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The Basal Ganglia (Chapter 3) Aspen 2020 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
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