Transcript Basal ganglia PP

Functional Anatomy of the
Basal Ganglia
Sharif Taha, Ph.D.
[email protected]
Department of Neurobiology and Anatomy
Outline
1. Anatomy
a. BG components
b. Anatomical connectivity
2. Function: Modulation through
disinhibition
3. Action Selection
4. Neuromodulators: dopamine
What do the basal ganglia do?
1. Modulate the initiation, termination,
amplitude, and selection of movement
- Initiation and selection
2. Learning
-Response-outcome associations
- Stimulus-response associations
Basal ganglia:
a modulatory cortical loop
1. Basal Ganglia receives
robust input from the
cortex
- Almost all parts of
cortex; excludes primary
sensory cortices
2. Principal projection of the
BG - back to cortical
targets
- Motor associated areas
- Via ventral thalamic
relay
(Other targets: superior
colliculus)
Overview of BG organization
•
Input:
– Caudate and putamen (together, the
striatum)
•
Intrinsic:
– Subthalamic nucleus (STN)
– External segment of globus pallidus
(GPe)
SNc
•Output:
•Substantia nigra pars reticulata (SNr)
•Internal segment of globus pallidus
(GPi)
•Neuromodulator:
•Substantia nigra pars compacta (SNc)
Striatum: Medium spiny neurons
• Caudate and putamen
• Medium spiny neurons
– ~90% of neurons; primary
projection neurons
– GABAergic; inhibitory
– Very little spontaneous
activity; dependent on
excitatory input for
discharge
Up and down states
•
Inwardly rectifying potassium
channels keep striatal neurons
(very) hyperpolarized
•
Membrane potential shifts from
hyperpolarized potentials (−80 mV)
to more depolarized potentials
(−50mV)
•
Transitions to the up state are
correlated among nearby striatal
neurons
•
Selection mechanism – requires
concerted cortical activation to
move to upstate
Wilson 1998 Science
Striatum: Intrinsic interneurons
2 principle types
– 3 GABAergic
interneurons
– Tonically active
neurons (TANs)
• Cholinergic
• Large cell bodies
Globus pallidus
Two segments
→ Internal: Principle
output nucleus
→ External: intrinsic
circuitry
Neurons in both areas high tonic firing rates
GABAergic, inhibitory
Subthalamic nucleus
Alone among the BG
circuit elements –
glutamatergic
Target for deep brain
stimulation (DBS)
Nigral Complex
• Midbrain
• Substantia nigra pars
reticulata (SNpr)
– GABAergic
– Output of BG
– Developmentally,
related to Gpi
• Substantia Nigra pars
Compacta (SNpc)
– Neuromelanincontaining cells
– Dopaminergic (A9)
SNc
Basal ganglia connectivity
Cortical input
Thalamus 
Cortex
Subthalamic
nucleus
Three organizing principles of
basal ganglia connectivity
• Anatomically parallel
loops with distinct
function
Cortical input
• Finer-grain
topographic
organization within
loops
Thalamus 
Cortex
• Patch/matrix
Subthalamic
nucleus
Functional topography:
Parallel loops w/in the BG subserve distinct functions
Functional topography:
Parallel loops w/in the BG
subserve distinct functions
• 4 pathways:
– Skeletomotor
– Oculomotor channel
– Association
• Behavior, learning,
cognition
– Limbic
• Addiction, emotional
behavior
•J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996
Topography is also maintained within loops: Somatotopy
•J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996
Oculomotor topography
•J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996
Patch/matrix compartments:
neurochemical organization
• Neurochemically
distinct areas (patch,
mu opioid receptor;
matrix, calbindin)
• Dendrites observe
boundaries
• Afferents/efferents are
distinct
• Functional roles –
– Patch: limbic
– Matrix: sensorimotor
Outline
1. Anatomy
a. BG components
b. Anatomical connectivity
2. Modulating action through
disinhibition
3. Direct and Indirect Pathways
4. Action Selection
5. Neuromodulators
6. Pathology
Movement modulation through disinhibition
Movement modulation through disinhibition
Output nuclei of the basal ganglia are
inhibitory
Output nuclei maintain a high tonic level of
discharge, suppressing activity in target regions
Firing under quiescent conditions
(in the absence of movement)
Movement modulation occurs through
disinhibition of thalamocortical target regions
What advantages does modulation
through inhibition confer?
• Strong tonic
inhibition allows
basal ganglia to
serve as a master
regulator –
arbitrating between
multiple excitatory
inputs
• Initiating and
• Discriminating
Cortical regions
Saccade
generator
Basal ganglia: movement
modulation through disinhibition
1. Output nuclei of the basal ganglia are
inhibitory
2. Output nuclei maintain a high tonic level of
discharge, suppressing activity in target
regions
3. Phasic decrease in firing rate transiently
releases target regions from inhibition.
4. Disinhibited thalamocortical circuit
discharges, promoting movement.
Outline
1. Anatomy
a. BG components
b. Anatomical connectivity
2. Modulating action through
disinhibition
3. Direct and Indirect Pathways
4. Action Selection
5. Neuromodulators
6. Pathology
Direct and Indirect Pathways
Direct Pathway
Basal firing rates in the striatum are very low,
and dependent upon strong cortical excitation.
Under these conditions, striatal firing has
little impact on GPi/SNr discharge
Phasic cortical excitation drives excitatory
discharge in the striatum.
This causes a transient inhibition of GPi/SNr firing.
Activation of the direct pathway promotes action.
Indirect pathway
Striatal neurons have low tonic firing rates;
again, dependent upon strong cortical inputs
GPe neurons are similar to those in GPi;
they have high tonic firing rates
Firing under quiescent conditions
(in the absence of movement)
What happens with strong, phasic cortical
excitation?
Transient inhibition of GPe firing…
Followed by phasic excitation of the STN
(through disinhibition)…
And finally, a increased rate of discharge in the
output nuclei -
Activation of the indirect pathway suppresses action.
Rate model & basal ganglia
pathology
http://www.youtube.com/watch?feature=player_detailpage&v=fCL7RWaC3RA
http://www.youtube.com/watch?feature=player_detailpage&v=AvBrP4yRTRA
Indirect pathway suppresses action.
Direct pathway facilitates action.
How do they cooperatively regulate motor output?
Outline
1. Anatomy
a. BG components
b. Anatomical connectivity
2. Modulating action through
disinhibition
3. Direct and Indirect Pathways
4. Action Selection
5. Neuromodulators
6. Pathology
Action selection
Action encoding in output nuclei of
the BG
Action encoding in the output nuclei
of the BG
Direct pathway inputs are focused
and robust
Direct pathway inputs are focused and
robust
Indirect pathway inputs are widespread and
diffuse
Together, these inputs create a centersurround mechanism for action selection
Movement modulation occurs through
disinhibition of thalamocortical target regions
Competing alternatives are actively inhibited
Why do we need to ‘sharpen’ selection
mechanisms?
• Multiple/ambiguous stimuli in our environment
often demand our attention/action (e.g., visual
stimuli)
• However, we’re often confined to making a
single action to address these stimuli (e.g., a
saccade).
• Particularly where conflicting needs are present,
action may require active inhibition
Action selection (in action)
•
Multiple/ambiguous stimuli in our
environment often demand our
attention/action.
•
However, we’re often confined to
making a single action to address
these stimuli (e.g., a saccade).
•
Selection through surround
inhibition likely occurs on large and
small scales – i.e., not only
saccade left or right, but how far to
saccade?
Direct and indirect pathways together
facilitate action selection
• Activation of direct pathway facilitates movement
• Activation of indirect pathway suppresses movement
• Direct output makes focal inhibitory contact on GPi/SNr
• Indirect output makes diffuse, widespread excitatory contact on
GPi/SNr
• Co-activation of these pathways facilitates action selection through
center-surround mechanism
Outline
1. Anatomy
a. BG components
b. Anatomical connectivity
2. Modulating action through
disinhibition
3. Direct and Indirect Pathways
4. Action Selection
5. Neuromodulators
6. Pathology
Dopamine input arises from the
SNc
Direct and Indirect pathways express distinct
dopamine receptors
D2 signaling suppresses firing in
indirect pathway neurons
D2 signaling suppresses firing in
indirect pathway neurons
Thus, D2 effects on indirect pathway act to facilitate movement
Strong cortical inputs are facilitated
by D1 signaling
Strong cortical inputs are facilitated
by D1 signaling
Thus, D1 facilitates movement in the presence of strong cortical drive
Up and down states/DA action
• D1 receptor signaling
- In down state, increases voltage-dependent
K+ current
- In up state, increases voltage-dependent
Ca++ current
• D2
– Generally inhibit firing by decreasing Ca++
currents.
Dopamine effects on direct and
indirect pathways
• Dopamine signaling through D2 receptors
in the indirect pathway suppresses striatal
activity
• Dopamine signaling through D1 receptors
in the direct pathway:
– Facilitates strong, phasic inputs
– Suppresses weak inputs
Acetylcholine effects
Cholinergic signaling promotes firing in the indirect
pathway  suppresses movement
Cholinergic signaling in the direct pathway inhibits
firing  suppresses movement
Net effect of cholinergic signaling (through both direct
and indirect pathways) is an inhibition of movement
Under what conditions do DA,
ACh neurons fire?
• Both neurons are sensitive to rewardrelated stimuli, particularly rewardpredictive cues (i.e., Pavlov’s bell).
• However their response differs:
– DA neurons increase firing
– ACh neurons decrease firing
• Net effect: facilitation of movement in
response to reward predictive cues
Examples of DA firing/release
Tomorrow’s paper discussion!
Outline
1. Anatomy
a. BG components
b. Anatomical connectivity
2. Modulating action through
disinhibition
3. Direct and Indirect Pathways
4. Action Selection
5. Neuromodulators
6. Pathology
Parkinson’s Disease: What happens when
DA input is lost?
Parkinson’s Disease: What happens when
DA input is lost?
http://www.youtube.com/watch?feature=player_detailpage&v=3VrnOtmZBtc
Direct pathway become less active; indirect
pathway becomes more active
Action selection (direct pathway) is suppressed:
action inhibition (indirect pathway) is facilitated
Summary
1.
Modulating action through disinhibition
2.
Direct and Indirect Pathways
Direct pathway facilitates action
Indirect pathway suppresses action
3.
Neuromodulators
Dopamine
Facilitates action through both pathways
Increases firing in response to reward directed cues
Acetylcholine
Suppresses action through both pathways
Decrease firing in response to reward directed cues
4.
BG Role in Action Selection
Selection through direct pathway;
surround suppression through indirect pathway
5.
Parkinson’s Disease: DA loss suppresses action selection
Limitations
1. ‘Rate model’ does little to explain other
BG-related phenomena, such as
tremor…though this model been very
useful
2. Dopamine function is not confined to
facilitating action – very likely plays an
important role in learning.
3. BG function is not confined to regulation
of movement!
References
• Kandel is fine for the basics
• Excellent review of BG function and role of
BG in guiding reward-directed (eye)
movements:
– Hikosaka 2001, Physiological Reviews - Role of
the Basal Ganglia in the Control of Purposive
Saccadic Eye Movements
• General review of striatal function:
– Kreitzer Annu. Rev. Neurosci. 2009. 32:127–47,
Physiology and Pharmacology of Striatal Neurons