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

- Circuitry involved in movement disorders discussed

 Basal Ganglia
1. 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)
 What do the basal ganglia do?

Basal ganglia are involved in generation of

goal-directed voluntary movements:

• Motor learning

• Motor pattern selection

 Location in human brain

From Neuroscience,
Purves et al. eds., 2001
Forebrain

Midbrain
Forebrain
Input to
basal
ganglia

Midbrain
 Regions of cortical input to the basal
ganglia (blue)

Lateral view Medial view

 Output to
Forebrain thalamus
and
cortex

Midbrain
Neurons of the basal ganglia
Synaptic input to and
output from striatal
medium spiny
neurons

Smith and Bolam 1990

Medium spiny neuron projections
 Basal ganglia loops

Convergence

– large dendritic trees

of striatal output
neurons (medium
spiny neurons) dendritic
spines
 Basal ganglia loops

Convergence 150,000,000 Cortex

500:1
– large dendritic trees
30,000 Striatum
– decreasing cell 300:1
number
100 GPe
100:1

1 GPi/
SNr
Basal ganglia loops – motor and non-motor
Prefrontal loop
Motor loop (Associative) Limbic loop
Input Output and
internal circuitry
 Cortex
Direct pathway

Striatum Excitation (glutamate)

Inhibition (GABA)

VA/VL
* GPe

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

Inhibition (GABA)

VA/VL
* GPe
Disinhibition

STN
* GPi/SNr * tonically active
~100 Hz
Modified from Wichmann and Delong,
Brain stem/ Curr Opin Neurobiol. 6:751-758, 1996.
Spinal cord
Patterns of activity when glutamate is applied in striatum
Patterns of activity during motor behavior
 Cortex

Striatum
Indirect pathway
pathway:
inhibits
movement

VA/VL
* GPe
Excitation (glutamate)

Disinhibition Inhibition (GABA)

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

Inhibition (GABA)

STN
* GPi/SNr * tonically active
~100 Hz
Modified from Wichmann and Delong,
Brain stem/ Curr Opin Neurobiol. 6:751-758, 1996.
Spinal cord
Direct and
indirect
pathways in
mouse brain

Gerfen Nat. Neurosci. 2006

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
Patch-matrix organization of corticostriatal and
striatonigral pathways

Gerfen TINS 1992

Ionotropic versus metabotropic

R
R 2nd messenger

ionotropic metabotropic
Ionotropic versus metabotropic

Glutamate Dopamine

R
R 2nd messenger

ionotropic metabotropic
Direct transmission vs. modulation

glu

R EPSP

DA

Direct transmission
Direct transmission vs. modulation

glu

DA
No direct effect of DA
Direct transmission vs. modulation
Striatal medium spiny neuron

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

glu enhanced
or diminished
response
R
DA D2-Rs in the indirect pathway:
1) decrease GluR phosphorylation
2) alters ionic conductances
to dampen cortical input
Modulation
Direct pathway
Release of DA in substantia nigra, as well as
in striatum is required for control of
movement by the basal ganglia
Synaptic DA release Somatodendritic DA
in striatum 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

 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 disinhibition of the thalamus and facilitation of movement
 DA neuron
Striatonigral axon
terminal (direct pathway)

SNc GABA

Presynaptic D1 dopamine receptors

SNr enhance striatonigral GABA release
 DA neuron
Striatonigral axon
terminal (direct pathway)
Somatodendritic
dopamine

SNc GABA

Presynaptic D1 dopamine receptors

SNr enhance striatonigral GABA release

Somatodendritic DA release, therefore, enhances the effect

of the direct striatonigral pathway to facilitate movement
Direct and indirect pathways
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
 Parkinson’s disease

Michael J. Fox Muhammad Ali Pope John Paul II Janet Reno Katherine Hepburn

Striatum
Pathophysiology
Primary: loss of
nigrostriatal DA
projection
SNc
 Human midbrain

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

…even with mild tremor

and bradykinesia
Parkinson’s disease
Rigidity
 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.
 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.
 Hyperkinetic disorders:
choreatic syndromes
Causes:
1. Huntington’s chorea Genetic (autosomal dominant)

2. Dystonia Genetic or idiopathic

3. Tardive dyskinesia Chronic neuroleptic use

4. DOPA-induced dyskinesia Parkinson’s therapy

Unilateral vascular accident,
5. Hemiballismus
typically subthalamic nucleus
6. Tourette’s syndrome Excessive D2-subtype
DA receptor expression(?)
 Choreatic symptoms

Involuntary (unwanted) movements

• Chorea (dance-like)

• Athetosis (changeable or writhing movements)

• Dystonia (torsion spasm)

Hyperkinetic disorders: choreatic syndromes

Huntington’s disease

Dystonia

Tardive dyskinesia

DOPA-induced dyskinesia

Hemiballismus

Tourette’s syndrome
 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
Huntington’s disease pathology

Huntington’s

Normal
 Huntington’s disease
Choreatic gait

Symptoms
Early motor signs
• chorea (brief,
involuntary Dystonic movements
movements)
• dystonia (abnormal
postures)
 Huntington’s disease
Cognitive 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)
Huntington’s disease
 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
Hyperkinetic disorders: choreatic syndromes
Cervical dystonia (torticollis)
Huntington’s disease

Dystonia

Tardive dyskinesia

DOPA-induced dyskinesia After botulinum toxin

Hemiballismus

Tourette’s syndrome
Hyperkinetic disorders: choreatic syndromes

Huntington’s disease

Dystonia

Tardive dyskinesia

DOPA-induced dyskinesia Axial (thoracic and/or

lumbar) dystonia
Hemiballismus

Tourette’s syndrome
Hyperkinetic disorders: choreatic syndromes

Huntington’s disease

Dystonia

Tardive dyskinesia

DOPA-induced dyskinesia

Hemiballismus

Tourette’s syndrome
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
Hyperkinetic disorders: choreatic syndromes

Huntington’s disease

Dystonia

Tardive dyskinesia

DOPA-induced dyskinesia

Hemiballismus

Tourette’s syndrome
Hyperkinetic disorders: choreatic syndromes

Huntington’s disease

Dystonia

Tardive dyskinesia
After treatment with the D2-R blocker sulpiride
DOPA-induced dyskinesia

Hemiballismus – unilateral
STN stroke

Tourette’s syndrome
Hyperkinetic disorders: choreatic syndromes

Huntington’s disease

Dystonia

Tardive dyskinesia

DOPA-induced dyskinesia

Hemiballismus

Tourette’s syndrome