Introduction to Human Neurophysiology -1- PDF

Introduction to human Neurophysiology -1- Prof. Dr. Leda Dimou WS 24/25  Function of the brain „today“ Central control organ for all arbitrary and automatic action sequences „personal intranet“ Recording, integration and storage of...

Introduction to human Neurophysiology -1- Prof. Dr. Leda Dimou WS 24/25  Function of the brain „today“ Central control organ for all arbitrary and automatic action sequences „personal intranet“ Recording, integration and storage of all sensory information, control of behavior and motor skills Area of emotions, motivation, thougths, planning, problem solving, consciousness, memory and learning abilities Condition of the brain determines life and death 2  Some “facts“ about the health of the brain In 2019, 20% of all healthcare costs in Germany were caused by brain- related diseases = approximately € 100 billion. In the course of life, every 4th person suffers from a brain-related illness. Depression is causing > 30,000 deaths in the US each year The Lancet Neurology, 2024 3 Development of the number of dementia patients The number of dementia patients will increase to more than 2,8 Mil 115 million patients worldwide by 2050 1,8 Mil The reason: The risk increases with age. Thus, between the ages of 65 and 69, every twentieth person suffers, between the ages of 70 and 74, one of ten is affected. Affected at age > 85 2022 ~ 40% 4 Weight of a human brain ~ 1,4 kg 5  Brain size brain size proportional to body weight (muscle mass) NO correlation with intelligence or cognitive performance Disproportionately large growth of the cortex during evolution 6  Brain size brain size proportional to body weight (muscle mass) NO correlation with intelligence or cognitive performance Disproportionately large growth of the cortex during evolution DeFelipe et al., 2011 6  ~ 600 km of blood vessels 9-12 m² area Distance between vessels ~ 40 μm, each neuron is supplied by its own blood vessel Blood supply 500-600 ml per minute Susceptibility of the brain: 7 sec without blood supply (ischemia or stroke): unconsciousness > 4 min: irreversible brain damage Nevertheless, hardly any substances enter the brain blood-brain barrier 7  Function of the blood-brain barrier Separates the blood vessel space from the brain and prevents the entry of toxins, ions (Na, K, Cl, Ca) and other substances (glutamate, glutamine) into the brain (CSF contains only 0.5% of the plasma protein) While the composition of the plasma varies greatly (food, hormones, antibodies), the composition of the extracellular milieu in the brain must be kept extremely constant Discovered by Paul Ehrlich (1885: Injection of "Evans Blue" into the blood: stains the entire organism, except the brain). Brain can however be stained when injected into the ventricle. 8 Blood-brain barrier 9  Function of the blood-brain barrier BBB formed by tight junctions between endothelial cells. These special "tight junctions" are only formed in the brain. "Tight junctions" ensure that all substances have to go THROUGH the endothelial cells to enter the brain. Therefore, entry into the brain is essentially determined by the lipophilic properties of a substance. For many hydrophilic molecules (essentially: glucose!): There are efficient transport systems (GLUT-1) or ion channels. Transport systems can be used to transport substances into the brain ("piggyback"). 10 Blood-brain barrier 11a Tight junctions 11  Blood-brain barrier Same principle for blood-retina barrier and blood-testis barrier (protection of germ cells from their own antibodies), blood-liquor barrier 12  Permeability of the Blood-brain barrier Alcohol, caffeine and nicotine - go through because lipid-soluble as well: oxygen and CO2 Ketone bodies can pass - including cortisone and lithium BBB impermeable to fatty acids, potassium, glutamate, mannitol Penicillin does not go into the brain - a few other antibiotics do, cytostatics in brain tumors must be able to pass! Heroin passes BBB 100 times better than morphine; "Crack" is more lipophilic than heroin and passes the blood-brain barrier even easier L-DOPA - much better than dopamine: Parkinson's therapy! Antibodies usually cannot penetrate the BBB: there are exceptions (mechanism unknown) - therefore Rasmussen Encephalitis with auto-antibodies against glutamate receptor (epileptic seizures) The (im) permeability of the BBB may be impaired after trauma, tumor, or infection Fenestrated blood-brain barrier in the circumventricular organs (e.g. area postrema, pituitary gland) - important !!!! 13 The brain can be examined on different levels that span several orders of magnitude Macroscopic (about 100 regions) Microscopic (about 1000 different types of neurons; other cells) cell body, processes, myelin Electron microscopic: synapses and vesicles Submicroscopic: channels and other 14 proteins  Possibilities to examine the brain "Top-to-bottom" (systemic neurobiology or behavioral neurobiology) Bottom-to-top (molecular or cellular neurobiology) Problem I: both approaches do not (yet) meet. In between, the "Bermuda Triangle" of neuroscience. The brain is more than the sum of its nerve cells. Problem II: without animal testing, neither approach works 15  Topics of this and the first upcoming weeks "bottom to top" approach! membrane potential action potential Saltatory, continuous and electrotonic conduction Synaptic transmission Molecular structure of ion channels Integration of synaptic potentials Learning and memory 16 S. Ramon y Cajal Camillo Golgi Nobel Prize for Medicine 1906 "in recognition of their work on the structure of the nervous system" 17 S. Ramon y Cajal Camillo Golgi Nobel Prize for Medicine 1906 "in recognition of their work on the structure of the nervous system" 17 "Method shows more by coloring less" 18 Different types of nerve cells in different brain areas Classification according to: Function eg motoneuron Transmitter Dendritic structure (amacrine cell, pyramidal cell) Number of processes 19  Nerve cells are bipolar ! Regardless of nerve cell type, almost all neurons have four functional regions: 1/ Dendrites are input region 2/ Cell bodies contain integration and trigger region (axon hilock) 3/ Axons are a conductive region 4/ Synapses are an output region Information always flows in one direction (input - integration - conduction - output) Problem: Nerve cells are postmitotic, synapses are far from the cell body 20 IN „Typical“ nerve cell OUT Problem: no ER, ribosomes or Golgi apparatus in the axon. Proteins must be transported to the synapse 21 The nerve cells are connected by axons. Estimated length of all axons in the human brain: about 500,000 kilometers !!! Distance Earth - Moon ~ 380,000 km 22 Rat hippocampal neuron with * dendritic tree (purple) and * a ~ 1 cm long axon (red) Please keep in mind: a motor neuron in the anterior horn of the human spinal cord may be more than 1 meter long Carlos F. Ibánez (2007) Trends Cell Biol. 17: 519-528. 2 23 Axoplasmic transport 24 Fast and slow axonal transport Slow transport (cytoskeletal proteins and intracellular proteins, enzymes for neurotransmitter biosynthesis, only anterograde): 0.2 - 5 mm per day Fast transport (membrane- associated material, peptide neurotransmitters, anterograde and retrograde) 200-400 mm per day (VESICULAR !!) 25  Motoproteins of the Fast axonal transport Anterograde transport: Direction given by the polarized microtubules kinesin - end towards Soma + end direction distal Retrograde transport: Kinesin from - to + end dynein / MAP 1C Dynein from + to - end ~ 20 nm per ATP Transport system is used by some viruses (polio, rabies, herpes) to enter the CNS 26  How fast is the axonal transport ? How long does a protein take to get through a ~ 35 cm long axon? A: fast transport ~ 1 day B: slow transport ~ 1 year Axonal transport is too slow ➔ synapses must be independent structures 27 The brain has to collect, integrate and distribute information To brain Action potential Synaptic potential Spinal cord Cell body of motoneuron Cell body of sensory neuron Action potential Axon of sensory neuron Axon of Motoneuron Receptor potential All these signals are ELECTRICAL signals 28  Information processing in the brain What are these signals? How are they generated? How are they transmitted - from cell to cell and within one cell? How can electrical signals be relayed, even though nerve cells are extremely bad electrical conductors? The ability to generate signals is based on the ability of nerve cells to rapidly change their voltage difference between the interior and the exterior. In other words, they are based on a rapid change in the Resting Potential The changes require * ion channels and * permeability changes of cell membranes by opening and closing these ion channels 29  Recapituation electricity The movement of electric charge: Current "I" [amp] The force acting on a charged particle (equivalent to the difference in charge between anode and cathode) is called electrical potential or voltage; "U" [volt]. In the car: 12 V, in the socket: 220 V; high power current: 380 V The relative ability of a charged particle to move from one point to another is the electrical conductance „g" Siemens [S]. Electrical resistance "R", measured in ohm "Ω": R = 1 / g A simple relationship between current, voltage and resistance appears: Ohm's law: U = R * I or alternatively: I = g * U or R = U / I 30 Intracellular recording of a neuron If one punctures a very sharp glass electrode (diameter ~ 0.3 μm, filled with saline solution) into a nerve cell (without permanently injuring the cell membrane) and at the same time a reference electrode is present in the extracellular medium, a voltage difference of - 40 to -90 mV (more negative inside than outside) can be measured Electric charge is distributed differently along the nerve cell membrane (inside vs. outside) This voltage difference was first measured ~ 1940 and is called resting membrane potential 31  Questions concerning the resting membrane potential Where does the resting membrane potential come from? How can you measure and calculate it? How is it maintained? What do nerve cells need a resting membrane potential for? Electrical properties of nerve cells and properties of ion channels 32