Title: BV4 / Modul 3 / Basal ganglia in motor control

Q: What are the basal ganglia?
A: The basal ganglia are a group of subcortical nuclei that are highly connected

Q: What have teh basal ganglia been implicated in?
A: The basal ganglia have been implicated in a wide variety of motor functions

Q: Which motor functions have the basal ganglia been implicated in?
A: - Planning, initiation and execution of movements
- Performance of learned movements
- Motor learning

Q: What is one way of learning how motor-brain functiosn are doing?
A: One way of learing how motor-brain regions are doing is by understanding what happens when it doesnt function properly

Q: What can be the cause of movement disorders?
A: Movemnet disorders - the spectrum of abnormal movements caused by disorders of the basal ganglia

Q: What are ex. of movement disorders connected to teh basal ganglia?
A: - Neurodegereative and neurodevelopmental disorders
- Hypokinetic and hyperkinetic movement disorders
- Abnormalities in muscle tone and motor control

Q: What is a common ex. of movement disorder connected to teh basal ganglia?
A: Parkinson's disease and parkinsonism

Q: What type of movement do we have in PD?
A: In parkinsons we have too little movement - hypokinetic

Q: What type of movement do we have in Huntington's disease?
A: In Huntington's we have too much movement - hyperkinetic

Q: Which are the components of the basal ganglia?
A: - Caudate nucleus
- Putamen
- Globus pallidus (interna/externa)
- Subthalamic nucleus
- Substantia nigra
- (Thalamus)
- (Cerebral cortex)

Q: WHich sub regions can globus palidus be divided into?
A: - External (lateral)
- Internal (medial)

Q: WHich sub regions can thalamus be divided into?
A: - Ventral anterior
- Ventral lateral

Q: What does (corpus) striatum consist of?
A: - Putamen
- Caudate nucleus

Q: WHich sub regions can substantia nigra be divided into?
A: - Pars compacta (SNc) - Dopaminergic region
- Pars reticulata (SNr) - GABAergic region

Q: WHich is the dopaminergic region of substantia nigra?
A: Pars compacta (SNc) - dopamine (D1+/D2-)

Q: WHich is the GABAergic region of substantia nigra?
A: Pars reticulata (SNr) - GABA (-)

Q: Which -ergic are most of the nuclei in teh basal ganglia?
A: Most of the basal ganglia are nuclei that are gabaergic, in contrast to the thalamus and the cortex that are glutamatergic (they provide glutamatergic imput to the basal ganglia)

Q: What will GABAergic nuclei do?
A: The cells will release GABA on ther targets and inhibit them

Q: Which are the exceptions to the claim that most of teh nuclei in the basal ganglia are GABAergic?
A: - The STN which is an exciatory structure in the basal ganglia
- The substantia nigra pars compacta (SNc) is a dopaminergic center, the cells there will produce dopamin and relases on their target

Q: Which ergic is caudate nucleus?
A: GABAergic (-)

Q: Which ergic is putamen?
A: GABAergic (-)

Q: Which ergic is the subthalamic nucleus?
A: Glutamatergic (+)

Q: Which ergic is the cerebral cortex?
A: Glutamatergic (+)

Q: Which ergic is the thalamus?
A: Glutamatergic (+)

Q: Which ergic is GPe?
A: GABAergic (-)

Q: Which ergic is GPi?
A: GABAergic (-)

Q: Which ergic is SNc?
A: Dopaminergic (D1+/D2-)

Q: Which ergic is SNr?
A: GABAergic (-)

Q: Where does output from the basal ganglia happen?
A: - Globus pallidus interna (GPi)
- Substantia nigra pars reticulata (SNr)

Q: How is the output from the SNr and GPi projected, briefly?
A: These
2 structures are projecting out of the basal ganglia and providing information
form the BG to their targets

Q: WHich is the main input structure of the basal ganglia?
A: Striatum

Q: From where does the striatum receive input?
A: It
recieves its input from outside the BG particually from cortex and thalamus

Q: How is the information form the cortex (and thalamus) being conveyed to the striatum?
A: - The information from cortex is being conveyed in an organised fashion into the striatum so there are region specialised in processing information from the cortex, and these will project into specific regions within the striatum - and this info will be conveyed to a certain area within the striatum that deals with that same info
  - Like ex. one region deals with movement of the head
- The same applies for info from the thalamus into the striatum

Q: What is the functional organisation/subdivision in the striatum of info being processed?
A: We have special regions dealing with it, such as:
- Associative region (for associative info)
- Sensorimotor region (for sensorimotor info)
- Limbic region (for limbic info)

Q: What is the main cell population witin the striatum?
A: Striatum Medial Spinal Neurons (MSN's)

Q: What does MSN's stand for?
A: Striatum Medial Spinal Neurons

Q: What else can the MSN's be called?
A: Can also be called striatum projection neurons or SPN's

Q: How big a part of the striatum does the MSN's constitute?
A: MSN's constitute for 95% of striatal cells, they are the majority of the cells

Q: WHat is characteristic for the MSN's?
A: Anatomically they are characterized by having very dense spines on their dendrites which gives them their name

Q: WHich conductances are the membranes of MSN's dominated by?
A: The membrane of MSN's are dominated by K+ conductances, these are the Kir-channels, the K+  inward rectifiers

Q: What is meant by Kir conductance?
A: K+ inward rectifiers

Q: What do the Kir-channels do?
A: They "clam/claim/clamp" the membrane potential
of MSN's to the reversal potential for potassium, meaning that
MSN's are very hyperpolarized, so we need to supply excitatory input to these
cells to get them to the threshold for spiking

Q: How are the Kir-channels special?
A: These channels are very special since they are open at negative membrane potential at very hyperpolarized membrane potentials and they are closeding down in more depolarized membrane potentials, that would ofc change the input resistance of the cell - this is what we see when we are  plotting it

Q: When are the Kir channels open?
A: At
negative membrane potentials, at very hyperpolarized membrane potentials

Q: When are the Kir channels closed?
A: They
are closing down in more depolarized membrane potentials, that would ofc
change the input resistance of the cell

Q: Which NT is particulary important when talking about MSN's?
A: Dopamine

Q: How does dopamine act?
A: Dopamine is a neuromodulator that acts by binding to differnet dopamine receptors

Q: Which groups of dopamine receptors are there?
A: - D1-like dopamine receptors
- D2-like dopamine receptors

Q: What are D1-like dopamine receptors?
A: D1-like dopamine receptors are excitatory, including D1 and D5

Q: What are D2-like dopamine receptors?
A: D2-like dopamine receptors are inhibitory, including D2, D3, D4

Q: What are all dopamine receptors coupled to?
A: G-protein coupled

Q: WHich G-protein are D2-like
dopamine receptors coupled to?
A: Gi couples

Q: WHich G-protein are D1-like dopamine receptors coupled to?
A: Gs coupled

Q: What do MSN's express and what can that be used for?
A: MSn's express dopamine receptors and can be subdivided into groups depedning on their expression of their dopamine receptors

Q: WHich grops of MSN's are there?
A: - One group expresses D1
- Another group expresses the D2

Q: Where are the D1-MSN's and D2-MSN's projected respectively?
A: These D1-MSN's and the D2-MSN's will be projected to different structures within the BG

Q: To where do D1-MSN's project?
A: - SNr
- GPi
(The outputs of the BG)

Q: What connetion do we have with the D1-MSN's?
A: Here we have a connection between the input structure, the striatum, and the output structure of the basal ganglia

Q: To where do D2-MSN's project?
A: GPe

Q: DO we have a connection of the projections of the D2-MSN's?
A: D2-expressing MSN's will project to the external part of the globus pallidus (Gpe)
- So here we dont have a direct connection between inputs and outputs

Q: What is the pathway mediated by the D1-expressing MSN's?
A: The direct (GO) pathway, because there is a direct connection between input and output

Q: Why is the pathway called the direct (GO) pathway?
A: Because there is a direct connection between input and output
- The D1- expressing MSN's from the striatum (input) will project to the SNr and the GPi (output)

Q: What is the pathway mediated by the D2-expressing MSN's?
A: The indirect "STOP" pathway

Q: Why is the pathway called the indirect "STOP" pathway?
A: Because there is no direct connection between output and input
- The D2-expressing MSN's from the Striatum (input) will project towards the GPe

Q: What will both populations of MSN's receive (both D1- and D2-expressing MSN's)?
A: Both these populations receive input from the cortex, these are the pyramidal cells of the cortex, whithout necessarily differences in these input cells

Q: From which cells in the cortex do the MSN's receive their input?
A: Pyramidal cells

Q: What other celltype except for the MSN's is there in the Striatum and how big a part does it constitute?
A: The other 5% are striatal interneurons

Q: What are striatal interneurons?
A: Cells that operate locally in the striatum and don't project outside of the striatum

Q: What can the striatal interneurons express?
A: - Diverse molecular markers
- Electrophysiological properties
- Connectivity patterns to MSN's

Q: What is the functions of striatal interneurons?
A: They are there to influence the activity of the MSN's

Q: What can be said about the -ergic properties of the cells (interneurons) in the striatum?
A: Most of the interneuorns in the striatum are GABAergic but there are also cells that are kolinergic interneurons

Q: What can generally be said about the microcircuitry in the striatum?
A: If we think of the microcircuitry within the striatum we have the MSN's of both types, and they are surrounded by different types of interneurons that will be connected to them and modulate their activity

Q: Where does input to the stratum come from?
A: From outside of the striatum:
- cerebral cortex
- Thalamus

Q: Where are the D1- and D2-expresssing MSN's located respectively?
A: D1 and D2-expressing MSN's are not confied to certain regions but are distributed within the striatum

Q: Which types of MSN's do we have in terms of pathways?
A: We have 2 types of MSN's: the ones forming the direct pathway and the ones forming the indirect pathway and their different projection targets

Q: What are the targest of the D1-expressing MSN's?
A: The GPi and the SNr are the targets of D1-expressing MSN's in the direct pathway from the striatum

Q: What are the targest of the D2-expressing MSN's?
A: The terminals for the D2-expressing MSN's are in the GPe, which we suspect due to the indirect pathways, but we dont see terminals for these for the SNr and the GPi

Q: What does the baseline activity look like in the putamen or the striatum when we stick in an electrode?
A: If stick an extracellular electrode in the  putamen or in the striatum we can see very scarce firing

Q: What does the baseline activity look like in the GPi, GPe, STN or the SNr when we stick in an electrode?
A: If we do it in the Gpi, STN, SNr or the Gpe we can see that there is a lot of spontaneous firing - they are quite actve
- So, these regions are highly active and fire spontaneously while the striatum is very quiet

Q: What are the input and output structures of the BG?
A: The main input structure is the striatum and the output structures are the SNr and the GPi

Q: What can be said about the firing in the SNr and the GPi?
A: The SNr and the GPi are continously spiking structures

Q: Which other property does the GPi and SNr have?
A: They are also inhibitory structures, meaning that these 2 nuclei are continously inhibiting their targets

Q: Which targets do the SNr and GPi have?
A: - Thalamus
- Motor centres in the brainstem

Q: What does the GPi and SNr continously provide to the thalamus and the motor centres in the brainstem?
A: These provide continuous
inhibition for the thalamus and the motor centres in the brain stem and
preventing them of spiking and transmitting information

Q: What are the GPi and SNr continouly doing?
A: They are continously preventing undesired, unwanted movements

Q: What needs to happen to the Snr and the GPi if we wanna allow movement?
A: If we wanna allow movement we need to make the Gpi and the SNr stop firing, and in this weay we can allow the motor centres of the brainstem and the thalamus to transmitt information and to promote movement - this is exactly what the direct pathway is doing

Q: What happens in the beginning of the direct pathway?
A: There is a direct connection from the D1-MSN's to the output structures (GPi and SNr), meaning that excitatory input from the cortex and the thalamus will excite D1-MSN's

Q: What happens in the direct pathway when the D1-MSN's are excited by the cortex and thalamus?
A: When these cells are excited tey can inhibit the GPi and the SNr, so we have a tempory stop in the firing form the GPi and the SNr, meaning that there will be less info coming from the BG, less inhibition of the thalamaus, which will allow movement

Q: Why is the direct pathway also called a GO-signal?
A: It
is also called a GO-signal bc it promotes movement

Q: What does the indirect pathway do in relation to the direct pathway?
A: The complete opposite of the direct pathway, meaning it inhibits movement

Q: What happens in the indirect pathway of the BG?
A: Here we have D2-expressing MSN's of the striatum that inhibit the GPe

Q: What is the GPe in terms of inhibition?
A: The GPe is a continously active inhibitory centre, which means that it continously inhibits the GPi and SNr

Q: What happens if the GPe is highly active?
A: If the GPe is highly active it means that the GPi and SNr stop working

Q: What happens when the GPe is inhibited by D2-MSN's?
A: If the GPe is inhibited by input coming from D2-MSN's, it means that the GPi and the SNr are de-inhibited (Active) - we have inhibition on inhibition (stopping movement since active GPi and SNr inhibits output)

Q: What happens if the D2-MSN's are activated by cortical input?
A: 1. If D2-expressing MSN's are excited by cortical input they will inhibit the GPe
2. The GPe will stop firing and stop suppressing the GPi and SNr
3. So, the GPi and the SNr are now allowed to fire more, so there is an increase in the output from the basal ganglia
4. This means more inhibition of the thalamus and the motor centres in the brainstem, and so suppression of movemnets

Q: What else is the indirect pathway called?
A: The
indirect pathways is also called a no-go signal

Q: What are dMSNs?
A: Direct pathway MSN's

Q: What are iMSNs?
A: Indirect pathway MSN's

Q: What is the hyperdirect pathway?
A: The hyperdirect pathway is a pathway that bypasses most of the BG

Q: Where does cortical infromation go in the hyperdirect pathway?
A: Cortical input goes directly to the STN, which is an excitatory centre

Q: How does the hyperdirect pathway work?
A: 1. There is excitation from the cortex to the STN
2. Excitation from the STN onto the GPi/SNr
3. This means more activity in the GPi/SNr, meaning more output from the basal ganglia and more inhibition of the thalamus and motor centres in the brainstem - so we are suppressing movements

Q: What is the net effect of the hyperdirect pathway?
A: Suppression of movements, by activating the GPi/SNr

Q: What is Parkinson's disease?
A: Parkinsons disease is a progressive neurodegenerative motor disorder that affects millons world wide

Q: What are the motor symtomes of PD?
A: It has well-characterized motor symtomes such as ridgidity, bradykinesia, akineasia and difficulty in initiating movement

Q: What is the pathophysiology of Parkinson's Disease associated with?
A: - Loss of dopaminergic cells in the substantia nigra pars compacta (SNc)
- Loss of dopaminergic innervation particulary to the striatum

Q: Where is dopamine produces and released?
A: Dopamine is produced by the cells in substantia nigra pars compacta and it is released in the striatum where it can bind to the dopamine receptors

Q: How can dopamine set the balance of the activity between the direct and indirect pathways?
A: Since dopamine receptors can be both excitatory and inhibitory, Dopamine can acti and set the balance of the activity between the direct- and indirect pathways

Q: What happens with the BG pathways when dopamine is present?
A: When dopamine is present it will favor the activity of the direct pathway by binding to D1 rceptors on the MSN's

Q: How will dopamine supress the activity of the indirect pathway?
A: Supresses the activity of the indirect pathway by binding to D2-receptors on MSN's

Q: What happens with the dopamine when the cells of the SNc die?
A: When the cells of the SNc die and there is a drop of the dopamine levels in the striatum we can see that the balance between the activity of the direct/indirect pathways is lost

Q: What happens with the direct/indirect pathway balance when the cells of the SNc die and we have less dopamine?
A: Here the direct pathway rest, and the indirect pathway is overly active, the end result will be an increased output coming from the basal ganglia in supression of movement

Q: What can explain the symtomes ridgidity and difficulty in
initiating movements in PD?
A: When there is less dopamine due to that the cells of the SNc die, the direct pathway will rest and the indirect will be overly active, resulting in an increased output from the BG in suppression of movement

Q: WHich PD symtome cannot be explained?
A: Tremor

Q: WHich are the motor symtomes of PD?
A: - Tremor
- Rigidity
- Akinesia/Bradykinesia
- Postural disturbance

Q: What are some ex. of the non-motor symtomes of PD?
A: - Sleep difficulties
- Constipation
- (motor disorders)
- Speech
- Bladder dysfunction
- etc.

Q: What can be said about when which symtomes appear in PD?
A: Many of the non-motor symtomes occur before the occurance of motor symtomes

Q: Is there a cure for PD?
A: There is no cure for PD or to halt the proggression of the disease or reverse its course, however there are treatments to ameliorate (make better) the symtomes for the pat

Q: What was a treatment for PD in the 50s?
A: In the 50s there was a surgical option that included lesions of structures in the BG like GPi and thalamus

Q: What did the treatment of PD in the 50s result in?
A: - Reduced tremor and rigidity
- Success of 80-89% of patients
- Hypokineasia was not directly influenced

Q: What treatments were there fpr PD in the 60s?
A: In the 60s pharamacology helped with the discovery of dopamine and dopmaine replacement therapy, pat were given L-DOPa, still today the standard treatment of PD

Q: What is a problem with L-DOPA treatment?
A: However with long treatment the side effects of L-DOPA are becoming more present and its difficult to maintain pat with L-DOPA and it's ineffective

Q: What treatments for PD were there in the 90s?
A: Deep brain stimulation (DBS) - an
electrode is insetred in the BD (BG?) - ameliorate the symtomes

Q: How many patients world wide are treated for PD with deep brain stimulation (DBS)?
A: Ca 200 000 patients worldwide

Q: Which brain structures are targets for deep brain stimulation (DBS)?
A: - STN
- GPi
- Thalamus
- GPe (more recently)

Q: How are the electrodes inserted in deep brain stimulation (DBS)?
A: Unilateral/bilateral insertions

Q: What is usually the frequency used in deep brain stimulation (DBS)?
A: Typically >120 Hz - high frequency stimulation (this is done continously)

Q: Do we know how deep brain stimulation (DBS) works?
A: It's still not clear how it works

Q: What do hypo- and hyperkinetic disorders do with respect to teh BG?
A: Hypo- and hyperkinetic disorders alter the balance of inhibitory signals i the direct and indirect pathways

Q: What happens with the BG in PD?
A: In PD there is death of the SNc and the degeneration of the projections to the striatum

Q: What happens with the BG-pathways in PD (summary)?
A: We see the diminished activity of the direct pathway and the increased activity of the indirect pathway  - as a result from the imbalance in the pathways we have an increased output from the BG, more tonic inhibition of the thalamus - less activity/less movements

Q: What has happened in the body in Huntington's disease?
A: Mutated protein encoded by huntingtin-gene, and the mutated protein is toxic to particulary D2-MSN's

Q: What is the problem in Huntington's disease?
A: Here there is no problem with the activity of the SNc, here we have a degenerated D2-activity, as a result of less inhibition of the GPe, the GPe will become overactive - we have increased inhibition onto the output structures of the basal ganglia

Q: What is the result in Huntington's disease?
A: As a result we have too little output from the BG, les tonic inhibition of thalamus, which leads to too much movement, undesired movement and uncontrolled movement

Q: What type of disorder is Huntington's?
A: It's a hyperkinetic disorder

Q: What can be concluded from PD and Huntington's resulting from problems with the "same structure"?
A: The same circuit can produce different dissorders depending on which structure within it that is damaged

Q: What does the gene-coding look like in Huntington's disease?
A: - Prolongation of CAG repeats in the gene coding for the Huntingtin protein
- The mutated protein (mHtt) damages neurons and particulary the D2-MSN's population