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Neural structures involved in the control of movement

Neural structures involved in the control of movement. Basal Ganglia. Key take-home messages: - Components of the basal ganglia - Function of the basal ganglia - Functional circuitry of the basal ganglia e.g., direct and indirect pathways, transmitters

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Neural structures involved in the control of movement

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  1. Neural structures involved in the control of movement

  2. Basal Ganglia Key take-home messages: - Components of the basal ganglia - Function of the basal ganglia - Functional circuitry of the basal ganglia e.g., direct and indirect pathways, transmitters - Circuitry involved in movement disorders discussed

  3. Basal Ganglia • Neostriatum • Caudate nucleus • Putamen • Ventral striatum (nucleus accumbens) 2.Paleostriatum Globus pallidus external segment (GPe) Globus pallidus internal segment (GPi) 3. Substantia Nigra Pars compacta (SNc) Pars reticulata (SNr) 4. Subthalamic nucleus (STN)

  4. What do the basal ganglia do? • Basal ganglia are involved in generation of • goal-directed voluntary movements: • Motor learning • Motor pattern selection

  5. Location in human brain From Neuroscience, Purves et al. eds., 2001

  6. Forebrain Midbrain

  7. Forebrain Input to basal ganglia Midbrain

  8. Regions of cortical input to the basal ganglia (blue) Lateral view Medial view

  9. Output to thalamus and cortex Forebrain Midbrain

  10. Neurons of the basal ganglia

  11. Synaptic input to and output from striatal medium spiny neurons Smith and Bolam 1990

  12. Medium spiny neuron projections

  13. Basal ganglia loops Convergence • large dendritic trees of striatal output neurons (medium spiny neurons) dendritic spines

  14. Cortex Striatum GPe GPi/SNr Basal ganglia loops 150,000,000 Convergence • large dendritic trees • decreasing cell number 500:1 30,000 300:1 100 100:1 1

  15. Prefrontal loop (Associative) Limbic loop Basal ganglia loops – motor and non-motor Motor loop

  16. Input Output and internal circuitry

  17. VA/VL *tonically active ~100 Hz * Cortex Direct pathway Striatum Excitation (glutamate) Inhibition (GABA) * GPe STN GPi/SNr Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.

  18. VA/VL Disinhibition *tonically active ~100 Hz * Cortex Direct pathway Direct pathway: facilitates movement Striatum Excitation (glutamate) Inhibition (GABA) * GPe STN GPi/SNr Brain stem/ Spinal cord Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.

  19. Patterns of activity when glutamate is applied in striatum

  20. Patterns of activity during motor behavior

  21. Striatum VA/VL Excitation (glutamate) Inhibition (GABA) *tonically active ~100 Hz * Cortex Indirect pathway: inhibits movement Indirect pathway * GPe Disinhibition STN GPi/SNr Brain stem/ Spinal cord Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.

  22. Striatum D2 D1 VA/VL Excitation (glutamate) Inhibition (GABA) *tonically active ~100 Hz * Cortex Direct pathway: facilitates movement Indirect pathway: inhibits movement SNc * GPe STN GPi/SNr Brain stem/ Spinal cord Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.

  23. Direct and indirect pathways in mouse brain Gerfen Nat. Neurosci. 2006

  24. Patch-matrix compartmental organization of corticostriatal and striatonigral pathways Corticostriatal neurons deep in layer V provide -> patches Superficial layer V neurons -> matrix. Patch MSNs -> DAergic neurons in SNc Matrix MSNs -> GABAergic neurons in SNr Gerfen TINS 1992

  25. Patch-matrix organization of corticostriatal and striatonigral pathways Gerfen TINS 1992

  26. Ionotropic versus metabotropic R R 2nd messenger metabotropic ionotropic

  27. Dopamine Ionotropic versus metabotropic Glutamate R R 2nd messenger metabotropic ionotropic

  28. glu DA Direct transmission vs. modulation R EPSP Direct transmission

  29. glu DA Direct transmission vs. modulation No direct effect of DA

  30. glu DA Direct transmission vs. modulation Striatal medium spiny neuron enhanced or diminished response R D1-Rs in the direct pathway: 1) increase GluR phosphorylation 2) alters ionic conductances to amplify cortical input Modulation

  31. glu DA Direct transmission vs. modulation Striatal medium spiny neuron enhanced or diminished response R D2-Rs in the indirect pathway: 1) increase GluR phosphorylation 2) alters ionic conductances to dampen cortical input Modulation

  32. Direct pathway

  33. Release of DA in substantia nigra, as well as in striatum is required for control of movement by the basal ganglia

  34. SNc DA cell Somaticrelease (Jaffe et al. 1998) Dendritic release (Geffen et al. 1976; Rice et al. 1994) Synaptic DA release in striatum Somatodendritic DA release in SNc modified from Fallon et al. 1978 Smith and Bolam 1990

  35. DA neuron Striatonigral axon terminal (direct pathway) SNc GABA SNr SNr output neurons (GABAergic, tonically active, project to thalamus) are inhibited by the direct, striatonigral pathway, leading to disinhibitionof the thalamus and facilitationof movement

  36. DA neuron Striatonigral axon terminal (direct pathway) SNc GABA Presynaptic D1 dopamine receptors enhance striatonigral GABA release SNr

  37. DA neuron Striatonigral axon terminal (direct pathway) Somatodendritic dopamine SNc GABA Presynaptic D1 dopamine receptors enhance striatonigral GABA release SNr Somatodendritic DA release, therefore, enhances the effect of the direct striatonigral pathway to facilitate movement

  38. Direct and indirect pathways

  39. Motor behavior is determined by the balance between direct/indirect striatal outputs Hypokinetic disorders • insufficient direct pathway output • excess indirect pathway output Hyperkinetic disorders • excess directpathwayoutput • insufficient indirectpathway output

  40. Pope John Paul II Janet Reno Katherine Hepburn SNc Michael J. Fox Muhammad Ali Parkinson’s disease Pathophysiology Primary: loss of nigrostriatal DA projection Striatum

  41. Human midbrain Parkinson’s disease Normal

  42. Parkinson’s disease

  43. Parkinson’s disease Symptoms Motoric • Tremor (~4-5 Hz, resting) • Bradykinesia • Rigidity • Loss of postural reflexes Depression Dementia

  44. Parkinson’s disease Tremor (~4-5 Hz, resting) All video clips are from Movement Disorders in Clinical Practice, Guy Swale, Ed., Isis Medical Media, Oxford, 1998.

  45. Parkinson’s disease Bradykinesia

  46. Parkinson’s disease Loss of postural reflexes …even with mild tremor and bradykinesia

  47. Parkinson’s disease Rigidity

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