Lecture 10: Function & Dysfunction of Basal Ganglia PDF

Lecture 10: Function & dysfunction of basal ganglia What is the role of basal ganglia? ● Generation of goal-directed voluntary movements: ○ Motor learning (along with cerebellum) ○ Motor pattern selection ○ So it must have an aim + a stimulus with meaning ○ Movement must be directed with intention v...

Lecture 10: Function & dysfunction of basal ganglia What is the role of basal ganglia? ● Generation of goal-directed voluntary movements: ○ Motor learning (along with cerebellum) ○ Motor pattern selection ○ So it must have an aim + a stimulus with meaning ○ Movement must be directed with intention voluntary has no role in autonomic function ○ Basal ganglia also stores more appropriate motor plans to produce motor task Neuronal network in the basal ganglia: ● Plan from cortex sent striatum ● GPi is output of basal ganglia sends info to thalamic region ● Thalamus sends motor plan back to cortex to block or activate movement ● ANOTHER PATHWAY: ○ Projected striatum ○ Goes to GPe → goes to STN back to GPi ○ Then goes to thalamus → cortex CORTEX, STN, THALAMUS → GLUTAMATE STRIATUM + GLOBUS PALLIDUS → GABA Basal ganglia modulates movement through DISINHIBITION: ● Output nuclei of the basal ganglia are inhibitory ● Output nuclei maintain a ↑ tonic level of discharge ● Phasic ↓ in firing rate transiently releases target regions (namely thalamus & cortex) from inhibition ● Disinhibited thalamo-cortical circuit becomes active thus releasing movement programs Direct pathway: Indirect pathway: ● When basal striatal firing is ↓, the firing rate (activity) of GPi/SNr is ↑ → no movement ● Phasic cortical excitation induces an excitatory discharge in striatum → transient inhibition of GPi/SNr firing ● Thus activation of the direct pathway promotes action/movement ● Under basal condition, striatal neurons have ↓ tonic firing rates (low activity) ● GPe neurons (similar to GPi in the direct path) have ↑ tonic firing rates ● When a strong, phasic cortical excitation occurs, there is a transient inhibition of GPe firing rate ● Followed by a phasic excitation of the STN (remember disinhibition) ● Then GPi/SNr become highly activated ● Thus activation of the indirect pathway suppresses action/movement How does the DOPAMINERGIC input from the substantia nigra affect the direct & indirect pathways? Signaling through D1 receptor (direct path): ● In ↓ cortical activity → ↑ voltage dependent K+ current (hyperpolarization) ○ When there’s no need for movement ● During ↑ cortical activity → ↑ voltage dependent Ca2+ current (depolarisation) Signaling through D2 receptor (indirect path): ● Once activated, it inhibits electrical activity by ↓ Ca2+ current → hyperpolarization Impact of dopaminergic input from SNc on direct and indirect pathways: ● Dopaminergic neurons in the SNc send projection to the striatum ● Dopamine binds to D2R of the indirect path → facilitates movement by inhibiting the indirect pathway (disinhibiting the inhibitor) ● Dopamine activates D1R of the direct path → facilitates movement in the presence of a strong cortical drive, but suppresses weak signals/inputs What is the consequence of the loss of DA input from the SNc? ● Parkinson’s disease ● Direct pathway becomes less active → Action/movement selection is suppressed ● Indirect pathway becomes more active → Action inhibition is facilitated ● Net effect = action selection is suppressed Hemiballism: ● Lesion of the STN (small stroke) → ↓ tonic discharge of the GPi → thalamo-cortical neurons respond in an exaggerated (abnormal) manner to cortical inputs ● Subthalamic nucleus is needed to control indirect pathway if there is loss of control you will have multiple plans of movement competing with each other Huntington: Early stage (Chorea symptoms): Advanced stage (Rigidity/Akinesia): ● Death of striatal neurons in indirect path likely due to glutamate excitotoxicity → Hyperactive GPe → Functional inactivation of STN → Choreiform symptoms ● Occurs due to mutation of CAG repeat → excess glutamate production → ↑ activity of the cortical area → ↑ activation of striatum → neurons cannot handle this much excitation → apoptosis of hyperactive neurons ● Excessive uncontrolled movement ● So in the 1st stage the disease: ○ No inhibition of GPe ○ Inhibition less stimulation of STN ○ More inactivation of Gpi ○ Uncontrolled movement ● Loss of striatal neurons of the direct path → ↓ inhibition of GPi → ↑ firing of GPi neurons → Akinesia & rigidity ● Again: ○ Sustained excitotoxicity of the direct pathway → death of neurons in this pathway ○ There will be loss inhibition of GPi ○ Produces akinesia & rigidity Take home message: ● Motor behavior is determined by the balance between direct/indirect striatal outputs Hypokinetic disorders: (parkinsons) ● Insufficient direct pathway output ● Excess indirect pathway output Hyperkinetic disorders: (early huntington's & ballidism) ● Excess direct pathway output ● Insufficient indirect pathway output