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1
The basal ganglia: a functional approach
“But, what is it for?”
Finding out with computational neuroscience
2
Phenomenology● Damage to BG is main cause of:
■ Parkinson’s disease✴ Bradykinesia, akiensia, tremor
■ Huntington’s disease✴ Involuntary movements (when slow and extended = chorea)
● Damage to BG implicated in: ■ ADHD
✴ Attention deficit hyperactivity disorder
■ Schizophrenia✴ Complex condition with positive symptoms (e.g. delusions) and
negative symptoms (e.g. lack of affect)
PD video
3
Rationale for tackling the problem● If brain area/system X is damaged, what are
the consequences?
● Strategy: find out the main function of X.
● Then, understanding of the phenomena will be unified: each deficit is an aspect of loss of the main function of X.
● So, what do the basal ganglia do….?
4
Action selectionPredisposing conditions (sensory input, cognitive state,
homeostasis, etc)
Energy balance (A1: feeding)
Fluid balance (A2: drinking)
Threat (A3: escape)
Motor resources
Behavioural output (feeding)
5
Cognitive example● Students in this lecture
■ ‘shall I pay attention or think about plans for this evening’? [‘action’ of defining cognitive state]
■ ‘pay attention or act on my being hungry’■ but then fire alarm goes off….
● Salience issues (again)
● ‘lower’ and ‘higher’ level processing■ social protocols and long term planning versus
biological drives and homeostasis■ Probably mediated by cortical and sub-cortical
centres respectively
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Mediating competition between actionsCentral switch has a ‘wiring’ advantage over the ‘distributed’ alternative
A1
A1 A1
A1
Distributed (all-to-all) connectivity.
Number of connections ~ N2
A1
A1 A1
A1
S
Central switchNumber of connections ~
N
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Hypothesis for basal ganglia function
● basal ganglia is the central ‘switch’ in the vertebrate brain that enables ‘action’ selection
■ Here ‘action’ may mean ‘internalised behaviour’ defined by cognitive state
● Therefore disorders of the basal ganglia are disorders of action selection
■ E.g. PD, HD = inability to select motor actions appropriately
■ E.g. ADHD, Schiz. = inability to suppress unwanted actions or cognitive states
Redgrave ,et al. 1999
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Evidence for this hypothesis: 1If the action selection hypothesis is true then we require that …
1. The BG must take input from a wide variety of brain areas• i.e. putative ‘command centres’ for ‘action requests’• These should be cortical and subcortical
2. There must be some mechanism by which the BG can switch on selected motor resources
3. There must be evidence of a flow of information between command centres, BG, and associated motor centres
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Evidence for this hypothesis: 2
If the action selection hypothesis is true then we require that …
4. The BG must understand be able to extract the ‘salience’ of each request• Assuming that this is done in BG and is not sent
separately (otherwise we have a repeat of the ‘wiring argument’ )
5. There must be evidence of neuronal selection mechanisms in BG
Subsequent slides will be related back to these points by labels of the form E#
10
Basal ganglia input E1
putamen
head of caudatetail of caudate
globuspallidus
The main input nucleus isneostriatum (or sometimes simply the striatum) composed of the putamenand caudate nuclei.
The striatum is by far the largest nucleus in the basal ganglia and receives input from all over the brain including: all of cerebral cortex (except primary sensory areas) and subcorticalnuclei such as the superior colliculus (via the intralaminarthalamus)
Also shown is the globuspallidus (see next slide for details)
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Disinhibition gating hypothesis 1: basic mechanism
E2
striatum
GPi/SNr
striatum
GPi/SNr
Output nuclei of the BGGPi = globus pallidus internal segmentSNr = substantia nigra pars reticulata
Cortex
BGThalamus
subcorticalmotor nuclei
Tonic inhibition
Alexander,et al. 1990
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Disinhibition gating hypothesis 2: data with glutamate injections in striatum
E2
striatum
SNr
VM
SC
VM = ventromedial thalamus
SC =superior colliculus(midbrain sensory and motor motor nucleus)
Alexander,et al. 1990
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Representing discrete actions 1: cortico-basal ganglia loops
Cortex
BGThalamus
BrainstemMotor nuclei
Five main loops according to primary cortical input area
E3
‘Motor’ (supplementary motor area – SMA)
‘Oculomotor’ (frontal eye fields – FEF)
‘Prefrontal 1’ (dorsolateral prefrontal cortex – dlPFC)
‘Prefrontal 2’ (lateral orbitofrontalprefrontal cortex – LOF)
‘limbic’ (anterior cingulate area – ACA)
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Representing discrete actions 2: topography in BG
E3
Different body parts represented by different parts of BG and related structures
We conclude (from this slide and the last) that BG represents actions in discrete channels
15
Representing discrete actions 1: sub-cortical-basal ganglia loops
E3
Sub-cortical structures include:
Superior colliculus (SC)
Pedunculopontine tegmental area(or simply peduncularpontinenucleus - PPN)
Periaqueductal gray (PAG)
Sub-cortical structures
BG
Intra-laminar thalamus
BrainstemMotor nuclei
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Disinhibition gating and channels Predisposing conditions E2 & E3
Ctx1: action1 Ctx2: action2
BGThalamus
Motor resourcesfor action 1
Motor resourcesfor action 2
Probably some shared
resources
BGThalamus
17
Interlude – the anatomy
output nuclei
Coronalsection
putamen
head of caudatetail of caudate
globuspallidus
18
Salience extraction in striatumE4Medium spiny neurons
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Spines up close…
AT
Sp
DS
textbookPaul Bolam’s lab
20
Selection mechanisms in BG 1: basic idea
Cortical inputs
‘striatum’ Note: ‘striatum’is both excitatory and inhibitoryResolved later...
Output (GPi/SNr)
E5
inhibition excitation Model neuron
21
Selection mechanisms in BG 2: realistic Instantiation in basal ganglia
Striatum
input
STN
output
Diffuseprojection
striatum STN
inputs
‘output layer’
Assumes diffuse projections from STN = subthalamic nucleus
- +
E5
Mink and Thach,1993
22
Focussed and diffuse connectivityMedium spiny neuron
STN neuron
23
Striatal structure and BG architecture
Mainly D1 dopamine receptors
Mainly D2 dopamine receptors
NB – red/blue do NOT signify excitation/inhibition here
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Instantiation in basal ganglia: 2E5
Selectionpathway
Striatum (D1)
Cortex/thalamus
STN
EP/SNr
BG output Function?
?Striatum (D2)
Cortex/thalamus
STN
GPe
25
New functional architecture:selection and control pathways
Interpret GPefferents as
control signals for modulating
selection pathway
Gurney et al, 2001
Striatum (D1)
Cortex/thalamus
STN
EP/SNr
Striatum (D2)
GP
E5
Selection pathway Control pathway
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Simulation - basic selection dynamics
salience
EP/SNr output
27
Comparison with prevailing model: ‘Direct’ and ‘Indirect’ pathways
Cortex/thalamus
STN
EP/SNr
Striatum (D2)
GP
Striatum (D1)
Direct
Indirect• Never instantiated quantitatively
• No global selection
Selection
Control
28
Summary● Action selection is a key computational problem for
all animals.● Central switching appears to be an optimal solution● The BG appears well placed to do this in vertebrates
because■ It receives widespread input (cortical and subcortical)■ Tonic inhibition and its selective release appear to be a
mechanism for gating motor programmes■ Functional loops and topography support the idea of action
‘channels’.■ Medium spiny neurons could act to extract salience■ There is a multitude of selection mechanisms in BG,
including that supported by the innervation of SNr/GPi from striatum and STN.
● Under our hypothesis, disorders of the basal ganglia are understood as disorders of action selection
29
Suggested reading● The chapter in Squire et a (Fundamental
Neuroscience)
● The review by Mink (1996)
● Our paper outlining the action selection hypothesis (Redgrave et al 1999)
30
ReferencesAlexander, G. E. and M.D., C. (1990): Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends in Neuroscience 13, 266-271.
Redgrave, P., Prescott, T. J. and Gurney, K. (1999): The basal ganglia: a vertebrate solution to the selection problem? Neuroscience 89, 1009-1023.
Mink, J. W. and Thach, W. T. (1993): Basal ganglia Intrinsic circuits and their role in behavior. Current Opinion in Neurobiology 3, 950-957.
Gurney, K., Prescott, T. J. and Redgrave, P. (2001): A computational model of action selection in the basal ganglia I: A new functional anatomy. Biological Cybernetics 84, 401-410.
Gurney, K., Prescott, T. J. and Redgrave, P. (2001): A computational model of action selection in the basal ganglia II: Analysis and simulation of behaviour. Biological Cybernetics 84, 411-423.
Mink, J. W. (1996): The basal ganglia: Focused selection and inhibition of competing motor programs. Progress in Neurobiology 50, 381-425.
Squire, L. R., M. J., Bloom, McConnell, S.K., Roberts, J. L. Spitzer, N.C. and Zigmond,, F. E. (2003): Fundamental Neuroscience, Academic Press. Chapter 31