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BIO 150/250, Spring 2014: Human BehavioralBiology Introduction to Neuroscience, April 20th 2018By Themasap and Kendra + ’12, ’14, ’16 TA’s“The chief function of the body is to carry the brain around.” - Thomas EdisonFunction: communication, transmitting signalsI. A review: the many answers to “why” ...

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BIO 150/250, Spring 2014: Human Behavioral Biology Introduction to Neuroscience, April 20th 2018 By Themasap and Kendra + ’12, ’14, ’16 TA’s “The chief function of the body is to carry the brain around.” - Thomas Edison Function: communication, transmitting signals I.

A review: the many answers to “why” someone behaves the way they do a. Evolution: How is this behavior adaptive for the individual and her offspring? How did it develop over millions of years? b. Molecular Genetics: How do genes explain the mechanism of the evolution of this behavior? How exactly have the genes changed? c. Behavior Genetics: Which specific genes explain why this behavior happens in this way? How much do they contribute to variation in the behavior? d. Ethology: How does the behavior occur in nature? What stimulus elicits the behavior and how does the resulting behavior occur? e. Neuroscience: What is going on in the brain just before the behavior occurs? What cells and parts of the brain make the behavior happen?

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What makes up a brain? The cells of the nervous system Parts of the brain  Frontal lobe o Disproportionately large in humans o Executive memory, planning, higher order functions  Occipital lobe o Processes visual data  Cerebellum o Important for balance  Temporal lobe o Hearing a. Individual cells, rather than a network of continuous elements, make up the brain: the work of Santiago Ramon y Cajal (Nobel Prize in 1906) b. Glia (all cells of brains that are non-neurons) make up a large proportion of the cells in the central nervous system. They are more than just glue! i. Astrocytes – supply nutrients to neurons i.e. metabolic support (neurons need a lot of energy) and regulate their firing ii. Oligodendrocytes or Schwann Cells – make electrical signals faster for neurons (provides myelin that wraps around neurons, providing insulation which makes the signals go faster) iii. Microglia – act as the brain’s immune system to fight infection (respond to brain injury, infection etc.) iv. Ependymal Cells – make and move cerebrospinal fluid through the ventricular system (CSF cushions & protects the brain & regulates the flow of chemicals) (maintains ionic balance) c. Neurons: the wonderfully complicated stars of the show. Our brain has more than 100 billion neurons, each with an average of 10,000 connections (synapses) to other neurons.

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How does a neuron work? Electric gradient At resting sate, is negative. For it to transmit, needs to be positive. There are positive ions just outside of the neuron. Neurotransmitters bind to receptor-gated ion channels, which opens gates so that positive ions can go in. This stimulation results in positive charge, and then there’s action potential which transmits the signal Synapse: action potential in presynaptic neuron releases neurotransmitters into synaptic cleft, and then binds to the receptor-gated ion channels 2 types of receptors: ligand-gated ion channels (neurotransmitter binds, channel opens, ions flow across membrane), and G-protein-coupled receptors (neurotransmitter binds then something happens so gate opens – don’t need to have 1:1 ratio of neurotransmitter to receptor, more like 1:1000) Types of neurotransmitter: excitatory neurotransmitter (glutamate) (activates neuron), inhibitory neurotransmitter (keeps neuron at resting negative charge) Then need to clear neurotransmitters from synapse: one way is for enzymes to degrade the neurotransmitters (they’re super cheap to make for the cell) (e.g. acetylcholine gets degraded by the acetylcholinesterase enzyme into acetate and choline), another is reuptake (neuron uses transporter enzymes that can put the neurotransmitters back into the presynaptic neuron) In Parkinson’s, lose dopamine neurons (dopamine important in brain, e.g. for motor control) Strengthening synapses based on recent activity: long term potentiation (LTP) – if two neurons are active in a similar period of time, more likely to be active together in the future (initially neuron A might only sometimes trigger action potential in neuron B, but after a while will trigger action potential 100% time – potential mechanisms: 1) louder signal, 2) better listener (more receptors – AMPA receptor opens first, then NMDA one, and also once NMDA activated, creates more AMPA receptors)) a. Receive a chemical signal (synapses at the dendrites) b. Convert the chemical signal to an electrical signal (dendrites) c. Decide whether to pass on the signal to other cells (axon hillock) d. If so, send an electrical signal (axon) e. Convert that electrical signal to a chemical signal for the next cell (axon terminal) A neuron at rest: generating the resting potential

a. The neuron is a special cell that by its very nature needs to communicate signals quickly (more so than any other cell in the body). In order to make its message understood, a neuron makes a clear distinction between sending a LOUD message and being QUIET. The resting potential is the neuron’s way of staying QUIET until it decides to send a message. b. Neurons send their electrical messages through the movement of ions (charged atoms) across their cell membranes. c. At rest, the neuron keeps higher levels of one type of positive (+) ion OUTSIDE the cell. The net result is a negative charge inside the cell compared to the outside. d. A neuron creates this resting potential by using protein pumps in its membrane to actively pump some of the positive ions out of the cell. One main example is the Sodium/Potassium pump (Na/K), which dumps out three positively charged sodium (Na+) ions for every two positive charged potassium (K+) ions it takes in. The net result is a net negative charge of -70mV across the membrane (with the outside being MORE positive than the inside of the cell). The pump also creates a high concentration of sodium (Na+) ions outside the cell and a high concentration of potassium (K+) ions inside the cell at rest. e. The negative resting potential gives the external Na+ ions a high electrochemical potential because they are crowded together with like charges and attracted to the negative charges on the other side of the membrane (“electro”) and are crowded together with the same chemical ion while there are very few Na+ ions on the other side of the membrane (“chemical”). This means that once the membrane is made permeable to Na+ ions, the ions will have a huge impetus to flow down their electrochemical gradients into the neuron. V. A neuron in action: generating the action potential 1. When a neuron receives a chemical signal from another neuron, it opens ligand-gated (neurotransmitter-activated, ionotropic) channels on its membrane (at the dendrite receiving the signal) to let the positive ions flow into the cell from the outside. This makes the neuron less negative compared to the outside (more depolarized). 2. The signals from the dendrites get summed up at the axon hillock. If the difference in charge between inside and outside gets to a certain threshold here (say, -55mV in some cells), the neuron initiates an action potential. It opens up many voltage-gated Na+ channels to let positively charged sodium ions in. 3. Once this happens, there is no turning back! The neuron continues to let sodium ions in, and more channels start to open further down the axon to let ions in all the way down to the terminal. This process is called depolarization. Sodium channels stay open until an upper limit (say, +40mV). The steady state for resting membrane potential and peak

excitation depend on which of the 10,000 different neuronal subtypes one is recording from. 4. Once the action potential has passed through any given point on the axon membrane, the neuron ends the signal by closing sodium channels and quickly opening up potassium channels to let potassium out of the cell and restore the

charge balance, in a process called repolarization. Now, why would potassium “want” to flow out of the cell? This is because both the electrical and concentration gradients favor this process. Electrically, due to depolarization, the inside of the cell has become more positive than the outside, and thus potassium, being a positive ion, will want to flow down its electrical gradient. Additionally, as we know, the concentration of potassium inside the neuron is a lot higher than it is outside, and thus potassium will also want to flow down its chemical gradient. 5. Often, due to a lag in potassium channel closing, the process undershoots the resting membrane potential (thereby making the inside of the cell more negative, say -80mV), in a process known as hyperpolarization. Why is this process useful? This is because the neuron needs to make it ABSOLUTELY clear that the signal is over. As the neuron SHOUTS that it is excited/stimulated by depolarizes, so does it QUIET down by hyperpolarizing. This QUIET period is called the refractory period and usually lasts 1 millisecond. During the refractory period, a new action potential cannot be started yet. This clearly delineates the end of the action potential and promotes unidirectional signal transduction (preventing the action potential from moving backwards). 6. At the end of the refractory period, pumps (such as Na+/K+) on its membrane then help restore the difference in ion levels between the outside and inside of the cell, restoring the levels back to the resting membrane potential of -70mV. The voltage changes at a point on the axon membrane as the action potential passes through:

KEY NOTE #1: The action potential is an all-or-nothing signal. There are not stronger or weaker action potentials; as long as the ion flow from the dendrites gets the cell to at least its threshold, the neuron will always fire the same strength action potential. If the ion flow does not get the neuron to its threshold at the axon hillock, no signal is sent. KEY NOTE #2: The importance of individual differences and plasticity.

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There are differences that exist both at the cellular and organismal levels. Individual neurons vary greatly in responsiveness to certain stimuli. Thresholds, for instance, the threshold required to initiate an action potential at the axon hillock can vary between different individual neurons or individual organisms. There is enormous plasticity in the nervous system. There can be changes in the axon hillock threshold (a greater or smaller stimulation required to generate an action potential). For instance, say that in a neuron that is instrumental in the cocaine addiction pathway, an action potential is generated when the voltage reaches -55mV. Over time, the individual develops a “tolerance” for cocaine, and the threshold could reach -50mV. In other words, a greater stimulation at the dendrites, in the form of a greater influx of the stimulant, i.e. cocaine, is necessary to achieve the desired output, i.e. an action potential. There can be changes in the hyperpolarization threshold. For example, assuming a change in the potassium channels that allows them to close faster. Therefore, instead of hyperpolarizing to 10 mV below the resting membrane potential of -70 mV (i.e. -80 mV), the potassium channels close more quickly and the neuron thus stops hyperpolarizing past -75 mV. This

When the sodium ions flow in at the axon terminal, this change in ion concentration causes the terminal to release chemicals into the synapse and on to the dendrites of the next cell, communicating the signal onwards. 1. Easiest way to think about this is that the axon terminals (i.e. the ends of the axons farthest away from the cell body) of one neuron are communicating the signal with the dendrites of another neuron OR muscle cell. For instance, assume that you need to flex your biceps to impress another individual. The motor neuron (i.e. a type of neuron responsible for locomotion) that connects to your biceps fires an action potential, and chemical transmitters are released from the axon terminals of this neuron that bind to specific receptors on your muscle cell. Your muscle flexes, and the other individual is impressed. Mission accomplished. 2. What are these chemical messengers? They are known as neurotransmitters, and they encompass a diverse array of molecules. 1. Simple and plentiful precursors, such as amino acids 2. Cheap to create; only requires a few biosynthetic reactions 3. Dozens of neurotransmitters, but not millions or billions. Why? Because there are multiple applications of the same neurotransmitter (i.e. the same neurotransmitter can be used for a variety of purposes in different parts of the brain). 4. Specific neurotransmitters: 1. Glutamate – excitatory neurotransmitter 2. GABA – inhibitory neurotransmitter 3. Dopamine – reward pathway 3. What happens at the synapse? The neurotransmitter diffuses within the space between the axon terminal of the first cell and the membrane of the second cell, in

a space known as the synapse, or the synaptic cleft. The first cell (i.e. the one that the neurotransmitter originates from) is known as the presynaptic cell, and the recipient action potentials in rapid succession, as it is able to reach resting membrane in a motor neuron, a potential long-term consequence is the disease epilepsy, renders the neuron more able to fire

potential of -70 mV a lot faster. The neuron is thus more excitable. If this happens which presents typically with seizure-like activity. As we will see below, there are enormous possibilities for plasticity within the individual proteins. The sodium or potassium “channel" is actually another protein, thus a gene with introns/exons. Using the example above, plasticity is possible from cocaine exposure at the protein level; a change in alternative splicing patterns within the gene that codes for the sodium channel can produce an entirely different channel, one which may open or close at a slightly different threshold, thereby altering behavior. cell is known as the postsynaptic cell. The neurotransmitter binds to chemical receptor molecules located on the membrane of the postsynaptic cell. The binding of neurotransmitter causes the receptor molecule to be activated in some way. This is the key step by which the synaptic process affects the behavior of the postsynaptic cell. 4. What happens to the neurotransmitter once it does what it’s supposed to do? The neurotransmitter can be reabsorbed by the presynaptic cell and then repackaged for re-release following a later action potential, in a process known as reuptake. It can also be broken down metabolically. 5. One neurotransmitter can have many roles: Dopamine is important in both schizophrenia and Parkinson’s. Some treatments for schizophrenia reduce dopamine activity, and some treatments for Parkinson’s increase dopamine activity. One of the side-effects of antipsychotic medication is Parkinson’s-like symptoms. Similarly, serotonin is important in depression, and the most frequently-prescribed medications for depression affect serotonin. Serotonin is also central for gut motility, though, and one of the side effects of medication for depression is digestive problems. 6. In the end, it is proteins/genes/evolution/etc behind all the enzymes that make the neurotransmitters, the enzymes that degrade them, the reuptake pumps, the receptors... And a cool video that sums it all up: http://www.youtube.com/watch?v=90cj4NX87Yk 4/23/18 1:1 not enough  Temporal summation – multiple signals coming one after the other  Spatial summation – multiple signals coming from different places So what if all the neurons are sending conflicting signals?  Spatial sharpening – if a particular neuron has a really important message, it will send inhibitory dendrites to neighboring neurons (the further away the less intense because less likely to interfere) o Example: if your eyes see something bright, everything around it seems darker  Temporal sharpening o Inhibitory dendrite goes back to itself which inhibits itself (so you get series of action potential and then it stops)

o Can use other neurons: another neuron inhibits the original one after message sent o Or can use other neuron to silence the neuron you just sent message to after it passes it on Visual processing  First layer detects various dots  Then gradually have neurons that sum those dots and detect lines  Then gradually have neurons that sum those lines and detect moving lines  Then eventually have neurons that see complex images (e.g. grandmother neurons detect your grandmother – grandmother hypothesis however has been disproven?) Memory, brain  How does memory work? o Grandmother hypothesis disproven? o Remember things through networks  Hippocampus: inputs memories and then forming memories in other parts of brain  Patient HM had no hippocampus because of surgery o Didn’t lose old memory because hippocampus doesn’t store memory o However couldn’t remember new things because hippocampus inputs memory  CNS (Central Nervous System): brain & spinal cord o Core processing unit o Take in information and release it  Peripheral Nervous System (PNS): everything else o Sensory neurons take in information to brain o Motor neurons allow you to move  Parts of brain o Frontal lobe: executive function, voluntary movement, high-level thoughts o Parietal lobe: sensory, e.g. touch, taste o Occipital lob: visual cortex o Temporal lobe: language, vision o Cerebellum: simple things like breathing, temperature regulation, sleeping, circadian rhythms  What is a brain region? o Region, or brain structure, is a cluster or sheet of densely packed neuron cell bodies o Axons can project within the brain region, or to different parts of the brain  Phineas Gage o Worked on a railroad, had a loving family, great citizen o Got into an accident where a massive crowbar went through his brain o Personality entirely changed – got into fights, unpleasant o Went through his left frontal cortex, which has a lot to do with inhibitions and personality  Can map parts of brain to various body parts

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Remember some things appear twice – brain 3D, bilateral? The Triune Brain model (3 layers) o More simple from back/lower -> more complex from front/top o ‘Ancient’ brain: bottom, back of brain  Named as such since we share this with basically all other animals, e.g. lizards, bugs, rats. Controls base functions, e.g. sleeping, circadian rhythms, temperature regulation, hunger  Hypothalamus: command center of basic behaviors, e.g. if you’re cold, coordinates response, if you’re hungry, releases certain hormones etc. o The limbic system: middle of brain  One word: emotion  Used to think this was just olfaction since studied in rats, and for rats everything done through smell (e.g. pheromones etc.)  Amygdala: responsible for fear, aggression, male sexuality. Communicates directly with body for stress response  Septum: acts to inhibit aggression (acts in opposition to amygdala), also responsible for many reward pathways  Hippocampus: responsible for declarative memory (what you remember)  Mammillary bodies: not important, some component of maternal behavior, oxytocin, just part of limbic system  Two goals (of all different parts): 1) control hypothalamus 2) prevent other structures from controlling hypothalamus (e.g. prevent other parts of limbic system from controlling hypothalamus) o Cortex: makes us human (arch across the top)  Higher thought, recognition, sing songs, write songs, what makes us complicated  Far more developed in humans than other species, more in primates than in other species  Frontal cortex: executive function, front part o Expectation: cortex to ancient brain to body, but reality often like: limbic system to ancient brain (e.g. if emotional, palms sweaty); or sensory inputs to limbic system (two groups, one given warm cup of coffee, other given cold cup of coffee – warm coffee people more likely to rate other people as warm, friendly, cold coffee people more likely to rate other people as cold – so sensory factors affect emotional response); or cortex to limbic system (e.g. reading about climate change, something intellectual, become sad for grandchildren’s future, emotional response); or limbic system to cortex (e.g. amygdala fires to a...