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 2. Paleostriatum 3. Substantia Nigra
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

8. Forebrain
Midbrain

9. Forebrain
Input to basal ganglia
Midbrain

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

11. Output to thalamus and cortex
Forebrain
Midbrain

12. Neurons of the basal ganglia

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

14. Medium spiny neuron projections

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

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

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

18. Output and internal circuitry
Input
Output and internal circuitry

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

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

22. Patterns of activity when glutamate is applied in striatum

23. Patterns of activity during motor behavior

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

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

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

27. 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

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

29. Ionotropic versus metabotropic
2nd messenger
metabotropic
ionotropic

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

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

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

33. Direct transmission vs. modulation
glu DA
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

34. R Direct transmission vs. modulation glu enhanced or diminishedDA
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

35. Direct pathway

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

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

38. DA neuron SNc SNr SNr output neurons 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 disinhibition of the thalamus and facilitation of movement

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

40. 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

41. Direct and indirect pathways

42. Hypokinetic disorders
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 direct pathway output
insufficient indirect pathway output

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

44. Human midbrain
Parkinson’s
disease
Normal

45. Parkinson’s disease

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

47. 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.

48. Parkinson’s disease
Bradykinesia

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

50. Parkinson’s disease
Rigidity

51. Parkinson’s disease Treatment L-DOPA
The primary treatment for Parkinson’s is administration of the dopamine precursor, L-DOPA. This is initially effective, but after 5-10 years, 50% of patients develop DOPA-induced dyskinesia.

52. Parkinson’s disease Treatment Deep brain stimulation
The activity of the subthalamic nucleus (STN) is increased in Parkinson’s. This parkinsonian patient has bilateral STN stimulating electrodes:
high frequency stimulation inactivates the STN.

53. Hyperkinetic disorders: choreatic syndromes
Causes:
Genetic (autosomal dominant)
Genetic or idiopathic
Chronic neuroleptic use
Parkinson’s therapy
Unilateral vascular accident,
typically subthalamic nucleus
Excessive D2-subtype
DA receptor expression(?)
1. Huntington’s chorea
2. Dystonia
3. Tardive dyskinesia
4. DOPA-induced dyskinesia
5. Hemiballismus
6. Tourette’s syndrome

54. Choreatic symptoms Involuntary (unwanted) movements
Chorea (dance-like)
Athetosis (changeable or writhing movements)
Dystonia (torsion spasm)

55. Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome

56. Huntington’s disease Pathophysiology Atrophy of striatum
Loss of striatal GABAergic neurons
Neuropathological sequence
1st: loss of striatal GABA/enkephalin/D2-R neurons (indirect pathway)
2nd: loss of striatal GABA/dynorphin/D1-R neurons (direct pathway) & cortical atrophy

57. Huntington’s disease pathology
Normal

58. Huntington’s disease Symptoms Early motor signs Choreatic gait
chorea (brief, involuntary movements)
dystonia (abnormal postures)
Dystonic movements

59. Huntington’s disease Cognitive abnormalities Psychiatric changes
Executive function (complex tasks)
Recent and remote memory (poor retrieval)
Psychiatric changes
Depression
Psychosis
Later decline
Immobility
Weight loss
Death within years (often from pneumonia)

60. Huntington’s disease

61. Etiology of Huntington’s disease
Huntingtin mutation
Mutation near 5’ end contains >>CAG repeats
Produces protein with excess glutamines near NH2 terminus
Why cell death?
Not yet certain
Excitotoxicity? Glutamate acting via NMDA receptors can kill medium spiny neurons; glutamate antagonists block

62. Cervical dystonia (torticollis)
Hyperkinetic disorders: choreatic syndromes
Cervical dystonia (torticollis)
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
After botulinum toxin

63. Axial (thoracic and/or lumbar) dystonia
Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
Axial (thoracic and/or lumbar) dystonia

64. Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome

65. *50% of PD patients on L-DOPA will develop DOPA dyskinesia
Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
*DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
*50% of PD patients on L-DOPA will develop DOPA dyskinesia

66. Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome

67. Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus – unilateral
STN stroke
Tourette’s syndrome
After treatment with the D2-R blocker sulpiride

68. Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome