Basal Ganglia Flashcards
The basal ganglia plays a role in modulating what 3 things?
Movement
Motivation
Reward
From what 2 areas of the brain does the basal ganglia receive inputs? For each of these regions, which neurotransmitter do their axons release into the basal ganglia?
Cortex (glutamate)
Substantia nigra pars compacta (dopamine)
The basal ganglia includes the dorsal and ventral ____ as well as the internal and external ___ ___.
Striatum
Globus pallidus
The dorsal striatum of the basal ganglia includes which 2 subregions?
Caudate
Putamen
Is the striatum located on one or both sides of the brain?
Both
The caudate of the dorsal striatum is located ____ to the putamen, and the globus pallidus is located _____ to the putamen.
Superior (closer to top of brain)
Medial (closer to middle of brain)
The thalamus is located ____ to the basal ganglia.
Medial (closer to middle of brain)
The ventral striatum is also called the ___ ___. It contains what brain region important for sensation?
Nucleus accumbens
Olfactory tubercle
The dorsal striatum is most important for what basal ganglia function? The ventral striatum is most important for what 2 other basal ganglia functions?
Dorsal striatum- movement
Ventral striatum- reward and emotion
The thalamus, globus pallidus, and both top and bottom parts of the caudate can only be seen with a (rostral/caudal) coronal section of the brain. In this section, the caudate is seen as both superior to the ___ and caudal to the ___ ___.
Caudal
Putamen
Globus pallidus
What are the 2 motor loop striatal pathways called? What are the 2 non-motor loop straital pathways called?
Motor loop: body movement loop, oculomotor loop
Non-motor loop: prefrontal loop, limbic loop
Why are the striatal pathways called loops?
For each pathway, information coming from thalamus (and thus basal ganglia) is sent back to the cortex to modify its signaling
Limbic loop:
1) What 2 cortical areas send information to the striatum?
2) What striatal area receives information from the cortex and sends information to the pallidum?
3) What area of the pallidum receives information from the striatum and sends information to the thalamus?
4) What area of the thalamus receives information from the pallidum and sends information back to the cortex?
5) What does the limbic loop control?
1) Orbitofrontal cortex Anterior cingulate 2) Ventral striatum 3) Ventral pallidum 4) Mediodorsal nucleus (MD) 5) Emotion and motivated behavior
Prefrontal loop:
1) What cortical area sends information to the striatum?
2) What striatal area receives information from the cortex and sends information to the pallidum?
3) What 2 areas of the pallidum receive information from the striatum and send information to the thalamus?
4) What 2 areas of the thalamus receive information from the pallidum and send information back to the cortex?
5) What does the prefrontal loop control?
1) Dorsolateral prefrontal cortex
2) Anterior caudate
3) Globus pallidus internal (Gpi)
Substantia nigra pars reticulata (SNr)
4) Mediodorsal (MD) and ventral anterior (VA) nuclei
5) Cognition
Oculomotor loop:
1) What 2 cortical areas send information to the striatum?
2) What striatal area receives information from the cortex and sends information to the pallidum?
3) What 2 areas of the pallidum receive information from the striatum and send information to the thalamus?
4) What 2 areas of the thalamus receive information from the pallidum and send information back to the cortex?
5) What does the oculomotor loop control?
1) Posterior parietal cortex Prefrontal cortex 2) Caudate 3) Globus pallidus internal (Gpi) Substantia nigra pars reticulata (SNr) 4) Mediodorsal (MD) and ventral anterior (VA) nuclei 5) Eye movement
Body movement loop:
1) What 3 cortical areas send information to the striatum?
2) What 2 striatal areas receive information from the cortex and send information to the pallidum?
3) What area of the pallidum receives information from the striatum and sends information to the thalamus?
4) What 2 areas of the thalamus receive information from the pallidum and send information back to the cortex?
1) Primary motor, premotor, somatosensory
2) Putamen
Caudate
3) Globus pallidus internal (Gpi)
4) Ventral lateral (VL) and ventral anterior (VA) nuclei
The cortical neurons sending axons to the striatum are ____ (neurotransmitter released) while the SNc neurons sending axons to the striatum are _____ (other neurotransmitter released).
Glutamatergic
Dopaminergic
Output from the basal ganglia can take 1 of 2 main pathways. What are the 2 pathways? Which one has direct and indirect subpathways?
Striato-pallidal (has direct and indirect)
Striato-nigral
Output from basal ganglia via striato-nigral pathway:
Neurons with cell bodies in the ____ synapse on neurons with cell bodies in the ____ ____ ____ ____ (___). These neurons synapse on neurons with cell bodies in the ___ ___. What type of movement does this pathway control?
Caudate
Substantia nigra pars reticulata (SNr)
Superior colliculus
Eye movement
What is the difference between the direct and indirect versions of the striato-pallidal pathway?
The direct pathway routes directly into the globus pallidus internal (Gpi) without extra synapses
Output from basal ganglia via DIRECT striato-pallidal pathway:
Neurons will cell bodies in the ____ or ____ synapse on neurons with cell bodies in the ___ ___ ___ (___).
Caudate
Putamen
Globus pallidus internal (Gpi)
Output from basal ganglia via INDIRECT striato-pallidal pathway:
Neurons with cell bodies in the ___ synapse on neurons with cell bodies in the ___ ___ ___ (__). These neurons synapse on neurons with cell bodies in the ___ ___ (___). Then, these neurons synapse on neurons with cell bodies in the ___ ____ ___ (__).
Putamen Globus pallidus external (Gpe) Subthalamic nucleus (STN) Globus pallidus internal (Gpi)
Neurons coming from the globus pallidus internal (Gpi) via the striato-pallidal pathway (both direct and indirect) synapse on neurons in the ___ ___ and ___ ____ nuclei of the ____.
Ventral anterior (VA) Ventral lateral (VL) Thalamus
The putamen neurons in the direct and indirect striato-pallidal pathways express GPCRs for what neurotransmitter?
Dopamine
The putamen neurons in the direct striato-pallidal pathways express what dopamine GPCR? What G protein is this GPCR coupled to, and what effect does activation of this GPCR have on adenylyl cyclase? The putamen neurons in the indirect striato-pallidal pathway express what other dopamine GPCR? What G protein is this GPCR coupled to, and what effect does activation of this GPCR have on adenylyl cyclase?
Direct: D1 (Gs; activates adenylyl cyclase)
Indirect: D2 (Gi; inhibits adenylyl cyclase)
Medium spiny neurons in the DIRECT striato-pallidal pathway express ___ receptors and are (activated/inhibited) by exposure to dopamine.
D1
Activated
The caudate neurons in the striato-nigral pathway express what dopamine GPCR? What G protein is this GPCR coupled to, and what effect does activation of this GPCR have on adenylyl cyclase?
D1
Gs
Activates adenylyl cyclase
In the INDIRECT pathway of the basal ganglia, the striatum sends information directly to the _______.
Globus pallidus external (Gpe)
Activation of a D1 receptor causes activation of G alpha __, which causes (increased/decreased) activity of ___ ___, which leads to an (increase/decrease) of ____, which then leads to (increased/decreased) excitability of the neuron.
G alpha s Increased Adenylyl cyclase Increase cAMP Increased
Activation of a D2 receptor causes activation of G alpha ___, which causes (increased/decreased) activity of ___ ___, which leads to an (increase/decrease) of ___, which then leads to (increased/decreased) excitability of the neuron.
G alpha i Decreased Adenylyl cyclase Decrease cAMP Decreased
The input neurons of the basal ganglia are located in the ___ and ____. They are called ___ ___ ___ and can express (D1/D2/either) receptors. The input neurons are those of what 2 pathways?
Caudate Putamen Medium spiny neurons Either Direct and indirect striato-pallidal pathways
The caudate and putamen input neurons of the basal ganglia express a (low/high) level of ____ activity. What does this mean?
Low
Basal
Without any input, will fire at a low level
The output neurons of the basal ganglia are located in the ___ ___ (both ___ and ___). They express a (low/high) level of ___ activity.
Globus pallidus
External and internal
High
Tonic
What neurotransmitter do the caudate and putamen input neurons of the basal ganglia produce? What neurotransmitter do the globus pallidus output neurons of the basal ganglia produce?
GABA for both
Medium spiny neurons are called so because their cell bodies are ____ in size compared to other cell bodies in that brain region and their dendrites are covered in ___ ____.
Medium
Dendritic spines
The medium spiny neurons receive inputs from:
1) ____ (releases ____)
2) ____ ___ ___ ___ (___, which releases ____)
3) Other ___ ___ ___ (release ____)
4) Local ____ (release ____ or ___)
1) Cortex Glutamate 2) Substantia nigra pars compacta (SNc) Dopamine 3) Medium spiny neurons GABA 4) Interneurons GABA Acetylcholine
Medium spiny neurons in the dorsal striatum send out axons via what 3 pathways? What are the first destinations of these pathways?
Striato-nigral pathway (SNr)
Direct striato-pallidal pathway (Gpi)
Indirect striato-pallidal pathway (Gpe)
Medium spiny neurons of the caudate and putamen have synapses from the cortex, substantia nigra pars compacta (SNc), and interneurons on their ___ ___. The glutamate synapse from the ___ occurs where on this structure? The dopamine synapse from the ____ occurs what 2 other places on this structure? The GABA and acetylcholine synapses from the _____ occur where on the structure?
Dendritic spines Cortex Head of dendritic spine Substantia nigra pars compacta (SNc) Dendritic shaft Neck of dendritic spine Interneurons Dendritic shaft
Dopamine is made in what 2 regions of the midbrain?
Substantia nigra pars compacta (SNc)
Ventral tegmental area
Dopamine is packaged into synaptic vesicles by the ___ ____ ____ (___).
Vesicular monoamine transporter (VMAT)
Dopamine is removed from synapses what 2 ways? What molecule mediates the first removal mechanism, and what 2 molecules mediate the second?
Reuptake- Na+ dependent transporter (DAT)
Degradation- monoamine oxidase (MAO), catechol-O-methyltransferase (COMT)
What is the name of the enzyme that makes dopamine?
Tyrosine hydroxylase
Tyrosine hydroxylase is highly expressed in the ____ and its mRNA is highly expressed in the cell bodies of the ___ ___ ___ ___ (___).
Striatum
Substantia nigra pars compacta
Basal ganglia regulation of VA/VL of thalamus (part 1):
1) Neurons of the cortex can release what neurotransmitter onto what 4 brain regions? Is the effect of neurotransmitter release inhibition or activation of these regions?
2) Neurons of the substantia nigra pars compacta can release what neurotransmitter onto what 2 brain regions? For each of the regions, what is the effect of neurotransmitter release?
1) Glutamate Caudate Putamen Subthalamic nuclei Thalamus Activation 2) Dopamine Caudate Putamen Caudate- activation (D1 receptors only) Putamen- activation or inhibition (D1 and D2 receptors)
Basal ganglia regulation of VA/VL of thalamus (part 2):
1) The caudate contains neurons with what dopamine receptor? What neurotransmitter do they release, and in what brain region do they synapse? Is the effect of neurotransmitter release activation or inhibiton?
2) The putamen contains neurons with what dopamine receptors? What neurotransmitter do they release? Where do the neurons of the direct path release their neurotransmitter, and where do the neurons of the indirect path release their neurotransmitter? Is the effect of neurotransmitter release activation or inhibition?
1) D1 GABA GPi Inhibition 2) D1 or D2 GABA Direct (D1): GPi Indirect (D2): GPe Inhibition
Basal ganglia regulation of VA/VL of thalamus (part 3):
1) Neurons of the GPe release what neurotransmitter and synapse in what brain region? Is the effect of neurotransmitter release activation or inhibition? Do these neurons display a transient or tonic level of activity? The neurons of the second brain region synapse in what other brain region and release what neurotransmitter? Is the effect of neurotransmitter release activation or inhibition?
2) Neurons of the GPi release what neurotransmitter and synapse in what brain region? Is the effect of neurotransmitter release activation or inhibition? Do these neurons display a transient or tonic level of activity?
1) GABA Subthalamic nuclei (STN) Inhibition Tonic GPi Glutamate Activation 2) GABA VA/VL of thalamus Inhibition Tonic
Basal ganglia regulation of VA/VL of thalamus (part 4):
Neurons of the VA/VL of the thalamus release what neurotransmitter and synapse in what brain region? Is the effect of neurotransmitter release activation or inhibition?
Glutamate
Motor cortex
Activation
The striatum gets input from all cortical areas except for which 2?
Primary visual
Auditory cortex
In the basal ganglia regulation of VA/VL, which brain regions show tonic activity? Which show transient activity?
Tonic: GPi, GPe
Transient: all others
In the absence of transient input from the striatum, (transient/tonic) activity of the GPi will (activate/inhibit) VA/VL of the thalamus and thus (increase/reduce) motor activity.
Tonic
Inhibit
Reduce
Transient inputs from the direct and indirect striato-pallidal pathways have (the same/opposite) effects on VA/VL of the thalamus.
Opposite
When D1 MSNs of the direct path are activated, the effect is to (activate/inhibit) GPi through release of ____. Since GPi neurons release ____, the total effect on the VA/VL of the thalamus is (activation/inhibition).
Inhibit
GABA
GABA
Activation (lower levels of inhibition)
When D2 MSNs of the indirect path are activated, the effect is to (activate/inhibit) GPe through release of ____. The neurons of GPe then release (more/less) ____ onto the STN, causing (activation/inhibition) of this region. The neurons of the STN then release (more/less) ____ onto the GPi, causing (activation/inhibition) of this region. The GPi neurons then release (more/less) ____ onto the VA/VL of the thalamus, for a total effect of (activation/inhibition).
Inhibit GABA Less GABA Activation More Glutamate Activation More GABA Inhibition
In the example of optogenetic stimulation of mice using blue light, what type of MSNs were being activated? What was the effect on movement?
D2
Inhibition
Transient release of dopamine (increases/decreases) activity of VA/VL of the thalamus.
Increases
1) Dopamine release from the SNc (increases/decreases) activity of the D1 MSNs.
2) This causes (increased/decreased) release of ____ onto the GPi for an effect of (activation/inhibition).
3) The GPi then releases a(n) (increased/decreased) amount of ___ onto the VA/VL of the thalamus for an effect of (activation/inhibition).
4) The VA/VL of the thalamus then releases a(n) (increased/decreased) amount of ___ onto the motor cortex, for a total effect of (activation/inhibition).
1) Increases
2) Increased
GABA
Inhibition
3) Decreased
GABA
Activation
4) Increased
Glutamate
Activation
1) Dopamine release from the SNc (increases/decreases) activity of the D2 MSNs.
2) This causes (increased/decreased) release of ___ onto the GPe for an effect of (activation/inhibition).
3) The GPe releases a(n) (increased/decreased) amount of ___ onto STN for an effect of (activation/inhibition).
4) The STN releases a(n) (increased/decreased) amount of ___ onto the GPI for an effect of (activation/inhibition).
5) The GPi then releases a(n) (increased/decreased) amount of ___ onto the VA/VL of the thalamus for an effect of (activation/inhibition).
6) The VA/VL of the thalamus then releases a(n) (increased/decreased) amount of ___ onto the motor cortex, for a total effect of (activation/inhibition).
1) Decreases
2) Decreased
GABA
Activation
3) Increased
GABA
Inhibition
4) Decreased
Glutamate
Inhibition
5) Decreased
GABA
Activation
6) Increased
Glutamate
Activation
Disinhibition of VA/VL always involves:
A) Increased activity of GPe
B) Dopamine activation of the DIRECT pathway
C) Reduced activity of GPi
D) Cortical activation of the INDIRECT pathway
C) Reduced activity of GPi
3 symptoms of Parkinson’s disease:
1) _____, or decreased ____
2) ____, or slowed ability to start and continue ____ along with impaired ability to adjust the body’s _____
3) ____ gait once moving, seen as a _____ movement that may (increase/decrease) in speed
1) Hypokinesis Decreased movement 2) Bradykinesis Movements Posture 3) Fenestrated Shuffling Increase
What causes Parkinson’s disease?
Death of dopaminergic neurons in SNc
What percentage of SNc dopaminergic neurons must be dead before Parkinson’s symptoms appear?
80%
What is the normal age of onset of Parkinson’s disease? What is the effect of traumatic brain injury on development of Parkinson’s symptoms? At what age do people who have suffered traumatic brain injury develop Parkinson’s?
60-70 years old
Symptoms develop earlier
As early as 40 years old
Does death of dopaminergic neurons in the SNc only occur with Parkinson’s, or can it occur naturally as a result of aging?
Can occur naturally as a result of aging
Most cases of Parkinson’s are idiopathic. What does that mean?
They have no known cause
A small percentage of Parkinson’s cases are caused by ____ ____. In these cases, disease onset is at an (earlier/later) age.
Genetic mutations
Earlier
What is the most well studied of Parkinson’s-related genes? Is its function known, and if so, what is it?
SNCA (alpha-synuclein)
Function is unknown
Two other known Parkinson’s genes are ___, which is involved in ___ degradation, and ____, which regulates ____ production or breakdown.
PRKN (parkin)
Protein
LRRK2 (leucine-rich repeat kinase 2)
Mitochondrial
In Parkinson’s, the protein ___ -____ aggregates and accumulates in ____ ____ in ____ (cell type). Is the reason for the aggregation known?
Alpha-synuclein
Lewy bodies
Neurons
No
What type of neurons are particularly sensitive to death in Parkinson’s?
Dopaminergic
Are any of the Parkinson’s related genes neuron specific?
No
How do the SNc neurons appear in color naturally? How would the SNc of a person without Parkinson’s differ in appearance from the SNc of a person with Parkinson’s?
Dark (thus “nigra” in “substanatia nigra pars compacta”)
Person without Parkinson’s: SNc is dark
Person with Parkinson’s: SNc is lighter
In Parkinson’s, a loss of dopamine has what effect on the VA/VL of the thalamus? What effect does this have on the motor cortex? What is the symptom seen from the combined effect?
VA/VL is overly inhibited (decreased activity)
Activity of motor cortex is decreased
Reduced movement (hypokinesis)
Activity of brain regions in Parkinson’s disease (normal, none, reduced, greatly reduced, increased, or greatly increased):
1) Cortex
2) SNc
3) D1 MSNs
4) D2 MSNs
5) GPe
6) STN
7) GPi
8) VA/VL
9) Motor cortex
1) Normal
2) None
3) Reduced
4) Increased
5) Reduced
6) Increased
7) Greatly increased
8) Greatly reduced
9) Reduced
One drug treatment that has been used for Parkinson’s is _-___, a precursor for ____ that can cross the ___ ___ ___ and then be converted to ___ by ____ ___ ___ ___ (___) neurons.
L-DOPA Dopamine Blood brain barrier Dopamine Substantia nigra pars compacta (SNc)
L-DOPA is often used in combination with inhibitors for what dopamine degradation enzymes?
MAO
COMT
Prolonged use of L-DOPA can cause what to happen in the SNc? The striatum? Eventually, what happens to the neurons of the SNc as Parkinson’s progresses? What does that do for the ability to convert L-DOPA to dopamine? What happens to the progression of Parkinson’s at this point? Thus, is L-DOPA a good long-term solution for Parkinson’s?
SNc- neurons stop converting L-DOPA to dopamine
Striatum- neurons stop responding to dopamine
SNc neurons die and thus cannot convert L-DOPA to dopamine
Progression worsens
No
Treatment with what neurotrophin has been shown to have what effect on SNc neurons in Parkinson’s? What 2 methods of neurotrophin delivery have been tried? Has this treatment been shown to be effective in treating Parkinson’s? Is it considered to be a standard of care?
GDNF Prolong survival of SNc neurons Direct injection into brain Transplantation of GDNF expressing stem cells Yes No
Surgical ablation of what brain region has also been tried in Parkinson’s?
STN
What has been the most promising treatment for Parkinson’s? How does it work?
Deep brain stimulation
Stimulating desired brain region with electrode
What area of the brain is usually targeted for deep brain stimulation for treatment of Parkinson’s?
STN
A study of deep brain stimulation for Parkinson’s suggested that rather than stimulating the STN, deep brain stimulation of this area actually works on ____ axons from the ___ ___ cortex that pass near the STN on their way to the ___ ___.
Corticospinal
M1
Motor
Spinal cord
Increasing activity of the (direct/indirect) striato-pallidal pathway can reverse many Parkinson’s symptoms.
Direct (D1)
In the Parkinson’s experiment using mice, Parkinson’s symptoms were induced by treating the mice’s neurons that projected from the ___ ___ ___ ___ (__) to the ____ with the drug __-_____ (__-___). What was the effect on these neurons?
Substantia nigra pars compacta (SNc)
Caudate
6-hyrdroxydopamine (6-OHD)
Killed them
In the Parkinson’s experiment using mice, the D1 neurons of the caudate were optogenetically modified so that blue light would have what effect on them?
Activation
In the Parkinson’s experiment using mice, higher incidences of what 2 types of movement were considered to be “normal” (i.e. not Parkinsonian) and higher incidence of what type of movement was considered to be “abnormal” (i.e. Parkinsonian)?
Normal: walking and fine movement
Abnormal: freezing
In the Parkinson’s experiment using mice, killing the neurons from the SNc had what effect on movement? Activating the D1 neurons of the caudate had what effect on movement? What was the conclusion of this experiment?
Killing neurons from SNc increased abnormal movement (freezing)
Activating the D1 neurons of the caudate restored normal movement
Activating D1 neurons of caudate can reverse Parkinson’s symptoms
Parkinson’s disease is associated with:
A) Increased inhibition of VA/VL
B) Increased activity of the INDIRECT pathway
C) Decreased activity of the DIRECT pathway
D) More than one of the above
D) More than one of the above (all are true)
MPTP is a side product of synthesizing what drug? It is converted to ____ by ___-__. What does the converted product do to dopaminergic neurons? What is the effect on the person who took the drug?
Heroin MPP+ MAO-B Kills them Person cannot move
Why is it that giving rodents MPTP didn’t cause them to freeze up, but giving humans or primates MPTP does?
Rodents don’t have MAO-B
What is the name of the type of viral encephalitis that occurred in many parts of the world around 100 years ago? What was this disease also known as? What were its 2 main symptoms?
Encephalitis lethargica
Sleeping sickness
Lethargy, weak eye muscles
How was encephalitis lethargica similar to Parkinson’s? How was it later treated? Did the treatment work long-term?
Activated same hypokinetic pathways in basal ganglia
L-DOPA
No
2 symptoms of Huntington’s disease:
1) _____ movements referred to as ____
2) ____ dysfunction
Hyperkinetic
Choreiform
Cognitive
A person with Huntington’s disease will likely die how many years after onset of symptoms?
10-20 years
Huntington’s disease is caused by an ___ ___ gene mutation in the ____ gene (abbreviated ____). What triplet code is repeated highly in this disease and what protein does it code for?
Autosomal dominant (chromosome other than X or Y) Huntington HTT CAG Glutamine
Are repeats of CAG normal in the Huntington gene? If so, what makes CAG repeats cause Huntington’s disease?
Yes
Too many repeats
A greater number of CAG repeats in the Huntington gene means what for risk of disease in subsequent generations and onset of disease?
Greater risk of disease in subsequent generations
Earlier onset of disease
Where is the Huntington gene (HTT) expressed? 2 functions of this gene are regulation of ____ and ____-based transport. What do mutant forms of this protein make?
All over the body
Transcription
Cytoskeleton
Aggregates
What neurons of which area of the striatum are killed off in Huntington’s disease?
D2 MSNs of putamen
Activity of brain regions in Huntington’s disease (normal, none, reduced, greatly reduced, increased, or greatly increased):
1) Cortex
2) SNc
3) D1 MSNs
4) D2 MSNs
5) GPe
6) STN
7) GPi
8) VA/VL
9) Motor cortex
1) Normal
2) Normal
3) Normal
4) None
5) Increased (no inhibition from GABA-releasing D2 MSNs)
6) Reduced
7) Reduced
8) Greatly increased
9) Greatly increased
Huntington’s disease is associated with:
A) Increased inhibition of VA/VL
B) Decreased activity of the INDIRECT pathway
C) Decreased activity of the DIRECT pathway
D) More than one of the above
B) Decreased activity of the INDIRECT pathway
1) Less than ____ CAG repeats in the HTT gene is considered to be normal (i.e. no risk for Huntington’s disease).
2) ___-___ CAG repeats puts the person at intermediate risk. Will a person with intermediate risk develop Huntington’s? What is the percent likelihood of their offspring developing Huntington’s?
3) ___-___ CAG repeats means that the person will have reduced penetrance. They (may or may not/will) develop Huntington’s. What is the percent likelihood of their offspring developing Huntington’s?
4) ___ or more CAG repeats means that the person will have full penetrance. They (may or may not/will) develop Huntington’s. What is the percent likelihood of their offspring developing Huntington’s?
1) 26
2) 27-35
No
Elevated, but less than 50%
3) 36-39
May or may not
50%
4) 40
Will
50%
