Transcript 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 Resistance reflex excitatory loop from muscle spindle Schematic Feedback from muscle spindle muscle fiber, motoneuron measures length +ve loop to contracting muscle intrafusal golgi tendon organ in series measures load counteracts fatigue 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 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 ALS treatment: none > 22% longer survival in mice Descending control of motoneurons feedback and feedforward control ff = anticipation primary motor cortex somatotopic map neurons project to groups of muscles for coordinated act Primary motor cortex Primary motor cortex stimulation gives movement fire before voluntary movement Role of brainstem nuclei Major pathway in voluntary movements starts in association cortex caudate and putamen input globus from substantia nigra pallidus thalamus ends in motor cortex Circuit Schematic circuit from association (neocortex) to motor cortex 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 Neural circuit caudate neurons [GABA] degenerate, less inhibition of thalamus increased excitation of cortex more movement 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 Lewy bodies Immunoreactive to a-synuclein ubiquitin a-synuclein may be misfolded Adding ubiquitin to lys marks protein for degradation via proteasome 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 Changes to circuit more tonic inhibition of thalamus decreased excitation of cortex Therapy for Parkinson’s disease L-DOPA MAO-B inhibitors (selegiline = deprenyl) cell replacement fetal cells stem cells deep brain stimulation 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 Summary so far Role of basal ganglia is to combine with cortex to produce movement Next: role of cerebellum Anatomy of cerebellum Inputs and outputs Cell types Purkinje cell only output Circuit mossy fibers activate parallel fibers climbing fibers Purkinje cells compare signals during movement with expected 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 Neural basis of reward Olds & Miller 1954 electrical selfstimulation Motivated movement reinforcers + or dopaminergic neurons in ventral tegmental area project to nucleus accumbens [and amygdala, DA & delusions] Role of dopaminergic neurons human ventral tegmental area project to nucleus accumbens fire during feeding, drinking sex rat VTA pathway Dopaminergic A10 cell 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 Addictive behaviour tolerance to drugs dependence normal mechanisms of learning “malfunctioning” Addiction cocaine down regulates DA receptors in nucleus accumbens opioid [heroin] and ethanol activate neurons presynaptic to VTA cannabis - modulates GABA inputs to NAC Conclusion multiple mechanisms of control integration not yet well understood 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