APP Module (GTown) - Basal Ganglia Pathophysiology (Hrs 1 and 2) Flashcards
What is the generalized function of the basal ganglia?
the selection of action, or turning thoughts/ideas/motivations into action
What are the key pathologies of the basal ganglia?
1) Parkinson’s Disease
2) Huntington Disease
3) Tourette’s
4) dementia pugilistica
5) OCD
What is the main motor circuit called which includes the basal ganglia?
cortico-basal ganglia-thalamocortical circuit
What are the two brain areas of the dorsal striatum?
caudate and putamen
What separates the caudate and putamen?
internal capsule
What are the majority of neurons in the basal ganglia?
medium spiny neurons (MSNs)
What are the two motor pathways in the basal ganglia?
The direct and indirect pathways
What type of input does the basal ganglia get from the cortex?
mostly excitatory glutamatergic input
What type of input does the basal ganglia get from the substantia nigra?
both excitatory and inhibitory dopaminergic input
What is the role of the subthalamic nucleus?
suppression of unwanted movements
How do you differentiate between the two types of dopaminergic neurons which originate from the substantia nigra pars compacta and synapse on the dorsal striatum?
D1-like neurons will project to the substantia nigra pars reticulata. D2-like neurons will project to the globus pallidus externa.
What are the two neural components of the basal ganglia?
1) Principal, projecting neurons (~95%)
2) Aspiny interneurons (1-2%)
What neurotransmitters do the interneurons use?
GABA and acetylcholine
What do the interneurons in the basal ganglia do?
Modulate MSNs
What electrophysiological properties do the MSNs have?
bimodal nature: up and down states
What is the purpose of the MSNs?
to convey information out of the basal ganglia
What are the three main inputs onto the average MSN?
1) cortical glutamatergic input
2) interneuronal ACh input
3) substantia nigra DA input
What are the four cortical-basal ganglia loops?
1) motor
2) oculomotor
3) prefrontal
4) limbic
What are the main inputs into the striatum?
Dorsal striatum
What NT do neurons in the globus pallidus use?
GABA
Where do the majority of neurons from the GP synapse on?
Thalamus
How long does it take for a signal to cross a synapse?
2 ms
How do we know there is an indirect GABA influence on the basal ganglia?
There is a 20-30 ms lag between stimulation of the cortex and a spike in the basal ganglia.
Where do the majority of neurons from the STN project to?
GP
What NT does the STN use?
glutamate
Why is the STN unique in the BG?
It is the only brain region to use glutamate
What are the two subdivisions of the substantia nigra?
pars compacta and pars reticulata
What neuromodulator does the SN use?
dopamine
What regulates the firing patterns in the SN?
salience
What are the two types of GABA neurotransmission and what type of channels are they?
GABA-A (metabotropic)
GABA-B (ionotropic)
What are the two types of glutamatergic channels?
1) metabotropic (mGlu)
2) ionotropic (AMPA, NMDA, and kainate)
What type of channels are attached to NMDA receptors?
non-selective cation channels
What are the two major types of dopaminergic receptors?
1) D1-like
2) D2-like
What types of receptors are DAergic receptors?
GPCRs
What is the effect of D2R activation?
↓ [cAMP], ↑ K channels, ↓ Ca channels
What is the effect of D1R activation?
↑ [cAMP], ↑ [Ca]
What NT do tonically active neurons use?
acetylcholine
What are some clinical aspects of basal ganglia pathophysiology?
- tremor
- changes in posture and muscle tone
- poverty of movement
- shuffling gait with bending at the waist
- hyperkinetic involuntary movements
- obsessive-compulsive disorders
What is the theory of Parkinsonism?
unbalance activity of the direct and indirect pathway underlies development of PD
What is the neuroanatomical correlate of PD?
progressive death of DA cells of the substantia nigra in the midbrain
What are the features of Parkinsonism?
- resting tremor
- poor postural balance
- bradykinesia
- muscle rigidity
What are some demographics of PD diagnosis?
- usually occurs in late middle age
- both sexes affected equally
- Caucasians are affected more than Asians and Africans
- there is some genetic correlation
What is MPTP?
A meperidine derivative that causes Parkinson-like symptoms and can be used for animal models of PD
What are the effects on the basal ganglia motor pathways in PD?
increased activity in the indirect pathway
decreased activity in the direct pathway
What amount of cases in PD are sporadic?
> 95%
What is another exogenous cause of PD?
chronic pesticide exposure
What is the mainstay of treatment for PD?
levodopa
What is L-dopa?
precursor to dopamine which can cross the BBB
What is a side effect of taking L-dopa?
dyskinesia over time
What is L-dopa co-administered with and why?
coadministered with an AAD inhibitor so it is not converted to dopamine in the periphery
What are some dopamine receptor agonists used for PD?
bromocriptine, pergolide
What are some MAO-B inhibitors used for treatment of PD?
selegiline, rasagiline
What are the two main surgical therapies for PD?
1) ablation, usually unilaterally of the globus pallidus
2) deep brain stimulation of the STN/GP bilaterally
What is the neuroanatomical correlate for Huntington’s disease?
unique loss of the striatal projection neurons
Which pathway is affected more in HD?
indirect pathway
What are some of the motor movements seen in HD?
- grimacing of the face
- twitching
- gesticulating with the arms
- jerking
What genetic defect underlies HD?
expansion of DNA repeats in gene that produces huntingtin protein
What is treatment for HD?
usually no medication for the disease per se, but rather the associated depression, paranoia, irritability
What is hemiballismus?
hyperkinetic movement disorder, more severe than HD which effects one half of the body (or one extremity)
What is hemiballismus caused by?
unilateral lesion of the STN
What does hemiballismus cause in the basal ganglia motor pathway?
Decreased levels of GP output
What is Tourette’s characterized by and when is it usually diagnosed?
motor and vocal tics and is usually diagnosed in childhood
What do Tourette’s patients have an increased comorbidity for?
- OCD
- ADHD
- depression
What is the underlying neurological cause of Tourette’s?
hyperdopaminergic tone
What are some pharmacological therapies for Tourette’s?
Dopamine antagonists like haldol and risperdal
What are the disorders which are obsessive-compulsive nature characterized by in the brain?
dysfunctional limbic system also involving the basal ganglia
What seems to be the underlying brain region in addiction?
ventral striatum
What does all addictions share in common?
increased dopamine in the ventral striatum
