Basal Ganglia Flashcards
How does information reach the muscles
The motor cortex communicates with the Basal Ganglia, Cerebellum and Thalamus before sending a signal through the pyramids to the lower motor neuron, which innervates striatal muscle.
Characteristics of the Basal Ganglia
- Four nuclei
- Primary input from the cerebral cortex.
- No direct input or output connections with the spinal cord or the cerebellum.
- Send their output via the thalamus, back to the prefrontal, premotor, and motor cortices.
Three characteristic types of motor disturbances caused by issues in the Basal Ganglia
Tremor and other involuntary movements;
Changes in posture and muscle tone
Poverty and slowness or uncoordination of movement without paralysis.
Pyramidal tract vs the extrapyramidal tract
Pyramidal tract: the upper and lower motor neuron
Extrapyramidal tract: Basal Ganglia, Cerebellum and Thalamus
Pyramidal tract syndrome
Characterized by spasticity and paralysis
Extrapyramidal syndrome
Characterized by involuntary movements/un-controlled voluntary movements, muscular rigidity, and immobility without paralysis
The 4 Basal Ganglia nuclei
Striatum: Nucleus caudatus / Putamen
Golbus Pallidus: Pars interna / Pars externa
Substantia nigra: Pars reticulata / Pars compacta
Nucleus subthalamicus
What is the only excitatory component of the Basal Ganglia?
The subthalamic nucleus (use glutamate)
Striatal interneurons
5% in total
Parvalbumin, ChAT
Most of the tonic activity
extensive axon collaterals that reduce the activity of the striatal output neurons
D1/D2 receptor expression in the striatum
MSNs that expresss dopamine receptor D1 (DRD1) project directly over the GPi to the Thalamus (direct)
MSNs that expresss dopamine receptor D2 (DRD2) project to the nucleus subthalamicus to the Thalamus (indirect)
Placement of input for the Medium Spiny Neurons
From the cortex: input on the head of the spine
From the substantia nigra: the neck of the spine
From intrinsic inhibitory neurons (striatum): on the soma
The direct pathway to initiate movement
Dopaminergic neurons from the substancia nigra and the motor cortex activate DRD1-MSNs. DRD1-MSN in turn block inhibitory neurons which leave the GP to block the thalamus. By this way the thalamus is dis-inhibited (the so-called de-blockade of the thalamus).
The indirect pathway to initiate movement
Dopaminergic neurons from the substancia nigra and the motor cortex block DRD2-MSNs. GABAergic neurons are then de-blocked and in turn block the subthalamic nucleus (master regulator). By this way the GPi is not activated anymore and the thalamus is not blocked anymore.
Symptoms of hypokinetic disorders
excessive motor activity
involuntary movements (dyskinesias)
decreased muscle tone (hypotonia).
Symptoms of hyperkinetic disorders
impaired initiation of movement (akinesia)
reduced amplitude and velocity of voluntary movement (bradykinesia)
usually accompanied by muscular rigidity (increased resistance to passive displacement) and tremor
On a neuronal level, what causes movement disorders?
They come from an imbalance in the Direct and Indirect Pathways of the Basal Ganglia
Parkinsons symptoms
paucity of spontaneous movement, akinesia, bradykinesia,
increased muscle tone (rigidity)
characteristic tremor (4-5 per second) at rest
shuffling gait
flexed posture
impaired balance
mask-like facial expression
Pathway dysfunction in Parkinsons patients
DRD2-MSNs in the striatum are not activated anymore thus leading to an enhanced blockade of the thalamus. In addition, the indirect pathway in not blocked anymore and the subthalamic nucleus is constantly active thus blocking the GPi that in turn blocks the thalamus.
The indirect pathways is acting in the opposite way than in Huntingtons (the D2R signaling are causing the Globus Pallidus(external) to be super inhibited internal segment is becoming super excited)
Epidemiology of Parkinsons
it’s becoming more prenevelent. Between 10-240 per 100 K
Histology of Parkinsons
We seem to spot
1) Cell loss of dopamin neruons in the Substancia Nigra
2) Lewy bodies in the Substancia Nigra
The role of ROS in Parkinsons
The accumulation of oxygen radicals can cause many issues and are thought to underlie the degeneration of dopamine neurons in the Substancia Nigra.
ROS might also lead to disturbed chaperon function, which leads to misguided protein folding and therefore to protein aggregations (which are toxic)
The different forms of Parkinsons
Parkinsons comes in sporadic or mongetic forms. We have dominant and recessive forms and high/low risk loci
Genes for recessive Parkinson’s
Parkin 2 and PINK1 – they lead to autophagy of mitochondria
Most ressecive forms for Parkinsons don‘t have Lewy bodies
Genes for dominant Parkinson’s
Dominant Parkinson’s can be caused by SCNA and LRRK2.
Mutationes lead to a dominant negative effect (probably) by an increased Phosphorylation.
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release
SCNA in Parkinsons
Mutations of the gene perhaps a cause of dominant Parkinsons. mutated forms of SCNA compromises the lysosomes, and those with lysosomal storage disease are at greater risk of PD.
mutated SCNA also aggregates at:
- mitochondrial membranes
Causes degradation of them, apoptosis and ROS
- cytoskeleton/microtubules
block axonal transport, destabilizes microtubules, reduces polymerization of tubulin.
- presynaptic compartment
decreases vesicle release, disturbes the SNARE complex assembly, disturbes Ca2+ homeostasis
SCNA aggregation might be over the entire body and is released and distributed through dense-core vesicles
Gaucher disease
An example of a genetic lysosomal storage disease. Having this increased your risk of Parkinsons. We see glucosylceramide accumulations in multiple organs. Some forms of Gaucher’s disease may be treated with enzyme replacement therapy. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen.
SCNA in the mitochondrial membranes
Causes damage to the mitochondria,
Treatment of Parkinson’s
L-DOPA or similar substances
DBS that targets the external segment of the globus pallidus to inhibit the sub-thalamic nucleus
Hyperkinetic disorders and their characteristics
Huntington disease and hemiballism
excessive motor activity
involuntary movements (dyskinesias)
decreased muscle tone (hypotonia).
hypotonia
decreased muscle tone
dyskinesias
involuntary movements
akinesia
impaired initiation of movement
bradykinesia
reduced amplitude and velocity of voluntary movement
chorea (type of dyskinesias)
jerky, random movements of the limbs and orofacial (mouth and face) structures
ballism (type of dyskinesias)
violent, large-amplitude, proximal limb movements
dystonia (type of dyskinesias)
sustained abnormal postures and slower movements with underlying cocontraction of agonist and antagonist muscles
athetosis (type of dyskinesias)
slow, writhing movements of the extremities
Causes of Huntington’s
More than 37 The CAG repeats in the first Exon of the Huntingtin gene. It’s autosomal dominant neurodegenerative disorder
Epidemiology of Huntington’s
more common in Western countries compared to Asia or Africa (1:100000)
affects both men and women
Symptoms of Huntington’s
Primary: lack of coordination & uncoordinated, jerky body movements
But also: problems with mood or cognition, decline in mental abilities until dementia
no cure for HD - full-time care required in the later stages of the disease
What does the mutation in the Huntington’s gene do?
We don’t know - might be loss or gain of funciton
However, we do see endocytosis and lysosomal degradation – leads to accumulations and increased concentration of ROS
Where do Huntington’s patients lose the most brain tissue?
Putamen (64%) and the Caudate (57%)
How does the clinical symptoms of HD connect to the direct/indirect pathway?
We first see hyperkinesia and reduced muscle tone due to GABAergic neurons from the striatum degenerate, leading to issues in the indirect pathway.
Later, we have hypokinesia and increased muscle tone due to issues in the direct pathway
Also, the rigidity and akinesia in advanced Huntington disease are associated with the loss of the striatal neurons that project to the internal pallidal segment.
Neuronal cause of Hemiballism?
Lesions in the subthalamic nucleus leading to less activation of the internal Globus Pallidus and thereby decreased thalamus inhibition
Pathophysiology of Drug-induced dyskinesias
Mechanisms of L-DOPA
1) excessive dopaminergic inhibition of the striatal neurons that project to GPe, reduced inhibition of Gpi neurons (we’re putting the direct pathway out)
2) excessive inhibition of the subthalamic nucleus
lower output from the GPi segment (we’re also not exciting the GPi through the indirect pathway, leading to more movement)
Where do we think L-DOPA side effects (dyskinesia) comes from?
The symptoms probably result from receptor upregulation, supersensitivity, and altered gene expression caused by prolonged administration of the drug.
It’s also believed that we might need just the right dosis not the have these symptoms
What mouse models do we use for Huntingtons?
The PolyQ htt mouse.
It exhibits progressive neurological phenotype, intranuclear inclusions, and a disturbed axonal transport
PolyQ htt fly (Drosophila)
When expressed in the photoreceptor neurons, we see a similar degeneration as in the human brain.
C. elegans (worm)
Easy to work with as we know all the physiological components of the model
What are characteristic signs for diseases caused by protein aggregations?
Disturbed axonal transport and reduced mitochondrial functions
Htt (Huntingtin gene) regulates what?
apoptotic signaling and axonal transport
I has been suggested to regulate neuronal and glial function and is implicated in nuclear import and transcriptional regulation
What is the main take aways from the “Impaired TrkB Receptor SignalingUnderlies Corticostriatal Dysfunctionin Huntington’s Disease” paper?
Unlike previous believed, there is no problem with expressing of releasing BDNF in the corticostriatal pathway. The problem occurs as up-regulated PTEN blocks Akt, which is a component of the TrkB system
