1. CNS Neurotransmitter Pathways
Dr. G. R. Leichnetz

2. CNS Neurotransmitters
Classical (Simple) Neurotransmitters
Ionotropic- excitatory, inhibitory act through ion channels
Metabotropic- neuromodulatory act through G proteins, second messengers
Neuropeptides

3. 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.

4. 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)

5. GLUTAMATERGIC SYSTEMS

6. 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
Cortico-striate
Cortico-pontine
Cortico-spinal
Associational
Cortico-bulbar
Cortico-thalamic
Commissural

7. Associational fibers (intrahemispheric)- cortico-cortical fibers interconnect cortical regions within the same hemisphere; originate from layer III pyramidal cells and are glutamatergic.

8. Commissural fibers (interhemispheric)- cortico-cortical fibers interconnect cortical regions in opposite hemispheres; originate from layer III pyramidal cells and are glutamatergic.

9. Corticofugal projections (cortical efferents) that descend through the internal capsule originate from lamina V pyramidal cells and are glutamatergic.

10. 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

11. Corticostriate projections and thalamostriate projections (to caudate and putamen) are glutamatergic.
CM/Pf
Intralaminar complex, thalamus

12. 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

13. GABA-ERGIC SYSTEMS

14. Glutamate is metabolized to GABA by glutamic acid decarboxylase
Glutamate is metabolized to GABA by glutamic acid decarboxylase. Antibodies to GAD can be used to label GABA-ergic systems.
Glutamate
GABA

15. The substantia nigra has two parts: pars compacta (dopaminergic) and pars reticulata (GABA-ergic)
pars compacta (DA)

16. Nigral Efferents from the SNr are GABA-ergic
Nigrothalamics (to the motor thalamus, VA/VL, and intralaminar nuclei, CM/Pf)
Nigrotectals (to SC)
SNr

17. All striatal efferents are GABA-ergic.
Striatopallidals to globus pallidus (GPe & GPi)
Striatonigrals to substantia nigra (SNc & SNr)

18. Pallidothalamic projections in the fasciculus lenticularis and ansa lenticularis are GABA-ergic.
Pallidothalamics follow two different routes to the motor thalamus (VA) VA
CM/Pf
Thalamic fasciculus
All pallidal efferents are GABA-ergic
Fasciculus lenticularis
STN
Ansa lenticularis
Pallidal Efferents

19. Purkinje cells in the cerebellar cortex are GABA-ergic.
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..
Purkinje cell
Send their axons to deep cerebellar nuclei
Emboliform
Fastigial
Globose
Dentate
Deep cerebellar nuclei
Deep cerebellar nuclei

20. 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.

21. 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

22. CHOLINERGIC SYSTEMS

23. 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.

24. 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).
Caudate
Putamen
Cholinergic (ACh) aspiny neurons in the striatum

25. 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.

26. 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
Ch1-Ch3
NBM Ch4

27. The nucleus basalis of Meynert (Ch4) is the principal source of the cholinergic innervation of the cerebral cortex.
Ch4

28. 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, post-mortem studies show atrophy of associational areas of the cortex, neuritic plaques, and neurofibrillary tangles within cortical neurons.

29. Post-mortem studies show a profound loss of cholinergic neurons in the nucleus basalis of Meynert Ch4).
In the normal brain, the nucleus basalis of Meynert contains abundant large Nissl-rich cholinergic neurons that actively synthesize acetylcholine.
Normal
Alzheimer’s

30. 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

31. 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

32. NORADRENERGIC SYSTEMS

33. The catecholamine metabolic pathway for the synthesis of dopamine and norepinephrine begins with the amino acid tyrosine.
Dopamine
Norepinephrine

34. 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.

35. 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. LC

36. The other NE-producing cell groups (eg
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 (A1-A3) associated with control of visceromotor activities.

37. 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)

38. DOPAMINERGIC SYSTEMS

39. 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.

40. 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

41. 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

42. The ventral tegmental area (A10) contains the cells of origin of the dopaminergic mesolimbic & mesocortical tracts (“reward system”).
A10

43. 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

44. 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

45. Dopamine Hypothesis (“teeter-totter”)
Dopamine effects on movement.
Elevated acetylcholine Depleted dopamine
Depleted acetylcholine Elevated dopamine

46. Dopamine Hypothesis Dopamine effects on mood Elevated Dopamine
Depleted dopamine

47. 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

48. SEROTONERGIC SYSTEMS

49. The biosynthetic pathway for the synthesis of the indoleamine serotonin begins with the amino acid tryptophan.
Serotonin

50. 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).

51. Dorsal raphe nucleus B7 B7 IV
MLF B8 B8
Superior central nucleus
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.

52. 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).

53. 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. B3

54. 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