Eam 5: Basal ganglia Flashcards
(94 cards)
1
Q
The thalamus is the _____ to the _______-
A
grand central station gateway; neocortex, including M1
- The thalamus is like an eager puppy, anting to excite the cortex
2
Q
the output of the basal ganglia to the motor cortex is excitatory/inhibitory?
A
inhibitory
- In the motor system, the Basal Ganglia act as a variable gain “leash” on the motor thalamus
3
Q
In parkinson’s disease the (thalamic inhibition) leash is too _____ and in huntington’s disease the leash is too _____
A
tight; loose
4
Q
why does the motor cortex need the basal ganglia? (What NT is involved?)
A
it may not have enough juice to act on its own to cause movement
- Via direct and indirect pathways, the basal ganglia boosts intended motor programs and suppresses competing motor programs
5
Q
why are motor mistakes very risky to make?
A
they can be fatal
6
Q
where is the motor thalamus located relative to the BG and cortex?
A
between the BG and motor cortex
- 2 critical structures of the basal ganglia for skilled and directed movements with the limbs
7
Q
what roles does the BG play in modulation? (4)
A
- Movement
- Motivation
- Reward
- Cognition
8
Q
what is the body movement loop of the BG? (5)
A
- cortical input from the motor, premotor, and somatosensory cortex
- striatum which has the caudate and putamen
- palladium which has the lateral globus pallidus and internal segment
- ventral lateral and ventral anterior nuclei
- input to the motor, premotor, and supplementary motor cortex
9
Q
Putamen
A
movement of the body ⇒ skilled and directed movements
10
Q
caudate
A
movement of the eyes and thoughts ⇒ skilled and directed movements
11
Q
Ventral striatum
A
movement of emotions ⇒ also has nucleus accumbens
12
Q
Nucleus accumbens
A
is ground zero for drug addiction
13
Q
T/F the thalamus is part of the BG?
A
False it is not
14
Q
what is the striatum made up of?
A
the caudate and putamen
15
Q
what segments is the globus pallidus divided into?
A
external and internal
16
Q
Disinhibition
A
two negatives make a positive
- via the direct + indirect pathways, the basal ganglia boost intended motor programs and suppress competing motor programs
17
Q
what structures make up the basal ganglia? (4)
A
- striatum => caudate/putamen/nucleus accumbens
- globus pallidus
- substantia nigra
- sub thalamic nucleus
18
Q
which BG + thalamus structures are lateral to medial?
A
lateral = putamen => globus pallidus => thalamus = medial
19
Q
the globus pallidus represents the ______ of the basal ganglia
A
output
20
Q
what is the firing rate o the globus pallidus at rest? NT release? Effect?
A
high baseline firing rate releasing GABA on the thalamus and inhibiting it
21
Q
what BG structure has a very low baseline firing rate at rest? NT release?
A
the striatum which typically fires GABA on the globus pallidus
- the striatum is fairly quiet at rest with little spontaneous activity
22
Q
what happens when the striatum fires an action potential? For how long?
A
it transiently releases GABA on the GP which will stop releasing GABA on the VA/VL transiently
- The thalamus can then activate (disinhibited) the motor cortex which activates lower motor neurons
- generates movement transiently
23
Q
what is the direct (start) BG pathway? (W dopamine)
A
- the cerebral cortex releases glutamate to excite the striatum (caudate/putamen)
- the SNc releases dopamine on the striatum too and excites it even more
- the striatum releases inhibitory GABA on the Gpi
- the Gpi can no longer release GABA on the VA/VL
- the VA/VL can release excitatory NT on the motor cortex
24
Q
are cortical EPSPs enough to excite the direct pathway? Necessary/sufficient?
A
No
- they are necessary but not sufficient
- the substantia nigra is the dopamine releaser that impinge on the striatum to take the cells past threshold
25
where is the substantia nigra located?
in the midbrain as part of the brainstem
26
what happens to particular BG neurons in Parkinson's?
the substantia nigra pars compacta neurons die and there is a lack of neuromelnin seen at the SNc area
27
what are the two inputs to the striatum? NT?
cortex and midbrain (SNc)
- The cortex input are glutaminergic and midbrain provides dopamine
28
what areas of cortex do not give input to the striatum?
the primary visual and primary auditory cortex
29
where does the SNc get input from? (2)
- Medium spiny neurons of the striatum
- Raphe nucleus of the brainstem
30
what are the 2 striate-pallidal paths?
1. Direct pathway: D1 neurons in putamen/caudate ⇒ Gpi ⇒ VaVL (thalamus) ⇒ cortex
2. Indirect pathway: D2 neurons in putamen ⇒ Gpe ⇒ STN ⇒ Gpi ⇒ VA/VL ⇒ cortex
31
where are the medium spiny neurons?
the caudate and putamen
32
what type of NT output do the caudate and putamen medium spiny neurons have? receptors?
GABAergic; dopamine receptors
- D1 Coupled to Gs
- D2 coupled to Gi
- the output is NOT dopamine, they release GABA ⇒ they just have dopamine receptors
33
what is the basal activity of MSNs?
low activity
34
T/F the putamen has D1 and D2? Caudate? Output?
True; false
- caudate only has D1 but putamen has D1 and D2
- caudate sends D1 output to SNr and Gpi while putamen sends output to GPi and Gpe
35
what type of output does the globus pallidus have? Basal activity?
GABAergic neurons; High tonic activity
36
how many medium spiny neurons are there? what % of the dorsal and ventral striatum do they make up?
75 million; 75%
37
what neuron types send input to MSNs? (4)
- Cortex (glutamate)
- SNc (dopamine)
- Other MSNs (GABA)
- Local interneurons
38
what type of output do local interneurons send to MSNs?
GABA and Acetylcholine
39
What are the two output pathways (names) from the MSNs?
1. Striato-nigral pathway to SNr
2. Striato pallidal pathway
- Direct = GPi
- Indirect = GPe
40
what NT synapse on the MSNs dendritic shaft? (3)
- GABA
- acetylcholine from Raphe into brainstem
- some glutamate
41
T/F D1 and D2 receptors are on the same cell?
False they are not
42
what is the D1 pathway mechanism? End game?
D1 increases cAMP which increase PKA ⇒ end game is to close potassium channels and lead to depolarization
- Excitatory pathway
43
what is the D2 pathway mechanism?
D2 decreases cAMP and PKA ⇒ cause the opening of potassium channels
- Inhibitory pathway
44
where are dopaminergic neurons generally found?
the midbrain
45
what types of dopaminergic neurons are there in the midbrain? (2)
- Substantia nigra pars compacta (SNc)
- Ventral tegmental area (VTA)
46
where do dopaminergic neuron axons go?
Extend axons to many brain regions
47
______ converted to L-DOPA by ___________
Tyrosine; tyrosine hydroxylase
48
what puts dopamine into SVs?
vesicular monoamine transporter (VMAT)
49
how is dopamine taken up (reuptake) form the synapse?
- Reuptake into neurons and glia
- Na+ dependent transporter (DAT) => highly expressed on dopaminergic neurons
50
what is the site of action for amphetamine and cocaine?
where dopamine is reuptook
- DAT and neurons/glia
51
what degrades dopamine?
monoamine oxidase (MAO) and catechol O-methyltransferase (COMT)
52
what inhibits dopamine degradation?
phenelzine (MAOI)
53
what type of receptor does dopamine bind to?
G-protein coupled receptors
- Activate (D1R) or inhibit (D2R) adenylyl cyclase
54
what are the dopamine release pathways? (3)
dopamine goes everywhere and is unrelated to movement too
- mesolimbic
- mesocortical
- nigrostriatal
55
Mesolimbic
Pleasure and reward seeking behaviors
56
mesolimbic pathway
ventral tegmental area (VTA) ⇒ ventral striatum (nucleus accumbens (NAc)) and hippocampus
57
Mesocortical
cognition, memory, emotional behavior, learning
58
Mesocortical pathway
Ventral tegmental area (VTA) ⇒ cortex
59
Nigrostriatal
movement
60
Nigrostriatal pathway
Substantia nigra pars compacta (SNc) ⇒ dorsal striatum (caudate and putamen)
61
what is the indirect pathway without dopamine?
1. cerebral cortex sends glutamate and excites the D2 striatum MSNs
2. these release GABA on the Gpe which is inhibited
3. the Gpe stops releasing GABA on the sub thalamic nucleus
4. the STN can send activating NT to the Gpi
5. the Gpi sends GABA to the VA/VL resulting in reduced activity
6. the motor cortex does not initiate movement
62
what does dopamine do to the indirect and direct pathways?
dopamine overexcites the direct pathway and inhibits the indirect pathway ⇒ results in a huge boost to the thalamus to activate it
- the substanta nigra only releases dopamine and its effects are complementary which increases cAMP in direct vs decreasing cAMP in indirect pathway based on the MSN receptors
- the indirect pathway is inhibited because the MSN neuron doesn't release GABA on the Gpe which allows the Gpe to release GABA on the STN
63
who wins if both the direct and indirect pathway are activated without dopamine?
neither, locked in and cannot execute movement
- you are frozen ⇒ can't move
- if there is an intent in moving and both the direct and indirect pathways are activated at the same time
- D1 = excitatory ⇒ Gs
- D2 = inhibitory ⇒ Gi
64
what effect does the indirect BG pathway have with 2 extra synapses?
4-5 ms longer latency than direct path
- Latencies are amplified by the time one gets to the muscle
- so frozen and tremor leakage at rest ⇒ start-stop-start-stop cycle forever
65
what happens with leakage in the locked state?
depending on cortical drive and how many dopamine cells are killed, when you wipe out everything it's more difficult to not lock up
66
how is the center surround organized in the BG?
- The indirect pathway is more spatially diffuse ⇒ this overlaps with the direct pathway so it can shut down motor programs that want to do other things
- The direct pathway is the center pathway and more spatially restricted and it can punch through to drive the intended motor program
67
T/F some neurons are affected by both direct and indirect but indirect plays a stronger role laterally?
True
- it's not always identical cells affected
- lateral cells will mostly be activated by the indirect pathway
68
what is Parkinson's caused by? How do conditions change onset?
death of dopaminergic neuron in the SNc
- when there is a genetic mutation or TBI you get more damage to the cells and larger amount of cell death ⇒ rapid decline of neurons
- early onset genetic has the most lost, environmental has the second, and idiopathic PD has the least but all are below the motor symptoms threshold
69
at what point in SNc cell death do Parkinson symptoms appear?
Symptoms may only appear after >50% of neurons are dead
70
how does normal aging affect SNc neurons?
Neural, age related death of the SNc neurons occurs ⇒ you get some symptoms from this
- the system can compensate for modest lost of dopaminergic cells ⇒ drugs increase dopamine synthesis
71
what are Parkinson motor disease symptoms? (6)
- bradykinesia
- vocal symptoms
- rigidity and postural instability
- tremors
- walking or gait difficulties
- dystonia (repetitive muscle movements that twist body parts)
72
what are Parkinson non-motor disease symptoms? (5)
- mental/behavioral issues
- sense of smell
- sweating and melanoma
- gastrointestinal issues
- pain
73
what brain areas are involved in generating intended facial expression
Spontaneous facial expressions are from basal ganglia
- Basal ganglia dysfunction may cause masked face in parkinson’s disease
- Not due to depression
- Can still display some volitional facial expressions
74
Primary motor cortex
voluntary (volitional) facial movements
75
what does Parkinson do to the typical movement (direct + indirect) pathway?
No dopamine means intent in moving and both the direct + indirect pathways are activated leading to freezing
- Parkinsons reduces to the basic indirect + direct circuit without the dopamine input ⇒ can no longer modulate like before
- Attenuated dopamine = parkinsons
76
L-DOPA
treatment drug for Parkinson's disease that crosses the blood brain barrier then is converted to dopamine by SNc neurons
77
what does L-DOPA need to be used in combination with?
MAO or COMPT inhibitors
78
what does prolonged use of L-DOPA result in?
may cause the cells to either stop converting it to dopamine (in SNc) or to stop responding to dopamine (in striatum)
- Eventually the dopaminergic neurons all die and there are few/no remaining cells to convert L-DOPA into dopamine
79
what does neurotrophic (GDNF) do?
it can prolong survival of remaining SNc neurons
- Inject directly into brain
- Transplant stem cells that express GDNF
- there is also surgical ablation of the STN and deep brain stimulation of the STN or Gpi or other
80
how does deep brain stimulation work?
an electrode is placed into a patients brain going into the GP or putamen
- the current is passed through an electrode which can excite neurons
81
what are side effects of electrode stimulation?
you could stimulate the neurons you want or you could stimulate fibers in passage ⇒ extracellular stimulation can lead to axon excitation that have nothing to do with the cells you want to activate
- could also cause changes in astrocytes which modulate the release and reuptake of neurotransmitters
82
what does neuroimaging show us about electrode stimulation?
activation is somewhat random in the imaging of neurons
- Electrical stimulation can lead to monosynaptic excitation, prolonged inhibition and rebound excitation
- You get monosynaptic AP at the beginning but then you can get inhibition and rebound excitation
- it's unclear if its the monosynaptic action potential or the inhibition and rebound driving the circuits
83
why not electrically stimulate the thalamus?
off target effects
- don't go for thalamus because of damage to other thalamic nuclei, several cortical regions and ventricles
- All the thalamic nuclei are next to one another and electrical stimulation is messy
84
what effect does MRIs have on DBS?
MRIs can guide the electrode now
85
what pathway does Huntingtons disease affect?
turns off the indirect path only ⇒ hyper excites the thalamus
86
choreiform
doll like hyperkinetic movements
87
what is the genetic origin of Huntington's disease? What are fxns of HTT protein?
Caused by a single autosomal dominant gene mutation in the huntington gene
- Caused by CAG repeats (poly glutamine) in the huntingtin protein (HTT)
- HTT is expressed throughout the body
- Normal functions unclear ⇒ may include regulation of transcription and regulation of cytoskeleton based transport
88
what cognitive issues result from Huntingtons? how long do people typically live after diagnosis?
Cognitive dysfunction; death within 10-20 years
89
what amounts of CAG repeats cause Huntington disease?
- won't be affected below 36 repeats
- possible affect between 36-39 repeats
- 40+ repeats has full penetrance for disease status
90
what is the risk of passing Huntingtons on to offspring?
- below 50% or none with less than 36 repeats
- 50% above 36 repeats
91
what brains structure is mostly gone in Huntingtons disease? neurons?
striatum is mostly gone
- genetic death of medium spiny neurons in the indirect pathway ⇒ don't even have to worry about dopamine
- Direct pathway is unaffected
92
what brain structures change firing patterns due to Huntingtons disease?
The Gpe neurons are firing like crazy and the subthalamic nucleus gets shut down which leads to no drive of the rest of the inhibitory pathway ⇒ leading to the hyperkinetic movement
93
why is killing D2 cells worse than inhibiting them?
Gpi cells extra inhibited when killing D2 cells vs modest Gpi excitation when inhibiting D2 cells
- inhibition of firing does not necessarily mean zero action potentials
- the STN at modest inhibition can still act in the indirect pathway part of the time to decrease movements
94
What is attenuated dopamine related to?
Parkinson’s disease
