Hallett: Basal Ganglia Summer 2020
The Basal Ganglia (Chapter 3) Aspen 2020
1
THE BASAL GANGLIA ARE COMPLICATED!
2
1 Hallett: Basal Ganglia Summer 2020
Horizontal section of the brain at two levels
Lateral view of the basal ganglia
3
Roberts M & Hannaway J. Atlas of the Human Brain in Section, Lea & Febiger, Philadelphia, 1970
4
2 Hallett: Basal Ganglia Summer 2020
Basal ganglia pathways
Cortex
Striatum Striatum D2 D1 Thalamus
Hyperdirect Indirect Substantia Nigra Pars Direct Compacta
STN GPe
Direct pathway: Facilitation GPi Indirect pathway: Inhibition
5
8
3 Hallett: Basal Ganglia Summer 2020
More connections in the BG: bridging collaterals
Cazorla et al. Movement Disorders 2015; 30:895
9
11
4 Hallett: Basal Ganglia Summer 2020
Basal ganglia pathways
Cortex
Striatum Striatum D2 D1 Thalamus
Hyperdirect Indirect Substantia Nigra Pars Direct Compacta
STN GPe
Direct pathway: Facilitation GPi Indirect pathway: Inhibition
12
Basal ganglia pathways With more newly identified connections
Cortex
Striatum Striatum D2 D1 Thalamus
Hyperdirect Indirect Substantia Nigra Pars Direct Compacta
STN GPe
Direct pathway: Facilitation GPi Indirect pathway: Inhibition
13
5 Hallett: Basal Ganglia Summer 2020
Groenewegen 2003
14
BG Connect to the Front of the Brain
Hanakawa, Goldfine, Hallett 2017 eNeuro
15
6 Hallett: Basal Ganglia Summer 2020
Dynorphin
Kopell et al 2006
16
Neurotransmitters • Dopamine • Acetylcholine • Glutamate • GABA • Norepinephrine • Serotonin • Adenosine • Endogenous opioids • Neuropeptides • Endocannabinoids
17
7 Hallett: Basal Ganglia Summer 2020
Dopamine Pathways
Substantia nigra, pc
Ventral tegmental area
Hypothalamus (to pituitary gland)
Canadian Institutes of Health Research
18
Comes into cell via tyrosine transporter
GTP Cyclohydrolase I (TOH)
Dopamine Metabolic
Pathway (DDC) (AADC)
Put into vesicles by VMAT2
Modified from http://en.wikipedia.org/wiki/Dopamine
19
8 Hallett: Basal Ganglia Summer 2020
AADC
Stahl’s Essential Psychopharmacology 2008
20
MAO-B in glia and non-dopaminergic cells
Only MAO-A in COMT minimal in dopamine neurons basal ganglia
Stahl’s Essential Psychopharmacology 2008
21
9 Hallett: Basal Ganglia Summer 2020
whyfiles.org
Increase in cAMP tends to be excitatory; Decrease tends to be inhibitory. Hence, D1 activation is generally excitatory, D2 generally inhibitory.
22
www.researchgate.net
23
10 Hallett: Basal Ganglia Summer 2020
Basal ganglia pathways
Cortex
Striatum Striatum D2 D1 Thalamus
Hyperdirect Indirect Substantia Nigra Pars Direct Compacta
STN GPe
Direct pathway: Facilitation GPi Indirect pathway: Inhibition
24
Acetylcholine (ACh)
• Two neuron types – The “giant aspiny interneuron” of the striatum – A projection neuron arising in the PPN • ACh receptors: – Nicotinic: ionotropic – Muscarinic: metabotropic, G‐protein coupled
25
11 Hallett: Basal Ganglia Summer 2020
26
Acetylcholine Projection Systems
Cooper, Bloom, Roth 2003
28
12 Hallett: Basal Ganglia Summer 2020
Glutamate
• Primary excitatory neurotransmitter • Receptors – Metabotropic (3 classes) • Group I, II, III, depending on mGluR composition – Ionotropic (3 classes) • NMDA • Kainate • AMPA
29
www.researchgate.net
31
13 Hallett: Basal Ganglia Summer 2020
GABA
• Primary inhibitory transmitter • Receptors – GABA‐A (& GABA‐C): ionotropic • Open chloride (and potassium) channels • Benzodiazepine sensitive or not – GABA‐B: metabotropic • Open potassium and inhibit calcium channels • G protein coupled
32
D5
D2 D2
AMPA NMDA
D2
34
14 Hallett: Basal Ganglia Summer 2020
Norepinephrine Serotonin
35
Sasaki M et al. NeuroReport 19: 1649, 2008
36
15 Hallett: Basal Ganglia Summer 2020
Noradrenergic pathways
Stahl’s Essential Psychopharmacology 2008
37
Serotonergic pathways
Stahl’s Essential Psychopharmacology 2008
38
16 Hallett: Basal Ganglia Summer 2020
Cooper, Bloom, Roth 2003
40
Serotonin Metabolic Pathway
After release taken back in presynaptic neuron by the serotonin transporter (site of action of the selective serotonin reuptake inhibitors – SSRIs)
Modified from http://en.wikipedia.org/wiki/Serotonin
41
17 Hallett: Basal Ganglia Summer 2020
(Site of action of SSRIs)
Bortolato et al. 2008
42
From http://en.wikipedia.org/wiki/Serotonin
43
18 Hallett: Basal Ganglia Summer 2020
Adenosine
• Critical molecule in energy metabolism • Plays a role as a neurotransmitter • A2A receptors in basal ganglia, often coupled with the D2 receptor postsynaptically – Adenosine will reduce dopamine binding – Adenosine antagonists (like caffeine) will increase dopamine binding
44
Endogenous Opioids
• Dynorphins, enkephalins, endorphins, endomorphins and nociceptin • Opioid receptors (G‐protein coupled) – delta (δ) – kappa (κ) – mu (μ) – nociceptin receptor
45
19 Hallett: Basal Ganglia Summer 2020
Opioids Facilitate Dopamine Release
GABA Dopamine GABA neuron Dopamine neuron neuron neuron
47
Neuropeptides (other)
• Small proteins typically co‐released with other neurotransmitters • Examples – Opioids (as just discussed) – Substance P (as discussed shortly) – About 100 of them all together
48
20 Hallett: Basal Ganglia Summer 2020
Mestikawy et al. 2011 Nat Rev Neurosci 12:204
49
Dale’s Principle
Sir Henry Hallett Dale won the Nobel Prize in 1936
50
21 Hallett: Basal Ganglia Summer 2020
Endocannabinoids
• Principal receptor in the basal ganglia is the CB1
receptor, but also the TRVP1 receptor • Natural ligands are anandamide and 2‐ arachidonoylglycerol • Cannabinoids modulate dopaminergic effects, and generally seem to diminish dopamine release and slow down behavior
51
52
22 Hallett: Basal Ganglia Summer 2020
www.thehumanbrainproject.org
Cannabis (Marijuana) = THC + CBD + many others chemicals
THC = tetrahydrocannabinol
CBD = cannabidiol
53
54
23 Hallett: Basal Ganglia Summer 2020
New Yorker Today; July 21, 2018
56
Email on 7/21/2018
57
24 Hallett: Basal Ganglia Summer 2020
58
61
25 Hallett: Basal Ganglia Summer 2020
May 24, 2020
62
Washington Post, August 4, 2019
63
26 Hallett: Basal Ganglia Summer 2020
Striatum • Caudate, putamen, ventral striatum • Cells – 80‐95% medium spiny neurons (projection) • GABAeric • Those with D1 receptors also have the protein neurotransmitters substance P and dynorphin • Those with D2 receptors also have the protein neurotransmitter enkephalin – 5‐20% aspiny interneurons, 4 classes • Giant aspiny cholinergic cell = TANs • 3 classes of GABAergic interneurons – Patches (striosomes), AChE‐poor, are embedded in a matrix that is AChE‐rich
64
65
27 Hallett: Basal Ganglia Summer 2020
Groenewegen 2003
66
From BrainMaps.org, copyright UC Regents Davis campus
67
28 Hallett: Basal Ganglia Summer 2020
Dorsolateral
Ventromedial
Modified from
68
Imbalances of striosome and matrix compartments in various disorders
Favors striosome Favors matrix
69
29 Hallett: Basal Ganglia Summer 2020
Globus pallidus
• GPi and GPe; dorsal and ventral • SNr similar to the GPi • Most neurons are large, parvalbumin positive, GABAergic neurons with large dendritic arbors • Only few interneurons
70
Subthalamic nucleus
• Most neurons are glutamatergic with long dendrites • 7.5% neurons are GABAergic interneurons
71
30 Hallett: Basal Ganglia Summer 2020
Substantia nigra (compacta)
• Dopaminergic neurons! • Somatotopically organized • Variety of inputs from nuclear groups in the region including feedback loops from the other basal ganglia structures
72
Dopaminergic innervation of the basal ganglia
From Obeso 73
31 Hallett: Basal Ganglia Summer 2020
What is dopamine doing in the BG?
• Facilitates movement (tonic activity) • Signals reward (phasic activity) – Relevant for motor learning – Relevant for motivating behavior – Pathological relevance here for drug addiction and dopamine dysregulation syndrome
74
Graybiel 2008
76
32 Hallett: Basal Ganglia Summer 2020
Pedunculopontine Nucleus (PPN)
• Compacta (PPNc) – Cholinergic • Dissipatus (PPNd) – Glutamatergic with some cholinergic • Other nuclei in the vicinity – Midbrain extrapyramidal area (MEA) – Peripeduncular nucleus – Cuneiform nucleus – Sub‐cuneiform nucleus – Laterodorsal tegmental nucleus
77
78
33 Hallett: Basal Ganglia Summer 2020
79
The zona incerta (ZI) provides a GABAergic link between the basal ganglia output nuclei, the cerebello-thalamocortical loop and the brainstem nuclei.
MRF, medial reticular formation; PFC, prefrontal cortex; VA/VL, thalamic nuclei
Plaha, P et al. J Neurol Neurosurg Psychiatry 2008;79:504-513
Copyright ©2008 BMJ Publishing Group Ltd. 80
34 Hallett: Basal Ganglia Summer 2020
The lateral habenula
83
84
35 Hallett: Basal Ganglia Summer 2020
Kopell et al 2006
85
Rodriguez-Oroz et al., Lancet Neurology 2009;8:1128
86
36 Hallett: Basal Ganglia Summer 2020
Rodriguez-Oroz et al., Lancet Neurology 2009;8:1128
87
Cellular activity
• MSNs have a low firing rate, 0.5 to 2 Hz • GPi neurons have high rate, 60‐90 Hz • General idea is that movement is produced by input to MSNs causing an increase in firing via the direct pathway, leading to inhibition in the GPi (which will release the thalamus from tonic inhibition) ‐‐ but this will be balanced by “excitation” to the GPi from GPe and STN
88
37 Hallett: Basal Ganglia Summer 2020
Language • Information is passed in the CNS, to a certain extent, in oscillatory activity • A resting rhythm between BG and cortex is in the beta frequency and this goes away with movement • During movement, there is an increase in gamma frequency activity • In PD, there is excessive beta that correlates with bradykinesia – This beta may be mostly in the indirect pathway neurons (Sharott et al. 2017 J Neurosci)
89
What do the BG do? • Motor “energy”/Scaling of movement • Agility – facilitate the speed of brain processing • Movement selection (self selection, internal triggering) – Switching movements/sequential movement/terminating an ongoing motor program • Automatic running of motor programs • Reward, facilitates decision making and (motor) learning, operant conditioning (habits might result) – Reward is a critical factor in movement selection
90
38 Hallett: Basal Ganglia Summer 2020
Do we need the BG?
• Patients with PD who have a pallidotomy have improved function – They have lost most output from the BG • This implies that no function is better than bad function • And also implies that much of the function of the BG is a parallel brain function, useful when working well, but not absolutely necessary
91
Questions?
92
39