What are the basal ganglia?
The striatum (including cuadate nucleus, putamen and ventral striatum (Nacc)), globus pallidus in the cerebrum, the substantia nigra in the midbrain, and the subthalamic nucleus in the diencephalon.
What are the functions of the basal ganglia?
- Coordination of execution (info integration for smooth movements)
- initiation and termination of voluntary movements. Inhibition of unwanted movements. (motor circuits)
- Initiation and termination of cognitive and emotional processes (non motor loops (prefrontal and limbic circuits))
How does the basal ganglia fit within the motor pathway?
Filters information from cortical areas. This filtered information projects to different nuclei in brain stem via the thalamus, reaching spinal cord where motor circuits are activated.
What role does the cerebellum have?
Both the BG and cerebellum influence movement by regulating activity of upper motor neurones. Do not project directly to local circuits or lower motor neurones.
What are the 2 descending systems?
Motor cortex - planning, initiating and directing voluntary movements.
Brainstem centres - Basic movements and postural control.
Describe the anatomical organisation of inputs to the BG
- Sensory inputs from cortical areas project via glutamatergic neurones to input areas (putamen and caudate of striatum).
- Dopamine inputs from substantia nigra reach striatum too.
Where are excitatory neurones in the BG found?
The Subthalamic nucleus
Describe the anatomical organisation of outputs to the BG
- In the striatum there are 2 populations of medium spiny neurones.
- Population 1 of MSN project to the internal segment of the globus pallidum (DIRECT CIRCUIT) where they then project to thalamus by GABAergic neurones maintaining inhibition in the thalamus. When activated, they temporarily release inhibition in the thalamus, and projections to the cortex are allowed and projection to motor areas initiated.
- Population 2 of medium spiny neurones (inhibitory) project to the external area of globus pallidum. (INDIRECT CIRCUIT - projects to subthalamic nucleus, where there are excitatory neurones that project to the internal globus pallidus.)
What are the MSNs?
MSNs projecting to internal segment of pallidum have D1 receptors. When MSNs are excited by dopamine, D1 receptors are activated and project to internal pallidum.
MSNs project
What happens with dopamine application to the dopamine neurones?
D1 - Excites MSNs involved in direct pathway. Up regulation of adenylase cyclate and excitation. (Higher inhibition of globus pallidus internal via GABA- neurones.)
D2 - Excites MSNs involved in indirect pathway. Down regulation of adenylate cyclase. Suppression of activity.
How are MSNs activated?
AP generated in axon hilock
Dopaminergic neurones synapse very far from axon hilock on synaptic spines so they are very hard to activate.
Large amounts of convergence on single GPi/GPe neurones.
What is the direct pathway
EXCITATORY OF THALAMUS
- Stimulation of cerebral cortex
- Excitatory glutamatergic input to striatum (caudate and putamen)
- In striatum, GABAergic inhibitory neurones activated by MSNs project to the internal segment of globus pallidum.
- This inhibits tonic inhibitory GABAergic firing to the thalamus, disinhibiting it.
- Thalamus fires glutamatergic / cholinergic (excitatory) inputs to frontal cortex where movement can be generated.
What is the indirect pathway
INHIBITORY OF THALAMUS
- Stimulation of cerebral cortex.
- Activates excitatory glutamatergic neurones, exciting striatum.
- Striatum activated, sending inhibitory GABAergic signals to GPexternal.
- Supresses inhibitory neurones firing to the subthalamic nucleus, allowing excitatory glutamatergic firing to globus pallidus internal segment.
- GPinternal fires tonic GABAergic impulses to thalamus.
- Movement supressed.
what role does the substantia nigra have in the indirect and direct pathways?
Releases dopamine (via D1 or D2)
What is parkinson’s disease characterised by?
Diminished Substantia nigra.
Reduced dopaminergic firing to the striatum. Works in the motor loop.
- Without D1 (involved in direct pathway) - less excitation of GPi, so an increased inhibition of thalamus and diminished
activation of motor areas.
- Without D2 (indirect) - less inhibition of inhibitory neurones projecting to subthalamic nucleus. More excitation of GPi, higher inhibition of thalamus and motor areas.
How can Parkinson’s disease be treated?
- Replace dopamine - Cannot be administered orally as can not cross blood brain barrier.
- L -Dopa administeration (it is a dopamine precursor and can go through BBB.) (Can lead to hallucinations).
- Inhibition of MOA and COMT enzymes as degrade dopamine.
- deep brain stimulation (implant electrodes into parts of BG and batteries under skin keep electrodes activated causing excitation of BG).
What happens in a non - schizophrenic brain?
- D1 neurones in the VTA activate glutamatergic (excitatory) in the prefrontal cortex which feed back to the VTA (positive feedback loop) .
- These glutamatergic neurones descend onto GABAergic neurones in VTA, which keep D2 neurones projecting to the Nacc under tonic inhibition.
What happens in a schizophrenic brain?
- weakened D1 input from VTA to prefrontal cortex
- Less activation of GABAergic neurones.
- More D2 activity firing to Nacc and more dopamine in Nacc.
What are some schizophrenia treatments?
DA antagonists
What are the cell bodies in the midbrain?
VTA and SN
What forebrain areas do the VTA and SN project to?
Prefrontal cortex
Nacc
Dorsal striatum (including Nacc)
What is the mesocortical limbic system
System involved in perceiving reward and reinforcement.
Includes dopamine neurones projecting from VTA to NAcc and PFC.
How do natural reinforcers affect the NAcc
Increase activity of dopaminergic neurones in VTA which project to the NAcc and PFC releasing dopamine. After exposure of the natural reward, there is a decline in dopamine release.
How do addictive drugs differ to natural reinforcers.
Release far more dopamine in NAcc (250% more than basal levels for cocaine v 50% more for food).
Work pharmacologically, by consistently causing a heightened release of dopamine.
