Neurobiology
Outline
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Basic plan of the nervous system
Cellular neurobiology and –physiology
Neurotransmission
Neuroplasticity
Neuromodulation
Stem cells in neurology
Circadian rhythm, sleep, wakefulness
Windows on the brain
Pathophysiology of epilepsy and epileptogenesis
• Visual perception, attention and spatial cognition
• The prefrontal cortex and executive brain functions
Chapter 1:
Basic plan of the nervous system
Evolution
Evolution
Evolution
• excitatory/inhibitroy switches
• pattern detectors/generators
• pacemakers
Evolution
Development of vertebrate NS
Development of vertebrate NS
Development of vertebrate brain
Basic plan of system connectivity
Adult mammalian nervous system
Chapter 2:
Cellular Neurophysiology
Cellular components of nervous tissue
• Neurons
– Inhibitory neurons
• local connections
• distant connections
– Excitatory neurons
• local connections
• distant connections
– Neuromodulatory neurons
Inhibitory local circuit neurons
• Inhibitory interneurons of cerebral cortex
– Contain the inhibitory neurotransmitter GABA
– Local inhibitory effects
– Rich variety of targets and morphoogies
• Basket cells: inhibition to soma
– parvalbumin positive, cholecystokinin
• Chandelier cells
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axonal boutons
axon initial segment
axoaxonic cells
most powerfull
• Double bouquet cells
• Martinotti cells
• Neurogliaform cells
Inhibitory projection neurons
• Medium-sized Spiny cells (only in striatum)
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Densely covered with spines
Major output of striatum
GABA, neuropeptides and calbindin
Dramatic loss in Huntington diease
• invountary movements and dementia
• Purkinje cells
– Cerebellar cortex
– GABA and calbindin
– Spinocerebellar ataxia (ataxic gait, dysarthria, tremor)
Excitatory Local Circuit Neurons
• Spiny stellate cells
– lool like pyramidal neurons
– lack apical dendrite
– restricted cortical location
– Relay of thalamic inputs
Excitatory projection neurons
• Pyramidal cells
– highly polarized
– orthogonal to cortical surface
– large dendritic arborization
– axons with collateral
branches
– subdivisions based on
morphology, laminar location,
connectivity
Excitatory projection neurons
• Spinal motor neurons
– α-motor neurons
– skeletal muscles/spindle organs
– ventral root of peripheral nerves
– somatotopic representation
– acetylcholine
Neuromodulatory neurons
• Dopaminergic neurons
– pars compacta substantia nigra
– ventral tegmental area
– projects to large expanses of cerebral cortex and
basal ganglia
• Serotonergic neurons
– Raphe nuclei
• Noradrenergic neurons
– Locus coeruleus
Neuroglia
• Oligodendrocytes, microglia, astrocytes
• Schwann cells
Oligodendrocytes
• Myelination
– axonal size <<<< insulation
• Squid axon (10-20 m/s)
Schwann cells
• Schwann cells (diff with oligodendrocytes)
– individual myelinating schwann cells form a single
internode
– ECM secretion
– Respond vigorously to injury
• growth factor secretion
• debris removal
• axonal guidance function of basal lamina
• P0 (PNS) / PLP (proteolipid protein; CNS)
– heavy packing possiible
Astrocytes
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CNS homeostasis
Protoplasmatic
Fibrous astrocytes
Radial glia
Syncitium (gap junctions)
GFAP, S-100
Astrocytes
• Multiple roles
– Support function
– Brain homeostasis
– Blood brain barrier
– Angiogenesis
– Neurogenesis and guidance
– Growth factors
– Recycling/buffering of neurotransmitters and ions
– Hypertrophic/hyperplastic: astrogliosis
Astrocytes
Astrocytes
Microglia
• Bone marrow derived: monocytes
• Phagocytosis
• Growth factors and cytokines
– angiogenesis
– gliogenesis
• Antigen presentation
• Homeostasis
Vasculature
Vasculature
• Endothelial tight junctions
– Blood brain barrier (BBB)
– Regulated transfer
• P-gp/MDR (drugs)
• GLUT-1 (glucose)
• L-DOPA
– Disruption
• Edema
• MS/Epilepsy/AD
Subcellular Organization of the
Nervous system
selective mRNA in dendrites
(MAP2, no neurofilament)
dendritic remodelling with age
Dorsal root ganglion (no dendrites)
Amacrine cells (no axons)
Axonal transport
• Cytoskeletal proteins
(neurofilament/microtubuli)
• Soluble enzymes
• Dynein
• 0,1 – 4 mm/day
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Mitochondria
Membrane-associated receptors
Synaptic vesicle proteins
Neurotransmitters/Neuropeptides
100-400 mm/day
Anterograde/Retrograde
Kinesin
Packaged before transport
Electrotonic Properties of
Axons and Dendrites
Basic neuronal functions
• Spreading of activity?
– intrinsic activity
– synaptic potentials
– active potentials
• Determines input-output operations of neuron
• Passive membrane properties, membrane
receptors, internal receptors, synaptically gated
membrane channels, intrinsic voltage-gated
channels, second messengers
Electrotonic properties
• Cable properties (Rall compartmental model)
if x= λ
V/V0= 0.37
But also
Membrane potential
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Giant squid axon
Hodgkin and Huxley
Electrically polarized
Resting membrane potential-60 mV inside
versus outsoide
• Action potential: rapid depolarization followed
by rapid hyperpolarization
Hodgkin and Huxley
For example:
“shunt” effect at equilibrium potential !
Ion pumps
• Constant flow of ions across the membrane
• Ionic pumps
– Na+/K+ pump: ATP dependent
– Ca2+,Mg2+ ATP ase
– Na+-Ca2+ exchanger: Na+ gradient
– Cl-/Na+/HCO3- exchanger
Action potential
Increased conductance during action potential.
Extracellular Na+ concentration ~ amplitude of action potential
Action potential induced through rapid increase in conductance for Na+ ions?
measurment of ioninc currents necessary !!!
Patch clamp technique
• Kenneth Cole (1949)
INa versus IK
INa
IK
Fast onset
Slow onset (‘delayed rectifier’)
Transient
Continuous
Activation-Inactivation-Deactivation
Activation-Deactivation
• Ionic currents during action potentials cause
only minor change (<10 µM) in ion
concentration
• Action potential mostly generated at axon
initial segment
• Absolute refractory period:
– Inactivation of Na+ channels
• Relative refractory period:
– persistent IK
Action potential propagation
Distinct electrophysiological characteristics
• Morphology
• Ion channel properties