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mdeast

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So FA Basal Ganglia section is atrocious. Or at least, I feel like their image of the direct/inhibit pathway is poor because it doesn't demonstrate inhibition or excitatory connection or the NT's that are responsible.

Here's what it says for Excitatory pathway (Direct):

"cortical inputs stimulate the striatum, stimulating the release of ACh, which disinhibits the thalamus via the Gpi/SnR."

I thought it worked such that GPi/SNr normally inhibits activation of the thalamus (which first aid states). And that the striatum releases GABA which inhibits the GPiSNR mediated inhibition. Little confused as to where ACh is coming into this picture.
 

loveoforganic

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Striatum is definitely GABA-releasing. The striatum is stimulated by the cortex to release GABA. By the indirect pathway, this GABA will hit the GPe. By the direct pathway, the GABA will hit GPi. GPe inhibition leads to inhibition of the subthalamic nucleus, which leads to disinhibition of the GPi and thus inhibition of motion through GPi's suppressive action on the thalamus. GPi inhibition (through the direct pathway) leads to disinhibition of thalamus, allowing motion

Edit: This is a good picture

image002.jpg
 

mdeast

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Striatum is definitely GABA-releasing. The striatum is stimulated by the cortex to release GABA. By the indirect pathway, this GABA will hit the GPe. By the direct pathway, the GABA will hit GPi. GPe inhibition leads to inhibition of the subthalamic nucleus, which leads to inhibition of motion. GPi inhibition leads to disinhibition of thalamus, allowing motion

Edit: This is a good picture

image002.jpg

Right this is what I remember. I'm just need sure where ACh is coming into the picture.
 

iheartmints

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Right this is what I remember. I'm just need sure where ACh is coming into the picture.

Striatum has AChergic neurons which activates GABAergic neurons that ultimately project outside of the striatum (the images are just neglecting to show that intermediate step)
 

loveoforganic

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Striatum has AChergic neurons which activates GABAergic neurons that ultimately project outside of the striatum (the images are just neglecting to show that intermediate step)

Interesting, thanks. As a matter of curiosity, would drugs affecting ACh levels have any effect in parkinsons? Or would there be equal stimulation of both pathways?
 

VisionaryTics

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Interesting, thanks. As a matter of curiosity, would drugs affecting ACh levels have any effect in parkinsons? Or would there be equal stimulation of both pathways?

Right on. Tilting the dopamine-ACh axis towards dopamine helps in Parkinson's, no matter how you do it.

Benztropine is an anticholinergic used to treat Parkinson's, especially drug-induced Parkinsonism.
 

iheartmints

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Interesting, thanks. As a matter of curiosity, would drugs affecting ACh levels have any effect in parkinsons? Or would there be equal stimulation of both pathways?

Yes because Parkinsons has too much ACh activity and too little DA and you must balance the two

There are 2 types of GABAergic neurons that project out of the striatum, both activated by ACh, but they also have 2 different types of DA receptors that compete with ACh signalling. D1 in excitatory pathway and D2 in inhibitory pathway. Whats the role of DA? Its ultimately excitatory by inhibiting inhibitory pathway and activating excitatory pathway. If you lose DA, now ACh is the only one signalling and you now have bradykinesia. Bradykinesia is not affected by antimuscarinics but you can control the tremors with antimuscarinics from the excess ACh in excitatory pathway or rigidity from too much ACh turning on GABA release in inhibitory pathway
 
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loveoforganic

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Interesting, I vaguely remembered ACh being implicated after this came up, but didn't realize there was a DA/ACh axis.

Thank you both!
 

mdeast

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Yes because Parkinsons has too much ACh activity and too little DA and you must balance the two

There are 2 types of GABAergic neurons that project out of the striatum, both activated by ACh, but they also have 2 different types of DA receptors that compete with ACh signalling. D1 in excitatory pathway and D2 in inhibitory pathway. Whats the role of DA? Its ultimately excitatory by inhibiting inhibitory pathway and activating excitatory pathway. If you lose DA, now ACh is the only one signalling and you now have bradykinesia. Bradykinesia is not affected by antimuscarinics but you can control the tremors with antimuscarinics from the excess ACh in excitatory pathway or rigidity from too much ACh turning on GABA release in inhibitory pathway

Wow, totally never made this connection. Right on thanks! Should post here more often when I have silly questions. :)
 

Kaputt

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Right on. Tilting the dopamine-ACh axis towards dopamine helps in Parkinson's, no matter how you do it.

Benztropine is an anticholinergic used to treat Parkinson's, especially drug-induced Parkinsonism.

Yep, also that anti-ACh drugs are the avenue of choice if Parkinson's is comorbid with psychosis. I don't remember if that was on my real exam or World, but it's a concept worth noting.
 

Aclamity

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So to extend the discussion, for Huntington's Disease FA says "Neuronal death via NMDA-R and glutamate toxicity. Atrophy of striatal nuclei," and in the margin: "Caudate loses ACh and GABA"

Does this mean that the pathogenesis is glutamate excitotoxicity to the ACh neurons and GABAergic neurons in the striatal inhibitory pathway, leading to neuronal death and excessive movement?

Additionally, I'm wondering if the "loss of ACh" they're referring to is from the Basal nucleus (as in Alzheimers), as both alzheimers and huntington's involve dementia.

By the way, I thought it was a rookie mistake for them to make Red "excitatory" and Green "inhibitory" in the diagram. Everyone knows green means GO and red means STOP!
 

Phloston

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I'm glad the OP pointed this out. I've already done a read-through of FA2009 and am now using the 2012. The diagram in the 2012 is egregious, but it's GREAT in the 2009- no idea why they'd change it. I had to copy it over into the 2012.
 

iheartmints

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So to extend the discussion, for Huntington's Disease FA says "Neuronal death via NMDA-R and glutamate toxicity. Atrophy of striatal nuclei," and in the margin: "Caudate loses ACh and GABA"

Does this mean that the pathogenesis is glutamate excitotoxicity to the ACh neurons and GABAergic neurons in the striatal inhibitory pathway, leading to neuronal death and excessive movement?

Additionally, I'm wondering if the "loss of ACh" they're referring to is from the Basal nucleus (as in Alzheimers), as both alzheimers and huntington's involve dementia.

By the way, I thought it was a rookie mistake for them to make Red "excitatory" and Green "inhibitory" in the diagram. Everyone knows green means GO and red means STOP!

Yes excessive glutamate is the toxic nerve killer. In Parkinson's, loss of DA means you lose DA signalling in both the excitatory and inhibitory pathway (DA does opposite things in both pathways). In Huntingtons you lose the GABAergic neurons of the inhibitory pathway so you can no longer inhibit actions that you normally inhibit so you have chorea and swing your arms all over the place.

Basal ganglia is involved in movement. Both Parkinsons and Huntingtons affects neurons outside the basal ganglia. When theres damage to the cortex as seen in both eventually, you get dementia. The basal ganglia effects are just a part of the diseases and you need to consider whats going on outside in the rest of the brain to figure out the other things happening in the diseases

Edit: Wow I completely read your post wrong. I'm not sure where the outside damage is at to cause dementia in Huntington's to tell you the truth. Maybe someone else can chime in
 
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Morsetlis

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Well, the huntingtin gene gained a function that caused evasion of proteolysis and accumulation as inclusions. Aggregation efficiency of polyQ into the nucleus varies with severity and onset of disease. Note that aggregation in the cytoplasm is a cell-protective mechanism to evade huntingtin-induced cell death.

"When transfected into cultured striatal neurons, mutant huntingtin induced neurodegeneration by an apoptotic mechanism."

So, I guess your question is, where else besides the striatum?

"In the second family, several members had cerebellar signs as well as chorea and dementia; MRI and CT showed olivopontocerebellar and striatal atrophy."

"Petersen et al. (2005) described a dramatic atrophy and loss of orexin (HCRT; 602358)-producing neurons in the lateral hypothalamus of R6/2 Huntington mice and in Huntington patients. Similar to animal models and patients with impaired orexin function, the R6/2 mice were narcoleptic."

"Although the HD mRNA and protein product show widespread distribution, the progressive neurodegeneration is selective in location, with regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus, and hippocampus. Reddy et al. (1998) created an experimental animal model in transgenic mice that showed widespread expression of full-length human HD cDNA with either 16, 48, or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioral and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus, and hippocampus."

http://omim.org/entry/143100

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Although I am sorry to say that the hypothesis of degeneration in the nbMeynert has been refuted :(

"The nucleus basalis of Meynert (nbM) provides most of the cholinergic input to the cerebral cortex. The loss of cortical choline acetyltransferase (CAT) activity in Alzheimer's disease (AD) and senile dementia of the Alzheimer's type (SDAT) appears to be related to a severe depopulation of the nbM in this dementia. In Huntington's disease (HD), by contrast, there is no loss of cortical CAT activity. The present quantitative study indicates that (1) there is no significant loss of neurons from the nbM in HD, and (2) that the previously described cytologic changes in the neurons of this nucleus in HD patients do not differ significantly from controls. These findings are consistent with the working hypothesis that the types of dementia associated with reductions of neocortical CAT activity are characterized by dysfunction or death of neurons in the nbM, but dementing disorders with normal neocortical CAT activity manifest no major abnormalities in this cholinergic nucleus of the basal forebrain."
 

redsquareblack

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I don't know if this will be valuable for any of the rest of you, but for me, I almost have to think things through this way for them to make sense.

First question: What is the job of the basal ganglia? Broad strokes, it's essentially a circuit for reinforcing selection of one particular motor pathway while simultaneously inhibiting others.

Second: How does it do that?
Cortex sends Glutaminergic signal to striatum, as mentioned before. Striatum uses ACh interneurons to stimulate GABA-ergic medium spiny neurons (MSNs) of both direct and indirect pathways, somewhat indiscriminately, which then leave striatum along their respective pathways.

Direct pathway's pretty straightforward: GABA-ergic MSN from striatum inhibits GABA-ergic neurons in the GPi, which inhibit excitatory neurons in the thalamus that ultimately project back to cortex. Thus, direct pathway inhibits the inhibitory output of the basal ganglia, leading to net cortical excitation.

Indirect pathway's a rat's nest, but in short, GABA-ergic MSN from striatum inhibits GABA-ergic neurons in the GPe, which inhibit excitatory neurons in the subthalamic nucleus, which excite GABA-ergic neurons in the GPi. Thus, indirect pathway disinhibits stimulation of the inhibitory output of the basal ganglia, leading to net cortical inhibition.

As I said before, the striatal MSNs of both direct and indirect pathways are activated relatively indiscriminately, and all things being equal, inhibitory output from the basal ganglia prevails. Striatum also has output to SNc, which, when stimulated, sends DA outputs back to striatum, and it is this DA that "focuses" the output of the basal ganglia.

D1 receptors on MSNs of the direct pathway are stimulatory, acting synergistically with the ACh to increase direct pathway transmission. Meanwhile, D2 receptors on the MSNs of the indirect pathway are inhibitory, antagonizing ACh and decreasing indirect pathway transmission.

The net result is center stimulation of a particular motor program via the direct pathway, with surround inhibition of other nearby motor programs via the indirect pathway.

In Parkinson disease, losing DA neurons in SNc means one cannot select a motor program by fine-tuning striatal stimulation with DA, and therefore the tonic inhibitory output of the basal ganglia prevails, leading to akinesia.

In Huntington disease, the indirect pathway MSNs are selectively destroyed, leading to loss of inhibition of the GPe, leading to inhibition of the subthalamic nucleus. Since the STN usually excites the GPi to increase the inhibitory output of the basal ganglia, an inhibited STN ultimately leads to disinhibition of the motor cortex, and hyperkinesia.
 

Ronin786

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The Basal Ganglia pathway is probably one of the more convoluted things I've come across in med school. However, its a lot of fun once you can make sense of what the hell is going on. :laugh:
 

ijn

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Now tell me why my notes say D2 antagonists treat HD.
Do you mean risperidone? eMedicine lists antipsychotics, which make sense given it's a hyperkinetic disease. Screw the details, honestly. I think you can get by just knowing Huntington's is a high dopamine disease, so we lower it. :D
 

Morsetlis

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Huntington's = too much movement
Dopamine facilitates movement. So you want to antagonize it.

But I thought there were two populations of neurons in the striatum: D1-sensitive GABAnergic neurons of the direct (positive feedback) loop and D2-sensitive GABAnergic neurons of the indrect (negative feedback) loop. HD would destroy the D2-sensitive GABAnergic strial neurons.

Wouldn't a D1 antagonist be better?

Also: How are DA and Ach "opposite"?

DA facilitates the direct pathway, while DA inhibits the indirect pathway. Ach activates both pathways. + / - is not opposite + / +.

I have spent a day on this and still don't understand it.
 

redsquareblack

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But I thought there were two populations of neurons in the striatum: D1-sensitive GABAnergic neurons of the direct (positive feedback) loop and D2-sensitive GABAnergic neurons of the indrect (negative feedback) loop. HD would destroy the D2-sensitive GABAnergic strial neurons.

Wouldn't a D1 antagonist be better?

My understanding is that antipsychotics are for treating the behavioral/psychiatric symptoms. They won't have much of an effect with the chorea.

Also: How are DA and Ach "opposite"?

DA facilitates the direct pathway, while DA inhibits the indirect pathway. Ach activates both pathways. + / - is not opposite + / +.

I have spent a day on this and still don't understand it.

They're not "opposite". The DA/ACh "balance" thing is layspeak from like WebMD or something. Glutaminergic cortical output reaches putamen. ACh interneurons in putamen excite GABAergic neurons of both direct and indirect pathways. Dopamine doesn't oppose ACh, so much as modulate ACh's effect based on what receptors are involved.
 

redsquareblack

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Do you mean risperidone? eMedicine lists antipsychotics, which make sense given it's a hyperkinetic disease. Screw the details, honestly. I think you can get by just knowing Huntington's is a high dopamine disease, so we lower it. :D

Wha...? HD is selective loss of indirect pathway GABAergic striatal neurons, not "high dopamine".
 

ijn

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Wha...? HD is selective loss of indirect pathway GABAergic striatal neurons, not "high dopamine".

You use dopamine antagonists and dopamine depleting agents to treat Huntington's disease. Thinking of it in that way helps me remember. You don't use GABA agonists. Yeah, I do know you lose GABAnergic neurons in the caudate. But the end effect is too much dopamine/hyperkinetic.
 

redsquareblack

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lemonade90

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Why does the FA diagram show:
1-Direct stimulatory arrow from cortex to the STN?
2-GPi input to the pedunculopontine nucleus? Why is there a need for the hash tags?

How are they related to basal ganglia functions?
 
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