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Slide 1-

Functional Anatomy of the Basal Ganglia Sharif Taha, Ph.D. s.taha@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
Slide 3-

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)
Slide 5-

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 Subthalamic nucleus Thalamus  Cortex
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Three organizing principles of basal ganglia connectivity Cortical input Subthalamic nucleus Thalamus  Cortex Anatomically parallel loops with distinct function Finer-grain topographic organization within loops Patch/matrix
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Functional topography: Parallel loops w/in the BG subserve distinct functions
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J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996 Functional topography: Parallel loops w/in the BG subserve distinct functions 4 pathways: Skeletomotor Oculomotor channel Association Behavior, learning, cognition Limbic Addiction, emotional behavior
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J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996 Topography is also maintained within loops: Somatotopy
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J.H. Martin, Neuroanatomy: Text and Atlas 2nd Ed., 1996 Oculomotor topography
Slide 18-

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
Slide 20-

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 Saccade generator Cortical regions
Slide 27-

Basal ganglia: 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 Phasic decrease in firing rate transiently releases target regions from inhibition. Disinhibited thalamocortical circuit discharges, promoting movement.
Slide 28-

Outline Anatomy a. BG components b. Anatomical connectivity Modulating action through disinhibition Direct and Indirect Pathways Action Selection Neuromodulators Pathology
Slide 29-

Direct and Indirect Pathways
Slide 30-

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.
Slide 34-

Activation of the direct pathway promotes action. This causes a transient inhibition of GPi/SNr firing.
Slide 35-

Indirect pathway
Slide 36-

Striatal neurons have low tonic firing rates; again, dependent upon strong cortical inputs
Slide 37-

GPe neurons are similar to those in GPi; they have high tonic firing rates
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Firing under quiescent conditions (in the absence of movement)
Slide 40-

What happens with strong, phasic cortical excitation?
Slide 41-

Transient inhibition of GPe firing…
Slide 42-

Followed by phasic excitation of the STN (through disinhibition)…
Slide 43-

Activation of the indirect pathway suppresses action. And finally, a increased rate of discharge in the output nuclei -
Slide 44-

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
Slide 45-

Indirect pathway suppresses action. Direct pathway facilitates action. How do they cooperatively regulate motor output?
Slide 46-

Outline Anatomy a. BG components b. Anatomical connectivity Modulating action through disinhibition Direct and Indirect Pathways Action Selection Neuromodulators Pathology
Slide 47-

Action selection
Slide 48-

Action encoding in output nuclei of the BG
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Action encoding in the output nuclei of the BG
Slide 50-

Direct pathway inputs are focused and robust
Slide 51-

Direct pathway inputs are focused and robust
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Indirect pathway inputs are widespread and diffuse
Slide 53-

Together, these inputs create a center-surround mechanism for action selection
Slide 54-

Movement modulation occurs through disinhibition of thalamocortical target regions
Slide 55-

Competing alternatives are actively inhibited
Slide 56-

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
Slide 57-

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?
Slide 58-

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
Slide 59-

Outline Anatomy a. BG components b. Anatomical connectivity Modulating action through disinhibition Direct and Indirect Pathways Action Selection Neuromodulators Pathology
Slide 60-

Dopamine input arises from the SNc
Slide 61-

Direct and Indirect pathways express distinct dopamine receptors
Slide 62-

D2 signaling suppresses firing in indirect pathway neurons
Slide 63-

D2 signaling suppresses firing in indirect pathway neurons Thus, D2 effects on indirect pathway act to facilitate movement
Slide 64-

Strong cortical inputs are facilitated by D1 signaling
Slide 65-

Strong cortical inputs are facilitated by D1 signaling Thus, D1 facilitates movement in the presence of strong cortical drive
Slide 66-

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.
Slide 67-

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
Slide 68-

Acetylcholine effects
Slide 69-

Cholinergic signaling promotes firing in the indirect pathway  suppresses movement
Slide 70-

Cholinergic signaling in the direct pathway inhibits firing  suppresses movement
Slide 71-

Net effect of cholinergic signaling (through both direct and indirect pathways) is an inhibition of movement
Slide 72-

Under what conditions do DA, ACh neurons fire? Both neurons are sensitive to reward-related stimuli, particularly reward-predictive 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
Slide 73-

Examples of DA firing/release Tomorrow’s paper discussion!
Slide 74-

Outline Anatomy a. BG components b. Anatomical connectivity Modulating action through disinhibition Direct and Indirect Pathways Action Selection Neuromodulators Pathology
Slide 75-

Parkinson’s Disease: What happens when DA input is lost?
Slide 76-

Parkinson’s Disease: What happens when DA input is lost? http://www.youtube.com/watch?feature=player_detailpage&v=3VrnOtmZBtc
Slide 77-

Direct pathway become less active; indirect pathway becomes more active
Slide 78-

Action selection (direct pathway) is suppressed: action inhibition (indirect pathway) is facilitated
Slide 79-

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 Parkinson’s Disease: DA loss suppresses action selection
Slide 80-

Limitations ‘Rate model’ does little to explain other BG-related phenomena, such as tremor…though this model been very useful Dopamine function is not confined to facilitating action – very likely plays an important role in learning. BG function is not confined to regulation of movement!
Slide 81-

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
Slide 82-

Basal ganglia connectivity Cortical input Subthalamic nucleus Thalamus  Cortex