Neuroscience1201 (Module 2) - Lectures 7-11 - week 3-5 - w/kim hellemans PDF

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Lecture 8 - Genetics and EpigeneticsMolecular Biology living tissue was taken to consist largely of three different materials: carbohydrates, fats, and proteins. Proteins are by far the most complex molecules in our body. They are large, often very delicate, and seem to be critical for all of the bi...

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Lecture 8 - Genetics and Epigenetics! Molecular Biology • living tissue was taken to consist largely of three different materials: carbohydrates, fats, and proteins.! • Proteins are by far the most complex molecules in our body. They are large, often very delicate, and seem to be critical for all of the biochemical reactions that take place in our bodies. ! – The size and complexity of proteins makes them very fragile. By analogy a larger and more complex house of cards is more easily toppled than a smaller one. • For this reason, the name protein comes from a Greek word meaning ‘of first importance’. " • Proteins do a lot of different things, so there are several types to consider:! – Structural: Help to hold cells and tissue together, e.g. collagen. – Enzymes: Catalyze chemical reactions and aid in metabolism, e.g. monoamine oxidase (MAO). – Cell signalling: Peptide neurotransmitters, receptors for hormones, neurotransmitters, and cytokines. • Proteins are giant, complex molecules, but they are built from a very simple set of supplies.! – Proteins are chains of amino acids. There are 20 different amino acids to choose from, and the specific combination changes the function and structure of the protein. The specific combination of where amino acids are in the chain."

What are proteins? • Proteins do not last forever, so your body must not only make new ones as needed, it must also work to replenish old and degraded ones.! • Since proteins are chains of amino acids, building a protein is as simple as stringing together the right amino acids in the right order.

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• DNA is the recipe that tells your cells how to build proteins – which amino acids to use, and which order to put them in. • How does this happen?"

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The Role of DNA • Humans have 23 pairs of chromosomes. Each chromosome is a double stranded molecule of deoxyribonucleic acid (DNA)." • Like proteins, DNA is a chain of simple molecules. There are four nucleotide bases that can make up DNA: – Adenine (A) – Thymine (T)"

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– Guanine (G) – Cytosine (C)" • Unlike proteins, DNA can be copied. This allows for cell division and reproduction.

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• Genes are segments of DNA that code for particular proteins. • So genes are like recipes for proteins. Proteins do all of the work in the cell, but genes tells the cell how to build those proteins.

The Genetic Code • When DNA is sequenced, the end product is simply a string of letters, with each letter representing one of the four nucleotides.

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• You might be wondering how genes can be a recipe for protein. – After all, proteins have 20 amino acids to choose from, but DNA only has 4 nucleotide bases to encode that information. • Genes are organized into codons. Each codon is 3 nucleotides long, and ‘codes’ for a specific amino acid. – For example, AAG codes for the amino acid lysine, and GAC for aspartic acid. – There are 43 possible codons (a total of 64), but a lot of them are redundant."

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The role of mRNA • DNA cannot be directly made into proteins.

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• The process of transcription is the first step in gene expression. During transcription, a gene is copied into a strand of messenger RNA (mRNA).

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• The sequence of each mRNA strand matches the DNA sequence of that gene. – The sole exception to this is that in RNA, thymine is replaced by uracil. Since it’s a 1:1 swap, the meaning of the sequence is not affected. • The second step of gene expression is when mRNA strands are translated into proteins by ribosomes. • Gene transcription occurs in the cell nucleus" • Gene translation occurs in the cytoplasm "

Optogenetics • Transgenic technique that combines genetics and light to control targeted cells in living tissue – Based on the discovery that light can activate proteins"

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• Proteins can occur naturally or can be inserted into cells" • Fibre-optic light delivered to selective brain regions such that all neurons exposed to the light respond immediately"

Epigenetics

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• How changes in gene expression related to experience – Wide range of experiential factors • Chronic stress, traumatic events, drugs, culture, disease! • Example: born in a hot country, move to a cold climate "

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• Fraga and colleagues (2005) – Twins have nearly identical patterns of gene expression early in life, but remarkably different by age 50"

An Example With Greg

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• What made Greg so susceptible to cocaine? • How did his identical twin escape a similar fate? • How is it that some of us are able to maintain recreational drug use, whereas others go on to become addicts? • Epigenetics: the environment can switch on or off some genes • Nature via nurture"

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Epigenetics: The Basics

Genetic mutations alter meaning

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DNA wrapped around clusters of proteins: histones – Further bundled into chromosomes"

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Combination of protein and DNA in chromosomes: chromatin – Helps regulate behaviour of genes; keeps them in inactive state! – If gene is needed, section of DNA unfurls, making gene accessible"

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Epigenetic changes are often caused by physical changes in the structure of chromatin."

Epigenetic changes alter ac-vity

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Histone Acetylation Is an epigenetic mark that relaxes/loosens the chromatin which promotes gene transcription. Stage 1&2"

Histone Methylation Is an epigenetic mark that tighten/condenses the chromatin and decreases gene transcription. "

The Role of the Environment • Can influence gene activity by regulating the behaviour of epigenetic writers and erasers" – Addition/removal of acetyl and methyl groups can help the brain respond and adapt to environment"

Primed for Addiction

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• Can cocaine alter the activity of genes in the brain’s reward centre by changing their epigenetic tagging? – 1h post-injection, 100 new genes switched on – Chronic exposure: some genes turned on by acute exposure fall silent if given every day (“desensitized”); majority show greater activity, highly sensitized • Allows them to “remember” rewarding effects of the drug? Relapse?"

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Marked for Depression

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• Can cocaine alter the activity of genes in the brain’s reward centre by changing their epigenetic tagging? – 1h post-injection, 100 new genes switched on – Chronic exposure: some genes turned on by acute exposure fall silent if given every day (“desensitized”); majority show greater activity, highly sensitized • Allows them to “remember” rewarding effects of the drug? Relapse?"

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▪ This decreases the transcription of “feel-good” genes. ▪ Treating animals with anti-depressants reverses many of these

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▪ Do not show epigenetic changes!"

A Mother’s Legacy

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• Different levels of maternal care – High licking/grooming • Offspring less anxious, produce less stress hormone ! females become high lick/grooming mothers! – Low licking/grooming • Effects of maternal behaviour mediated through epigenetic mechanisms"

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• Low lick/grooming pups – More DNA methylation in a gene encoding the glucocorticoid receptor (mediates stress response) – Less of receptor is made in the hippocampus – Means less able to turn off stress response ! more anxious"

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The Take-Home Message • Your genes are not your destiny. Because epigenetic changes regulate the activity of genes, you are not necessarily doomed by the genes you were born with.

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• The science of epigenetics is showing us that the environment we live in (and make for ourselves) can affect how our genes operate. This appears to be especially important during childhood. – For this reason, it is incumbent on us to seek out the most positive environments for ourselves, and to help create the most positive environments for others.

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• This highlights the importance of providing support to mothers, particularly while they are pregnant. – The environment they encounter during this critical time has a large impact on the future health of their children."

Lecture 7 - Immune System The Mind-Body Connection •

The stress response affects the function of the brain, and nearly every organ in the body. –

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Because stress has a large psychological component, we can take this as an example of the mind affecting the body. ! –

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We can easily feel the physical effects of acute stress on our bodies. After an extended periods of chronic stress the wear and tear on our bodies becomes noticeable in more subtle ways as well.

The reverse is also possible, after all the stress response and its various hormones change how we think.

Since immunity, digestion, and the cardiovascular system are especially affected by stress, we can learn how to improve our health by studying the stress response (and how to minimize chronic stress.)! –

You might call this ‘psychosomatic medicine’, and indeed physical illness with an apparently psychological etiology is often called ‘psychosomatic’ (soma – ‘body’ G.)

What Is Sickness? •

The behaviour and physiology of sick people (and animals) changes dramatically. They tend to:! –

Ignore food and beverages.

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Lose interest in social interaction.

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Have excess or fragmented sleep.

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Have impaired attention and memory.

Feel depressed and irritable.

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The behavioural and cognitive changes that accompany physical illness have been termed sickness behaviour.!

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Sickness behaviour may represent a motivational state responsible for helping individuals cope with infection.!

What is Psychoneuroimmunology?! •

The study of the interaction between the mind, brain, and immune system.

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As we will see, one’s psychological state can interact with the immune system and the immune system can interact with the brain.! – These interactions are important for everything from the common cold to cancer.

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The brain and immune system therefore have bidirectional communication.! – Psychoneuroimmunology is a two-way street.

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This field of study constitutes a major advance from earlier viewpoints that saw infectious diseases as strictly physical phenomena.!

What is the Immune System? • •

The human body is a warm, moist and nutritive environment – a climate perfectly suited for microorganisms o all kinds.! The immune system is responsible for protecting your body from microbial overgrowth. !

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The immune system monitors the internal environment for signs of invasion by bacteria or viruses, as well as evidence of tissue damage.!

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The immune system is extremely powerful, and is highly regulated in order to maintain optimal levels of function.!

How Does the Immune System Work? •

Unlike the nervous system, the immune system is decentralized.! – Immune cells circulate throughout the blood stream and act directly where they are needed.

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Organs such as the spleen, lymph nodes, thymus, and bone marrow act as factories and repositories for immune cells.!

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Like the nervous and endocrine systems, the immune system relies on chemical communication to organize its functions.!

The Immune System, in brief •

The immune system has two basic divisions: ! – Innate immune system. – Adaptive immune system. • Cell-mediated immunity (T cells) • Antibody-mediated immunity (B cells)

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The immune response is a coordinated effort between all three systems that typically follows the same progression (see figure).! – Innate immune system activates the different divisions of the adaptive immune system

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The various branches of the immune system communicate with each other using chemical messengers called cytokines – “cell” + “movement” (G.).! – Cytokines are like hormones for immune signalling (travel in the bloodstream)

The Innate Immune System •

The innate immune system is used for “general purpose” immunity, and is sensitive to molecules that are universally present on bacteria.!

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Cells such as macrophages have receptors on their membranes that bind to pathogens and trigger phagocytosis (phago – ‘eating’, cyto – ‘cell’ (G).! –

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In phagocytosis, the macrophage destroys the pathogen by “eating” it.

When activated, cells of the innate immune system (such as macrophages) release cytokines into circulation.!

The Adaptive Immune System •

The adaptive immune system is activated by cytokines, and involves two systems of leukocytes (white blood cells).!

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Cell-mediated immunity involves T cells named because they develop in the thymus). – T cells are activated by cytokine signals and interaction with macrophages. Once activated, T cells proliferate and develop into a form that attacks body cells that have been infected.

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Antibody-mediated immunity involves B cells named because they develop in bone marrow). – B cells (plasma cells) produce antibodies that bind to antigens on pathogens to kill or deactivate them.

Cytokines & the Immune Response •

After ingesting pathogens, macrophages release cytokines such as interleukin-1 (IL-1) (inter “between”, leukos – “white”).!

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IL-1 stimulates T helper cells to release IL-2.!

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IL-2 induces the proliferation and development of antibody producing B cells (plasma cells) and cytotoxic T cells.

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Cytokines also: – Trigger an inflammatory response (redness, fever, aches, etc.) – Attract more innate immune cells. – Activate the adaptive immune system.

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So in general, cytokines are molecules that coordinate the immune response, and tell the body that it is under attack.!

The Immune System Can Affect The Brain Cytokines In The Brain •

Cytokines are like ‘sickness hormones’, so it makes sense that they can communicate with the brain.

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Cytokines like IL-1 signal sickness to the brain through a variety of mechanisms: – The vagus nerve connecting the brain to the abdominal organs. – Receptors on blood vessels in the brain detect circulating IL-1 or pathogens and stimulate cytokine production in the brain. – Circulating IL-1 can be actively transported into the brain.

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Cytokines in the brain are linked to sickness behaviour. – By informing the brain of infection, cytokines allow the animal to make appropriate adjustments to its behaviour.

Cytokines & Depression • 1.

Sickness behaviour is quite similar to depressed behaviour. Could cytokines play a role in depression? There are three pieces of evidence in favour of this view: Giving people cytokine treatment can produce depressive symptoms.! – Example: AIDS and cancer patients treated with cytokines often develop depression & suicidality.

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Depression is more common among people suffering from inflammatory diseases.! Example: Cardiovascular disease, type 2 diabetes, rheumatoid arthritis.

Anti-depressant treatment improves certain components of sickness behaviour in mice.! – Example: Sick mice show reduced preference for sugar water and social exploration, but these symptoms are improved by anti-depressants.

The Brain Can Affect The Immune System Stress & the Immune System •

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It has been known for some time that the HPA axis can affect the immune system.! – You can think of HPA axis hormones as a negative feedback signal for the immune system. – Cortisol is anti-inflammatory (remember, the immune system increases inflammation via cytokines) This fits into our view that the stress response is designed to help the body deal with short-term challenges. ! – For a short-term challenge, the body can save a lot of energy by shutting down the immune system. This energy can be used to cope with enemy attacks, survive starvation, etc.

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Problems arise when the HPA axis is over- or under-activated. ! – Chronic stress can lead to disease, and the interaction between the stress response and the immune system can explain why this happens. – On the other hand, having a weak HPA axis can lead to the immune system getting out of control.

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Still, this relationship is paradoxical. Stress suppresses immunity, yet seems to exacerbate (increases) inflammatory and autoimmune diseases.! – More later

Acute Stress & Immune Function •

Despite the simple relationship suggested in the previous slide, not all stress suppresses the immune system.!

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In fact, the short-term effect of a mild stressor is to augment immunity.!

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Leukocytes are redistributed following an acute mild stressor. They move from the spleen and blood to the skin, lymph nodes, and other ‘battle stations’. – This may be in order to prepare the animal for physical damage – a wound for example.

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These rapid effects appear to be mediated by the SAM axis, as treatment with epinephrine and norepinephrine can mimic the immune-enhancing effect of acute mild stress.!

Chronic Stress Makes You Sick •

Laboratory experiments that have exposed human volunteers to the common cold find that stress plays a role in getting sick.! – Specifically, they found that the odds of getting sick were directly related to how much stress the person had experienced during the past year. – A positive and optimistic cognitive style seems to protect against developing a cold.

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Exam periods at university are stressors that seem to produce increased rates of upper respiratory tract infection (common cold, influenza, etc.,)!

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The same relationship is seen with other viruses such as influenza, and bacteria like Toxoplasma.!

Stress & Disease •

Other diseases show evidence of being affected by stress. !

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The frequency and duration of genital herpes flare-ups can be reduced by stress control procedures such as relaxation.!

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There is no evidence that stressful life experiences cause cancer, however there is a fair bit of evidence that stress increases the rate of cancer progression and mortality.! – This is difficult to study in humans, as research is typically retrospective, and simply having cancer may colour your perception of past stressful experiences.

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Medical procedures themselves (surgery, etc.,) may be stressful. This danger must be balanced with possible benefits.! – Then again, treatments with no known physiological mechanism may work simply by reducing stress (we call this the placebo effect.) Positive social support seems to support the immune system. This may explain the success of “holistic” medical treatments that incorporate social support.!

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