Basal Ganglia

Question 1

What is the basal ganglia?

Answer 1

An extrapyramidal subcortical system
for the selection of internally generated, goal-driven motor programmes
(does not pass directly through the pyramids of the medulla oblongata so is not directly involved in executing motor instruction).
Forms a subcortical loop
Input from cortical regions, frontal, motor associative parietal areas and process that information and feed it back to the cortex via the ventral anterior and ventral lateral thalamic nuclei.
caudate nucleus
putamen
globus pallidus

Question 2

what are the functions of basal ganglia

Answer 2

decide and select what goal to achieve and what motor program will achieve it
solve a competing input selection problem
learn associations between outcomes of actions and their cues to adapt behaviour for effective responses to a specific environment
learning the relationship between stimulus and response underlies and establishes habits

Question 3

What is the anatomy of the basal ganglia?

Answer 3

input - striatum: caudate nucleus and putamen
output - Globus pallidus: external (GPe) and internal (GPi)
subthalamic nucleus
output - substantia nigra: pars compacta (SNc) and pars reticulata (SNr)
General inputs - from cortex to the striatum
General outputs - from substantia nigra reticulata and internal globus pallidus to thalamus which relays information back to the cortex
Descending pathway to brain stem nuclei involved in regulating some movements

Question 4

What are MSNs

Answer 4

medium spiny neurons
pinciple input neuron in striatum so recieve most of the afferent input from the cortex
fire in relation to cues for movement but not movement itself
GABAergic dopamine receptors
type D1 - substance P, dynorphin opioid
type D2 - A2A, enkephalin opioid

Question 5

what are the basal ganglia outputs

Answer 5

GABAergic neurons
Ascending’ From GPi/SNr to VLo/VA of thalamus for thalamocortical relay
Main loop responsible for the process of movement selection and planning
‘Descending’ From GPi/SNr to upper brainstem (e.g. superior colliculus, reticular formation, pedunculopontine nucl., habenular nucl.) - facial movements and gait.

Question 6

How do output pathways work?

Answer 6

act on disinhibition
Striatal neurons to SNr/GPi disinhibit thalamocortical relay
SNr/GPi cells fire tonically and inhibit thalamus (VM)
SNr/GPi cease activity in response to striatal stim (by ‘Glu’ injection) and permit activity in VM-Cx interneurons that releases motor programme = disinhibition

Question 7

What are the different pathways?

Answer 7

Direct pathway: from striatum → SNr/GPi
Indirect pathway: from striatum → GPe → STN → SNr/GPi
Hyperdirect pathway: from cortex to STN

Question 8

what is the ascending input?

Answer 8

Ascending nigrostriatal dopamine input
From SNc to striatum
Important dopaminergic input

Question 9

what neurotransmitters are active where in the basal ganglia

Answer 9

Glutamatergic (e.g. Cortical and thalamic) ~Excitatory (+)
GABAergic (e.g. striatum, GP) ~Inhibitory (-)
Dopaminergic (nigrostriatal) ~Excitatory or inhibitory

Question 10

What effect does the direct pathway have on the thalamocortical relay?

Answer 10

Direct pathway (GABAergic - inhibit SNr and GPi which inhibits their inhibition of the thalamus allowing it to be activated)
Striatal output inhibits SNr/GPi and so reduces GPi inhibition on thalamus
→ Disinhibition of thalamocortical relay
Overall, it facilitates movement

Question 11

What effect does the indirect pathway have on the thalamocortical relay?

Answer 11

Indirect pathway
Striatal output inhibits GPe and so reduces GPe inhibition of STN.
Increased activity in STN increases GPi inhibition on thalamus
→ Inhibition of thalamocortical relay
Overall, it inhibits movements

Question 12

which dopmaine receptors are present in which pathway

Answer 12

D1 - direct

D2 - indirect

Question 13

How does DA modulate the direct pathway?

Answer 13

Dopamine acts at excitatory D1 DA receptors on direct striatal projections and facilitate this pathway, promoting disinhibition
And so, dopamine facilitates movement

Question 14

How does DA modulate the indirect pathway?

Answer 14

D2 DA receptors on indirect striatal projections inhibit pathway
Acts to inhibit movement by promoting the SNr output and inhibiting thalamocortical relay
By inhibiting this pathway, dopamine is offsetting those consequences
And so, dopamine facilitates movement

Question 15

what are the symptoms of basal ganglia disease?

Answer 15

akinesia (inability to move)
bradykinesia (slowing of movement)
Involuntary movements: tremor at rest (contrast with cerebellum
chorea (irregualr dance like movements)
athetosis/dystonias (writhing movements
usually of distal limbs or neck)

ballismus (ballistic, trajectory-like flinging irregular movements)
tics (small, jerky repeating movements)
stereotypies (very repeated behaviours)
dyskinesias (large range of different types of irregular movements generally)
hyperactivity (too much movement)

Question 16

What are the diseases of the basal ganglia?

Answer 16

movement disorders 
Parkinson’s disease 
Drug-induced parkinsonism 
Huntington’s disease 
Hemiballismus 
Multiple system atrophy 
Tourette syndrome 
Dystonias 
Manganism 
Sydenham’s chorea 
Wilson’s disease 
Hatters disease 
Hallevorden Spatz 
Tardive dyskinesia

Question 17

What is Parkinson’s?

Answer 17

neurodegenerative disorder
manifests with age
progressive
PD “TRAP” Tremor at rest, Rigidity, Akinesia, Postural instability Also shuffling gait (and festination)

Question 18

What is the pathology of Parkinson’s disease?

Answer 18

progressive lost of SNc dopamine neurons
loss of nigrostriatal pathway supplying dopamine to the striatum (particularly in putamen - more motor part)
Flora-dopa is a radio ligand that can be used to assay the integrity of dopamine axons
Intraneuronal, cytoplasmic inclusions - lewy bodies.
Major aggregations of insoluble components are α-synuclein and ubiquitin in remaining dopamine neurons
granules in neurons and deposits in axons which sometimes give rise to steroids in axons

Question 19

What happens in the basal ganglia loop in Parkinson’s?

Answer 19

Lose modulation in direct and indirect pathways leading to a relative overdrive of the indirect pathway
This leads to a loss of inhibition of the subthalamic nucleus (STN)
STN would relatively increase its activity and promote its excitation on the SNr and GPi
Drive enhanced inhibition of the thalamus
Preventing the thalamocortical relay signal preventing the cortex from selecting movement.

Question 20

What causes Parkinson’s?

Answer 20

genetic components
PARK genes 1-23:
(e.g. PARK1 alpha-synuclein - inherited in autosomal dominant fashion)

Intrinsic physiology, anatomy, biochemistry and biophysics promotes selective vulnerability
Neuronal architecture - most arbourised of any CNS neuron;
high metabolic demand to produce lipids, proteins, ion gradients and be able to handle the calcium;
DA oxidation;
oxidative stress because of free radicals that are generated in the process;
Ca2+/mitochondrial/ER stress;
neuroinflammation;
protein misfolding and accumulation

Acquired/environmental contributions Neuroinflammation Pesticides +genetics Toxin exposure - MPTP parkinsonism

Question 21

what is MPTP toxicity

Answer 21

MPTP which is coverted to MPP+ in the brain
Substrate for the dopamine transporter which is only expressed on dopamine neurons
Selective entry of MPP+ into DA neurons via the DA transporter (DAT)
Sequestration into mitochondria inhibits complex 1:
↓ATP
Downstream increase in reactive oxygen species ROS (causing energy levels to fall and DA dumping)
Leads to selective death in dopamine neurons

Question 22

How does dopamine replacement therapy work?

Answer 22

Exploits the biosynthesis pathway of dopamine. Difficult to give directly as it doesn’t cross the blood brain barrier.
Immediate precursor in the dopamine biosynthesis pathway (L-DOPA) can be given and is taken up into the brain where it is converted by DOPA decarboxylase to dopamine
Important to stop the conversion of L-DOPA to domaine in the periphery by administering an inhibitor of a key breakdown enzyme
Usually also administered with inhibitor of peripheral decarboxylase (Carbidopa) (e.g. Sinemet®)
BUT L-DOPA is problematic - After about 5 years there are motor problems that develop that include sudden on/off effects, gait freezing and l-DOPA-induced dyskinesias - debilitating

Question 23

What alternative therapy options are there for Parkinsons?

Answer 23

Other DA replacement strategies e.g. DA agonists, MAO inhibitors (inhibit the breakdown of dopamine), COMT inhibitors
Non-DA pharmacotherapy exploit other parts of the circuitry mACh antagonists (benztropine), nAChR/5-HT/glu/adenosine receptor ligands, neurotrophic factors, autophagy/mitophagy modifiers
Molecular therapies e.g. antibodies/RNAi to α-synuclein, gene therapy
Surgery Transplants (adrenal medulla autografts, embryonic nigral, stem cells)
Deep brain stimulation (DBS) e.g. in STN

Question 24

How does deep brain stimulation work?

Answer 24

Stimulating electrode within BG nuclei e.g. STN, GP (or PPN) implanted during surgery
Microelectrode is placed very accurately to a specific part of the brain in order to be used to directly stimulate a malfunctioning nucleus
Chronically implanted within the brain
Stimulating wires put superficially on the skull
Pacemaker inserted on the clavicle so that this can be controlled with a remote control pacemaker unit
Good for some symptoms
Patient has to be able to withstand intense intracranial disruption
Doesn’t stop the onward progression of the disease
Successful target is the subthalamic nucleus
Activation of STN should promote inhibition of thalamus – undesirable
Paradoxical inhibition (or change) in STN activity?
May act through modifying axon tracts of afferent inputs

Question 25

What is Huntington’s disease

Answer 25

hyperkinesia
chorea
dystonia
rigitiy 
cognitive decline
striatal atrophy: loss of caudate nucleus GABAergic medium spiny neurons, particularly D2
cortical atrophy

Question 26

What is the aetiology of Huntington’s disease?

Answer 26

Inherited autosomal dominant
codon repeat disease
Encodes consecutive polyglutamines (CAG ) in protein product of huntingtin gene (HTT)
more repeats means early presentation of disease
HTT protein aggregates
Relatively greater loss of the indirect pathway
Functional imbalance in pathways: Direct > indirect → Decreased inhibition of thalamus Hyperkinetic phenotype
Treatments Antidopaminergics to offset the selection of movement: tetrabenazine, dopamine receptor antagonists: neuroleptics, proGABAergic drugs: benzodiazepines