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Human Brain

Human Brain. Introduction. Mechanisms of control of behavior Reflex Involuntary Voluntary Understanding from analysis of neural diseases. spinal cord. (and analogous brainstem) dorsal root ventral root. Motor neurons. each a motoneuron innervates part of muscle Size principle.

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Human Brain

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  1. Human Brain

  2. Introduction • Mechanisms of control of behavior • Reflex • Involuntary • Voluntary • Understanding from analysis of neural diseases

  3. spinal cord • (and analogous brainstem) • dorsal root • ventral root

  4. Motor neurons • each a motoneuron innervates part of muscle • Size principle

  5. Resistance reflex • excitatory loop from muscle spindle

  6. Schematic

  7. Feedback from • muscle spindle • intrafusal muscle fiber,  motoneuron • measures length • +ve loop to contracting muscle • golgi tendon organ • in series • measures load • counteracts fatigue

  8. Summary so far • Reflex control of muscles • feedback and feedforward control • motoneurons in spinal cord (and analogous brainstem) • each a motoneuron innervates part of muscle • size principle

  9. Motoneuron disease • Amyotrophic lateral sclerosis • a motoneurons die • in 10-15%cases inherited, • chromosome 21 • superoxide dismutase (SOD) gene • 20% of cases • 120 mutations known

  10. ALS treatment: none > 22% longer survival in mice

  11. Descending control of motoneurons • feedback and feedforward control • ff = anticipation • primary motor cortex • somatotopic map • neurons project to groups of muscles for coordinated act

  12. Primary motor cortex

  13. Primary motor cortex • stimulation gives movement • fire before voluntary movement

  14. Role of brainstem nuclei • Major pathway in voluntary movements • starts in association cortex • caudate and putamen • input from substantia nigra • globus pallidus • thalamus • ends in motor cortex

  15. Circuit

  16. Schematic circuit • from association (neocortex) to motor cortex

  17. Huntington’s disease • symptoms: faster jerky movements • gene for protein huntingtin (Htt) on chromosome 4 • mutates to include CAG (glutamine) repeats • gene repeats increase easily • Htt may disrupt synaptic transmission

  18. Neural circuit • caudate neurons [GABA] degenerate, • less inhibition of thalamus • increased excitation of cortex • more movement

  19. Parkinson’s disease • symptoms: hard to initiate and maintain movements (bradykinesia) • death of dopaminergic substantia nigra neurons • dying cells have Lewy bodies, • made up of neurofilaments • ubiquitin immunoreactivity

  20. Lewy bodies • Immunoreactive to • a-synuclein • ubiquitin • a-synuclein may be misfolded • Adding ubiquitin to lys marks protein for degradation via proteasome

  21. Parkinson’s disease • mimic with MPTP • 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine • metabolise to MPP+ • 1-methyl-4-phenylpyridinium • Causes ? • oxidative stress • glutamate toxicity • Parkin - fault in ubiquitination

  22. Changes to circuit • more tonic inhibition of thalamus • decreased excitation of cortex

  23. Therapy for Parkinson’s disease • L-DOPA • MAO-B inhibitors (selegiline = deprenyl) • cell replacement • fetal cells • stem cells • deep brain stimulation

  24. Parkinson’s summary • death of dopaminergic substantia nigra neurons • hard to initiate and maintain movements (bradykinesia) • more tonic inhibition of thalamus • decreased excitation of cortex • mimic with MPTP (metabolise to MPP+) • dopaminergic therapy • cells protected by Parkin

  25. Summary so far • Role of basal ganglia is to combine with cortex to produce movement • Next: role of cerebellum

  26. Anatomy of cerebellum

  27. Inputs and outputs

  28. Cell types • Purkinje cell • only output

  29. Circuit • mossy fibers activate parallel fibers • climbing fibers • Purkinje cells compare signals during movement with expected

  30. Cerebellum • Purkinje cell (only output) • mossy fibers activate parallel fibers • climbing fibers • Purkinje cells input synapses compare signals during movement with expected • motor learning much reduced if cerebellum removed

  31. Neural basis of reward • Olds & Miller 1954 • electrical self-stimulation

  32. Motivated movement • reinforcers + or - • dopaminergic neurons in • ventral tegmental area project to • nucleus accumbens • [and amygdala, DA & delusions]

  33. Role of dopaminergic neurons human • ventral tegmental area project to • nucleus accumbens • fire during • feeding, • drinking • sex rat

  34. VTA pathway Dopaminergic A10 cell

  35. Motivated movement II • amphetamine (blocker of DA uptake) enhances reinforcement • reinforcement reduced by 6-OH DA or surgical lesions • electrical stimulation of VTA axons (ICSS) reinforces

  36. Addictive behaviour • tolerance to drugs • dependence • normal mechanisms of learning “malfunctioning”

  37. Addiction • cocaine down regulates DA receptors in nucleus accumbens • opioid [heroin] and ethanol activate neurons presynaptic to VTA • cannabis - modulates GABA inputs to NAC

  38. Conclusion • multiple mechanisms of control • integration not yet well understood

  39. Summary of Lecture • Reflex control of muscles • Descending control of motoneurons • Role of brainstem nuclei in voluntary movement • Motivated movement and nucleus accumbens • Addictive behaviour

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