and are glutamatergic.
Thalamocortical projections are also glutamatergic, so
that the thalamic inputs to cortex (the principal source
of direct afferents) are excitatory.
All thalamic nuclei
are glutamatergic,
except the thalamic
reticular nucleus
CM/Pf
Intralaminar
complex,
thalamus
Corticostriate
projections and
thalamostriate
projections (to
caudate and
putamen) are
glutamatergic.
Glutamatergic Systems
Associational and Commissural Fibers
(origin: layer III pyramidal cells)
Corticofugal Fiber Systems:
(origin: layer V pyramidal cells)
corticospinals, corticobulbars,
corticopontines, corticostriates, etc.
(origin: layer V pyramidal cells)
Thalamocorticals
Thalamostriates
GABA-ERGIC SYSTEMS
Glutamate is metabolized to GABA by glutamic acid
decarboxylase. Antibodies to GAD can be used to
label GABA-ergic systems.
Glutamate
GABA
The substantia nigra has two parts: pars compacta
(dopaminergic) and pars reticulata (GABA-ergic)
pars
reticulata
GABA
pars
compacta
(DA)
Nigral Efferents from
the SNr are GABAergic
Nigrothalamics (to the
motor thalamus, VA/VL,
and intralaminar nuclei,
CM/Pf)
Nigrotectals (to SC)
SNr
All striatal
efferents are
GABA-ergic.
Striatopallidals
to globus
pallidus (GPe &
GPi)
Striatonigrals to
substantia nigra
(SNc & SNr)
Pallidothalamic projections in the fasciculus
lenticularis and ansa lenticularis are GABA-ergic.
VA
CM/Pf
Pallidothalamics
follow two different
routes to the motor
thalamus (VA)
Thalamic fasciculus
All pallidal
efferents are
GABA-ergic
Fasciculus lenticularis
STN
Ansa lenticularis
Pallidal Efferents
Purkinje cells in the
cerebellar cortex are
GABA-ergic.
Purkinje
cell
They project their axons to
the deep cerebellar nuclei to
exert a powerful inhibitory
influence on the excitatory
output of the cerebellum
that originates from the deep
nuclei..
Send their axons
to deep cerebellar
nuclei
Deep
cerebellar
nuclei
Emboliform
Fastigial
Globose
Dentate
Deep cerebellar
nuclei
Granule (stellate) neurons of the
cerebral cortex are predominantly
GABA-ergic.
These cells have short axons which
do not leave their local area of
cortex and are involved in intrinsic
columnar circuitry.
GABA-ergic Systems
Nigrotectals, nigrothalamics- from pars
reticulata, substantia nigra
Striatopallidals, striatonigrals- from
striatum (caudate & putamen)
Pallidothalamics- from globus pallidus
Purkinje cells, cerebellar cortex
Granule (stellate) cells, cerebral cortex
CHOLINERGIC SYSTEMS
All cranial nerve motor nuclei
(GSE, SVE, GVE) (red) are
cholinergic.
The oculomotor, trochlear,
abducens, and hypoglossal nuclei
(GSE), trigeminal & facial
nuclei, and nucleus ambiguus
(SVE), Edinger-Westphal,
sup. & inf. salivatory nuclei, and
dorsal motor nucleus of the
vagus (GVE) are cholinergic.
Caudate
Putamen
Cholinergic (ACh)
aspiny neurons in
the striatum
The striatum (caudate
and putamen) contains
a population of small
cholinergic (aspiny)
neurons which are
involved in intrinsic
striatal circuitry
(ie. do not give rise to
striatal efferents).
Huntington’s Chorea
hereditary disease produces
atrophy of the striatum
(caudate & putamen) with
loss of both cholinergic and
GABA-ergic neurons.
In Huntington’s disease, post-mortem
studies show atrophy of the striatum
with enlargement of lateral ventricles.
The septum/basal forebrain region contains numerous
cholinergic cell groups (Ch1-Ch4), the largest of which
is the nucleus basalis of Meynert (Ch4).
SEPTUM
Septum
BASAL FOREBRAIN
NBM Ch4
Ch1-Ch3
The nucleus basalis of Meynert (Ch4) is the principal
source of the cholinergic innervation of the cerebral
cortex.
Ch4
In Alzheimer’s disease, the
nucleus basalis (Ch4)
shows about a 75% loss of
neurons, leading to a
profound depletion of
acetylcholine in the cortex
which is thought to be at
least partially responsible
for the cognitive and
memory loss in the
disease.
In Alzheimer’s disease, postmortem studies show atrophy
of associational areas of the
cortex, neuritic plaques, and
neurofibrillary tangles within
cortical neurons.
Post-mortem studies
show a profound loss
of cholinergic
neurons in the
nucleus basalis of
Meynert Ch4).
Normal
Alzheimer’s
In the normal brain, the
nucleus basalis of Meynert
contains abundant large
Nissl-rich cholinergic
neurons that actively
synthesize acetylcholine.
The pedunculopontine nucleus (Ch5) is the principal
source of the cholinergic innervation of subcortical
structures. It provides the cholinergic trigger for onset of REM sleep.
Ch5
Cholinergic Systems
Brainstem motor nuclei- GSE, SVE, GVE
Striatum- intrinsic conn.’s, aspiny neurons
Basal Forebrain- Ch1-Ch4- proj.’s to cortex
Nucleus basalis of Meynert (Ch4)
Dorsolateral pontine tegmentum- proj’s to
subcortical structures
Ch5- pedunculopontine nucleus
NORADRENERGIC SYSTEMS
The catecholamine metabolic pathway for the synthesis
of dopamine and norepinephrine begins with the amino
acid tyrosine.
Dopamine
Norepinephrine
The locus ceruleus (A6), located in the periaqueductal
gray of the rostral pons, is the principal source of
norepinephrine in the brain.
The locus ceruleus (A6)
contains large numbers of
neurons whose cytoplasm is
filled with neuromelanin, a
byproduct of catecholamine
(NE) synthesis.
LC
Locus ceruleus (A6)
neurons has long
ascending and
descending branches
which supply NE to
all levels of the
neuraxis. These
projections become
activated in arousal,
anxiety (CNS aspects
of “fight or flight”).
The ascending fibers
constitute the dorsal
NE bundle, which
traverse the MFB to
reach higher levels of
the CNS.
The other NE-producing cell groups (eg. A5, A7) in the
lateral pontine and medullary reticular formation give rise
to ascending projections to the hypothalamus (Ventral NE
bundle) and (A1-A3) descending projections to the spinal
cord.
HYPOTHALAMUS
A5
A7
A1-A3
NE projections from A5, A7 to hypothalamus,
and nuclei in brainstem and spinal cord (A1A3) associated with control of visceromotor
activities.
Noradrenergic Systems
Dorsal Noradrenergic Bundle- from locus
ceruleus (A6) to entire CNS, except
hypothalamus
Ventral Noradrenergic Bundle- from A5, A7
in lateral pontine and medullary
reticular formation to hypothalamus
A1-A3 gives rise to NE descending projections
to the spinal cord (visceromotor, autonomic
nuclei)
DOPAMINERGIC SYSTEMS
Substantia Nigra
The pars compacta of the substantia
nigra contains dopaminergic neurons
whose cytoplasm is filled with
abundant neuromelanin, a byproduct
of catecholamine (DA) synthesis.
Most CNS dopaminergic neurons are located in the
ventral midbrain in the substantia nigra pars compacta
(A8, A9) and ventral tegmental area (A10).
Red
nucleus
A10
A8, A9
The nigrostriatal projection
from the pars compacta of the
SN to the caudate and
putamen is dopaminergic.
Loss of dopaminergic neurons
in the SNpc is associated with
Parkinson’s disease.
L-dopa therapy is recommended to
replace depleted DA (crosses blood
brain barrier)
Post-mortem
section of the
midbrain
from a patient
with
Parkinson’s
disease shows
loss of
neuromelanin
in the SN
The ventral tegmental area (A10) contains the cells of
origin of the dopaminergic mesolimbic & mesocortical
tracts (“reward system”).
A10
The mesolimbic and mesocortical tracts, which
originate from the VTA (A10) traverse the medial
forebrain bundle in the lateral hypothalamus to reach
the nucleus accumbens and prefrontal cortex.
PFC
NA
VTA
SNc
Mesocortical
to prefrontal
cortex
Mesolimbic
“Reward System” to
Nuc. Accumbens
The nucleus accumbens of the basal forebrain is the
principal target of the mesolimbic tract (“reward system”)
and has been called the “center for addiction.” It contains
receptors for a large number of chemical substances of
abuse.
NA
Dopamine Hypothesis (“teeter-totter”)
Dopamine effects on movement.
Elevated acetylcholine
Depleted dopamine
Depleted acetylcholine
Elevated dopamine
Dopamine Hypothesis
Dopamine effects on mood
Elevated Dopamine
Depleted dopamine
Dopaminergic Systems
Nigrostriatals- from pars compacta (A8, A9),
substantia nigra to caudate & putamen
(Parkinson’s disease)
Mesolimbic (“Reward System”)- from ventral
tegmental area (A10) to basal forebrain
(nuc. accumbens)
Mesocortical- from ventral tegmental area
(A10) to prefrontal cortex
SEROTONERGIC SYSTEMS
The biosynthetic pathway for the synthesis of the
indoleamine serotonin begins with the amino acid
tryptophan.
Serotonin
The serotonin-producing cell
groups are located in the
median reticular formation
(raphe) of the brainstem.
The midbrain raphe contains the
dorsal raphe nucleus (B7) and
superior central nucleus (B8).
The medullary raphe contains
the nucleus raphe pallidus,
obscurus, and magnus (B1-B3).
Dorsal raphe
nucleus
B7
B7
IV
MLF
B8
B8
This cross section of the monkey
brain at the level of the caudal
midbrain/ rostral pons, stained
using antibodies to serotonin,
shows that serotonin-producing
cell groups are clustered around
the raphe.
Superior
central
nucleus
Ascending
serotonergic
(5-HT) projections
project to all
structures at higher
levels of the CNS
and are involved in
synchronized sleep.
Descending 5-HT
projections to the
spinal cord are
involved in
analgesia (B3) and
effects on motor
tone (B1, B2).
B3
The nucleus raphe magnus
(B3) of the medullary
raphe, whose neurons are
activated by morphine,
projects via the
raphespinal tract to the
layers of the spinal cord
dorsal horn (laminae I and
V) that receive nociceptive
(painful) stimuli).
Illustrates the role of
descending serotonergic
projections in analgesia.
Serotonergic Systems
Ascending Projections- from midbrain raphe
(B7, dorsal raphe nucleus; B8, superior
central nucleus) to higher CNS levels
Descending Projections- from medullary
raphe to spinal cord
B3 Nucleus Raphe Magnus to dorsal horn,
modulation of pain
B1, B2 Nucleus Raphe Obscurus, Pallidus
to intermediate and ventral horns,
influence autonomics and movement