Functional Anatomy of the Basal Ganglia

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Functional Anatomy of the Basal Ganglia

• Sharif Taha, Ph.D.
• s.taha_at_utah.edu
• Department of Neurobiology and Anatomy

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Outline

• Anatomy
• a. BG components
• b. Anatomical connectivity
• Function Modulation through disinhibition
• Action Selection
• Neuromodulators dopamine

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What do the basal ganglia do?

• Modulate the initiation, termination, amplitude,
  and selection of movement
• - Initiation and selection
• 2. Learning
• -Response-outcome associations
• - Stimulus-response associations

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Basal ganglia a modulatory cortical loop

• Basal Ganglia receives robust input from the
  cortex
• - Almost all parts of cortex excludes primary
  sensory cortices
• Principal projection of the BG - back to cortical
  targets
• - Motor associated areas
• - Via ventral thalamic relay
• (Other targets superior colliculus)

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Overview of BG organization

• Input
• Caudate and putamen (together, the striatum)
• Intrinsic
• Subthalamic nucleus (STN)
• External segment of globus pallidus (GPe)

• Output
• Substantia nigra pars reticulata (SNr)
• Internal segment of globus pallidus (GPi)
• Neuromodulator
• Substantia nigra pars compacta (SNc)

SNc
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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

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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
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Striatum Intrinsic interneurons

• 2 principle types
• 3 GABAergic interneurons
• Tonically active neurons (TANs)
• Cholinergic
• Large cell bodies

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Globus pallidus
Two segments ? Internal Principle output
nucleus ? External intrinsic circuitry Neurons
in both areas - high tonic firing
rates GABAergic, inhibitory
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Subthalamic nucleus
Alone among the BG circuit elements
glutamatergic Target for deep brain stimulation
(DBS)
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Nigral Complex

• Midbrain
• Substantia nigra pars reticulata (SNpr)
• GABAergic
• Output of BG
• Developmentally, related to Gpi
• Substantia Nigra pars Compacta (SNpc)
• Neuromelanin-containing cells
• Dopaminergic (A9)

SNc
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Basal ganglia connectivity
Cortical input
Thalamus ? Cortex
Subthalamic nucleus
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Three organizing principles of basal ganglia
connectivity
Cortical input

• Anatomically parallel loops with distinct
  function
• Finer-grain topographic organization within loops
• Patch/matrix

Thalamus ? Cortex
Subthalamic nucleus
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Functional topography Parallel loops w/in the
BG subserve distinct functions
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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

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Topography is also maintained within loops
Somatotopy

• J.H. Martin, Neuroanatomy Text and Atlas 2nd
  Ed., 1996

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Oculomotor topography

• J.H. Martin, Neuroanatomy Text and Atlas 2nd
  Ed., 1996

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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

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Outline

• Anatomy
• a. BG components
• b. Anatomical connectivity
• Modulating action through disinhibition
• Direct and Indirect Pathways
• Action Selection
• Neuromodulators
• Pathology

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Movement modulation through disinhibition
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Movement modulation through disinhibition
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Output nuclei of the basal ganglia are inhibitory
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Output nuclei maintain a high tonic level of
discharge, suppressing activity in target regions
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Firing under quiescent conditions (in the
absence of movement)
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Movement modulation occurs through disinhibition
of thalamocortical target regions
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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
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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.

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Outline

• Anatomy
• a. BG components
• b. Anatomical connectivity
• Modulating action through disinhibition
• Direct and Indirect Pathways
• Action Selection
• Neuromodulators
• Pathology

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Direct and Indirect Pathways
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Direct Pathway
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Basal firing rates in the striatum are very
low,and dependent upon strong cortical
excitation.
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Under these conditions, striatal firing has
little impact on GPi/SNr discharge
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Phasic cortical excitation drives excitatory
discharge in the striatum.
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Activation of the direct pathway promotes action.
This causes a transient inhibition of GPi/SNr
firing.
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Indirect pathway
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Striatal neurons have low tonic firing
rates again, dependent upon strong cortical
inputs
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GPe neurons are similar to those in GPi they
have high tonic firing rates
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(No Transcript)
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Firing under quiescent conditions (in the
absence of movement)
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What happens with strong, phasic cortical
excitation?
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Transient inhibition of GPe firing
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Followed by phasic excitation of the STN (through
disinhibition)
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And finally, a increased rate of discharge in the
output nuclei -
Activation of the indirect pathway suppresses
action.
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Rate model basal ganglia pathology

• http//www.youtube.com/watch?featureplayer_detail
  pagevfCL7RWaC3RA
• http//www.youtube.com/watch?featureplayer_detail
  pagevAvBrP4yRTRA

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Indirect pathway suppresses action.
Direct pathway facilitates action.
How do they cooperatively regulate motor output?
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Outline

• Anatomy
• a. BG components
• b. Anatomical connectivity
• Modulating action through disinhibition
• Direct and Indirect Pathways
• Action Selection
• Neuromodulators
• Pathology

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Action selection
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Action encoding in output nuclei of the BG
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Action encoding in the output nuclei of the BG
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Direct pathway inputs are focused and robust
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Direct pathway inputs are focused and robust
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Indirect pathway inputs are widespread and diffuse
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Together, these inputs create a center-surround
mechanism for action selection
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Movement modulation occurs through disinhibition
of thalamocortical target regions
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Competing alternatives are actively inhibited
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Why do we need to sharpen selection mechanisms?

• Multiple/ambiguous stimuli in our environment
  often demand our attention/action (e.g., visual
  stimuli)
• However, were 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

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Action selection (in action)

• Multiple/ambiguous stimuli in our environment
  often demand our attention/action.
• However, were 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?

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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

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Outline

• Anatomy
• a. BG components
• b. Anatomical connectivity
• Modulating action through disinhibition
• Direct and Indirect Pathways
• Action Selection
• Neuromodulators
• Pathology

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Dopamine input arises from the SNc
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Direct and Indirect pathways express distinct
dopamine receptors
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D2 signaling suppresses firing in indirect
pathway neurons
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D2 signaling suppresses firing in indirect
pathway neurons
Thus, D2 effects on indirect pathway act to
facilitate movement
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Strong cortical inputs are facilitated by D1
signaling
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Strong cortical inputs are facilitated by D1
signaling
Thus, D1 facilitates movement in the presence of
strong cortical drive
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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.

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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

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Acetylcholine effects
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Cholinergic signaling promotes firing in the
indirect pathway ? suppresses movement
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Cholinergic signaling in the direct pathway
inhibits firing ? suppresses movement
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Net effect of cholinergic signaling (through both
direct and indirect pathways) is an inhibition of
movement
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Under what conditions do DA, ACh neurons fire?

• Both neurons are sensitive to reward-related
  stimuli, particularly reward-predictive cues
  (i.e., Pavlovs bell).
• However their response differs
• DA neurons increase firing
• ACh neurons decrease firing
• Net effect facilitation of movement in response
  to reward predictive cues

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Examples of DA firing/release

• Tomorrows paper discussion!

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Outline

• Anatomy
• a. BG components
• b. Anatomical connectivity
• Modulating action through disinhibition
• Direct and Indirect Pathways
• Action Selection
• Neuromodulators
• Pathology

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Parkinsons Disease What happens when DA input
is lost?
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Parkinsons Disease What happens when DA input
is lost?

• http//www.youtube.com/watch?featureplayer_detail
  pagev3VrnOtmZBtc

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Direct pathway become less active indirect
pathway becomes more active
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Action selection (direct pathway) is suppressed
action inhibition (indirect pathway) is
facilitated
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Summary

• Modulating action through disinhibition
• Direct and Indirect Pathways
• Direct pathway facilitates action
• Indirect pathway suppresses action
• 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
• BG Role in Action Selection
• Selection through direct pathway
• surround suppression through indirect pathway

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Limitations

1. Rate model does little to explain other
   BG-related phenomena, such as tremorthough 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!

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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. 3212747,
  Physiology and Pharmacology of Striatal Neurons

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Basal ganglia connectivity
Cortical input
Thalamus ? Cortex
Subthalamic nucleus