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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