neural structures involved in the control of movement
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Neural structures involved in the control of movement
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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
Basal Ganglia
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Basal Ganglia1. 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)
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What do the basal ganglia do?
Basal ganglia are involved in generation of
goal-directed voluntary movements:
• Motor learning
• Motor pattern selection
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Location in human brain
From Neuroscience, Purves et al. eds., 2001
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Forebrain
Midbrain
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Forebrain
Midbrain
Input to basal ganglia
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Lateral view Medial view
Regions of cortical input to the basal ganglia (blue)
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Output to thalamus and cortex
Forebrain
Midbrain
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Neurons of the basal ganglia
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Smith and Bolam 1990
Synaptic input to and output from striatal medium spiny neurons
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Medium spiny neuron projections
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Convergence
– large dendritic trees
of striatal output neurons (medium spiny neurons) dendritic
spines
Basal ganglia loops
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Convergence
– large dendritic trees
– decreasing cell number
Cortex
Striatum
GPe
GPi/SNr
500:1
150,000,000
30,000
100
1
100:1
300:1
Basal ganglia loops
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Basal ganglia loops – motor and non-motor
Motor loopPrefrontal loop(Associative) Limbic loop
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Input
Output and internal circuitry
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Cortex
VA/VL
GPi/SNr
Striatum
Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.
* * tonically active
~100 Hz
GPe
STN
*
Direct pathway
Excitation (glutamate)
Inhibition (GABA)
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Direct pathway
Brain stem/Spinal cord
VA/VL
Striatum
Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.
Direct pathway:facilitatesmovement
* * tonically active
~100 Hz
GPe
STN
*Disinhibition
Cortex
GPi/SNr
Excitation (glutamate)
Inhibition (GABA)
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Patterns of activity when glutamate is applied in striatum
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Patterns of activity during motor behavior
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Disinhibition
Brain stem/Spinal cord
VA/VL
Striatum
Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.
* * tonically active
~100 Hz
STN
*
Indirect pathway:inhibitsmovement
Cortex
Indirect pathway
GPe
GPi/SNr
Excitation (glutamate)
Inhibition (GABA)
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Cortex
Brain stem/Spinal cord
VA/VL
GPi/SNr
Striatum
Modified from Wichmann and Delong, Curr Opin Neurobiol. 6:751-758, 1996.
Direct pathway:facilitatesmovement
* * tonically active
~100 Hz
GPe
STN
*
Indirect pathway:inhibitsmovement
D1D2
SNc
Excitation (glutamate)
Inhibition (GABA)
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Gerfen Nat. Neurosci. 2006
Direct and indirect pathways in mouse brain
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Patch-matrix compartmental organization of corticostriataland 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
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Patch-matrix organization of corticostriatal and striatonigral pathways
Gerfen TINS 1992
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Ionotropic versus metabotropic
ionotropic metabotropic
RR 2nd messenger
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Ionotropic versus metabotropic
ionotropic metabotropic
RR
Dopamine
2nd messenger
Glutamate
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Direct transmission vs. modulation
R
glu
DA
Direct transmission
EPSP
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glu
DA
No direct effect of DA
Direct transmission vs. modulation
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R
enhanced or diminished
response
Modulation
glu
DA D1-Rs in the direct pathway: 1) increase GluR phosphorylation2) alters ionic conductancesto amplify cortical input
Direct transmission vs. modulation
Striatal medium spiny neuron
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R
enhanced or diminished
response
Modulation
glu
DA
Direct transmission vs. modulation
D2-Rs in the indirect pathway: 1) increase GluR phosphorylation2) alters ionic conductancesto dampen cortical input
Striatal medium spiny neuron
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Direct pathway
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Release of DA in substantia nigra, as well as in striatum is required for control of
movement by the basal ganglia
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Synaptic DA release in striatum
Smith and Bolam 1990
modified from Fallon et al. 1978
SNc DA cellSNc DA cell
Somatic release(Jaffe et al. 1998)
Dendritic release(Geffen et al. 1976; Rice et al. 1994)
Somatodendritic DA release in SNc
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DA neuron
Striatonigral axonterminal (direct pathway)
GABA
SNr
SNc
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
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DA neuron
Presynaptic D1 dopamine receptors enhance striatonigral GABA release
Striatonigral axonterminal (direct pathway)
GABA
SNr
SNc
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DA neuron
Presynaptic D1 dopamine receptors enhance striatonigral GABA release
Somatodendriticdopamine
Striatonigral axonterminal (direct pathway)
GABA
SNr
SNc
Somatodendritic DA release, therefore, enhances the effect of the direct striatonigral pathway to facilitate movement
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Direct and indirect pathways
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Hypokinetic disorders
• insufficient direct pathway output• excess indirect pathway output
Hyperkinetic disorders• excess direct pathway output• insufficient indirect pathway output
Motor behavior is determined by the balance between direct/indirect striatal outputs
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Parkinson’s disease
PathophysiologyPrimary: loss of nigrostriatal DA projection
SNc
Striatum
Michael J. Fox Muhammad Ali Pope John Paul II Janet Reno Katherine Hepburn
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NormalParkinson’sdisease
Human midbrain
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Parkinson’s disease
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Motoric• Tremor (~4-5 Hz, resting)• Bradykinesia• Rigidity• Loss of postural reflexes
Depression
Dementia
Parkinson’s diseaseSymptoms
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Parkinson’s diseaseTremor (~4-5 Hz, resting)
All video clips are from Movement Disorders in Clinical Practice, Guy Swale, Ed., Isis Medical Media, Oxford, 1998.
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Parkinson’s diseaseBradykinesia
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Parkinson’s diseaseLoss of postural reflexes
…even with mild tremor and bradykinesia
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Parkinson’s diseaseRigidity
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Parkinson’s diseaseTreatment
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.
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Parkinson’s diseaseTreatment
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.
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Hyperkinetic disorders: choreatic syndromes
1. Huntington’s chorea
2. Dystonia
3. Tardive dyskinesia
4. DOPA-induced dyskinesia
5. Hemiballismus
6. Tourette’s syndrome
Causes:Genetic (autosomal dominant)
Genetic or idiopathic
Chronic neuroleptic use
Parkinson’s therapy
Unilateral vascular accident, typically subthalamic nucleus
Excessive D2-subtypeDA receptor expression(?)
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Choreatic symptoms
Involuntary (unwanted) movements
• Chorea (dance-like)
• Athetosis (changeable or writhing movements)
• Dystonia (torsion spasm)
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Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
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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
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Huntington’s disease pathology
Huntington’s
Normal
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Huntington’s disease
Symptoms
Early motor signs• chorea (brief,
involuntary movements)
• dystonia (abnormal postures)
Choreatic gait
Dystonic movements
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Huntington’s diseaseCognitive abnormalities
• Executive function (complex tasks)• Recent and remote memory (poor retrieval)
Psychiatric changes• Depression• Psychosis
Later decline• Immobility• Weight loss• Death within 10-25 years (often from pneumonia)
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Huntington’s disease
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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
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Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
Cervical dystonia (torticollis)
After botulinum toxin
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Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
Axial (thoracic and/or lumbar) dystonia
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Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
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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
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Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome
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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
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Hyperkinetic disorders: choreatic syndromes
Huntington’s disease
Dystonia
Tardive dyskinesia
DOPA-induced dyskinesia
Hemiballismus
Tourette’s syndrome