Pathophysiology

• Give 5 dopaminergic pathways.

  Direct

  Indirect

  Hyperdirect

  Mesolimbic

  Mesocortical
• Describe the direct basal ganglia pathway.

  FUNCTION: Reinforces cortical activity

  Cortex sends excitatory impulse to striatum -> striatum sends inhibitory impulses to globus pallidus interna -> less inhibitory signals sent from GPI to thalamus -> more excitatory impulses from thalamus to cortex
• What is the effect of the substantia nigra pars compacta on the direct pathway?

  Promotes direct pathway

  Activation of dopaminergic neurons → dopamine released into striatum → dopamine binds to D1 receptors in striatum → activation of striatum → promotion of direct (’go’) pathway
• What is the function of the indirect basal ganglia pathway?

  Inhibits cortical activity of neighbouring areas of cortex
• Indirect basal ganglia pathway (w/o subthalamic nucleus)

  Cortex sends excitatory impulses to the striatum -> striatum sends inhibitory impulses to the globus pallidus externa -> GPE in inhibited from sending its inhibitory impulses to GPI -> so GPI sends more inhibitory signals to the thalamus -> thalamus is inhibited, so doesn’t send excitatory signals to the cortex
• Indirect basal ganglia pathway (w/subthalamic nucleus).

  Cortex sends excitatory impulses to the striatum -> striatum sends inhibitory impulses to the globus pallidus externa -> GPE is inhibited from sending inhibitory impulses to subthalamic nucleus -> subthalamic nucleus sends excitatory impulses to globus pallidus interna -> GPI sends inhibitory impulses to thalamus -> thalamus is inhibited, so doesn’t send excitatory signals to the cortex
• What is the effect of the substantia nigra on the indirect pathway?

  Substantia nigra pars compacta -> activation of dopaminergic neurons → dopamine released into striatum → dopamine binds to D2 receptors in striatum → inhibition of striatum → inhibition of indirect (’stop’) pathway
• What is the function of the hyperdirect basal ganglia pathway?

  Thought to prevent unwanted movement in advance
• Hyperdirect basal ganglia pathway.

  Cortex sends excitatory impulses to the subthalamic nucleus -> subthalamic nucleus sends excitatory signals to globus pallidus interna -> GPI sends inhibitory impulses to thalamus -> thalamus is inhibited, so doesn’t send excitatory signals to the cortex
• Mesolimbic pathway.

  Exposed to rewarding stimulus → increased release of dopamine from ventral tegmental area (VTA) → activation of dopaminergic neurons in VTA → neurons project to nucleus accumbens (via mesolimbic pathway) → dopamine levels in nucleus accumbens increase
• Mesocortical pathway.

  Exposed to rewarding stimulus → increased release of dopamine from VTA → activation of dopaminergic neurons in VTA → neurons project to cortex (esp. frontal lobes) → dopamine levels in cortex increases

  Considered part of the reward system
• Pathophys of PD.

  Alpha-synuclein aggregates & tangles → creation of Lewy body inclusions → neuronal cell death (esp. dopaminergic neurons in substantia nigra pars compacta) → decrease in dopamine & increase in ACh → less dopamine released at striatum via nigrostriatal pathways → less direct pathway & more indirect pathway → degeneration spreads as the condition progresses → spreads from lower brainstem to midbrain, then to cortex

  When someone loses around 80% of dopaminergic neurons → motor symptoms appear
• Pathophys of Huntington's

  Mutations in Huntington gene → CAG repeat sequence (encodes for glutamine) → misfolded Huntington protein (more than 40 CAG repeats) → protein aggregation & neuronal cell death in striatum → loss of indirect circuits → shift in direct vs indirect balance towards direct pathway → hyperkinesia (loss of inhibition)
• Fill in the blanks

  A) Indirect

  B) Cortex

  C) Striatum

  D) GPe

  E) Subthalamic nucleus

  F) GPi

  G) Thalamus

  
• Fill in the blanks

  A) Indirect

  B) Cortex

  C) Striatum

  D) GPe

  E) Subthalamic nucleus

  F) GPi

  G) Thalamus

  H) Substantia nigra

  I) D2

  
• Fill in the blanks

  A) Direct

  B) Cortex

  C) Striatum

  D) GPi

  E) Thalamus

  F) Substantia nigra

  G) D1