Quiz 3

Neuropathology of Alzheimer's: Amyloid Plaques and Neurofibrillary Tangles

Amyloid plaques and neurofibrillary tangles are the two major pathological hallmarks of Alzheimer's. Buildup of amyloid beta plaques in the extracellular space and accumulation of neurofibrillary tangles in the intracellular space. Amyloid beta peptides, which cause amyloid plaques, are thought to lead to the death of neurons in the hippocampus and prefrontal cortex. Neurofibrillary tangles destabilize and displace cellular components of neurons. There has been some evidence to suggest that amyloid beta plaque formation doesn't necessarily correlate with cognitive dysfunction; therefore, it is likely that there are multiple things happening with the disease etiology to disrupt cognition. Even as much as we know about AD, there is still a disconnect between the pathology and the actual mechanism of neuron cell death.

Louis Wain

Artist who first became famous in 1866 for publishing illustrations of cats. Developed schizophrenia and was institutionalized, but continued to draw and paint cats. His drawings of the cats after being diagnosed with schizophrenia are starkly different; shows how schizophrenics' view of the world changes. The world seems disordered and you can't make sense of it; it can make you have more anxiety and feel threatened.

Dmitry Belyaev: Domesticated Silver Foxes

Bred silver foxes based on their temperament in order to domesticate them. Took foxes that were not aggressive and more approachable to humans and bred them together; started to see changes after about 10 generations. After 40 generations of inbreeding, the foxes became docile; the foxes were friendly and very playful and liked to engage with humans rather than being aggressive or scared; changes in fur color and ear shape; loss of musky fox smell. In these docile foxes, the adrenaline levels were significantly lower than normal; lower adrenaline is thought to play a role not only in their fear/stress response to humans but also the change in their fur color (adrenaline shares a biosynthetic pathway with melanin). Highlights that some of these genes that are contributing to friendly/interactive behavior might also be linked to other genes that contribute to things in development or hormones. Good example of why a lot of the physical characteristics of some domestic animals are a lot different from their wild relatives. If the docile foxes were bred with wild animals, the offspring showed intermediate behavioral phenotypes; supports the idea that some of these personality/temperament aspects are genetically encoded.

Schizophrenia Article Summary

C4 genes (C4A and C4B) exhibit a distinct relationship with schizophrenia risk. Association is the most strong with variants that increase C4 expression. C4 promotes maturation of neuronal circuits by targeting synapses for elimination. Over-expression of C4 in the human brain may result in hyperelimination of synapses over the course of development. Pathological findings show loss of grey matter without cell death and reduced numbers of synaptic spines on cortical pyramidal neurons (specifically during adolescence and early adulthood is where we start to see the biggest manifestation of symptoms).

Why do drugs become addictive?

Drugs that produce addictive behaviors all converge on the mesolimbic pathway; hijack this pathway and cause changes in the signaling of these pathways to produce addictive behavior. Drugs make us feel good and become addictive because of their effect on the mesolimbic pathway; their other effects have to do with their neurochemical interactions in other areas of the brain. Generally, drugs of abuse increase the amount of dopamine release by 2-10X the amount of dopamine as natural rewards. In some cases, this occurs immediately (e.g. when drugs are smoked or injected) and the effects can last much longer than those produced by natural rewards. This creates a much stronger effect on the brain's pleasure circuit than those produced naturally (e.g. food, sex). The effect of such a powerful reward strongly motivates people to take drugs repeatedly. Most drugs of abuse will either directly or indirectly impact dopamine release from the VTA onto the NA.

Environmental Risk for Schizophrenia

Many of these environmental stressors that can increase the risk for developing schizophrenia occur during or prior to adolescence. Prenatal infections. Perinatal hypoxia. Drug abuse and stress during early adolescence. All of these environmental factors work with the genetic susceptibility to do things like changing gene expression and connectivity, and impairing information processing that will ultimately lead to altered behavior, cognition, and emotion.

Environmental Influence on Cognitive Ability in Humans

The other 50% of variance can be attributed to the environment. Data from adoptive siblings (i.e. siblings that are not genetically related but share an environment) and PO (i.e. parents that are not genetically related to their offspring but share the same environment) show that environment does play a role in cognitive ability. DZ twins raised together have a higher correlation than siblings raised together; because DZ twins share a uterus and develop at the same time, this suggests that there may be some prenatal environmental factor that could play a role in cognitive ability; DZ twins likely also have a more similar environment since they are in the same grade, share more friends, etc. Analysis suggests about 25% of variance is due to shared environment.

Genetic Influence on Cognitive Ability in Humans: Twin and Adoption Studies

Twin and adoption studies support that cognitive ability is heritable in humans; there is some genetic underpinning to the variation we see in cognitive ability across the population. On the graph, correlation is essentially the same thing as concordance rate (index of resemblance between the two siblings). Family designs: looked at first degree relatives that live together; PO means what is the relationship between parent and offspring and sib refers to genetically related siblings in individual pregnancies (i.e. not twins); results show there is some positive correlation, but they're all experiencing the same environment so it could mean that there is a genetic underpinning OR it could be due to environmental factors. Twin designs: MZ and DZ twins that live together; MZ twins had a very high concordance rate and DZ twins had a lower concordance rate than MZ twins; suggests a strong genetic component, but these individuals are also experiencing the same environment. Looking at adoption studies gives us an idea of the environmental influence over cognitive ability. Adopted-apart: study looked at parents and offspring (i.e. offspring adopted away) or siblings (i.e. siblings adopted to separate households) that were adopted apart from each other; these individuals share heredity but not environment; showed some correlation, which indicates that there is a genetic underpinning to cognitive ability. Adopted-apart twins: MZ twins adopted apart from each other; provides us with a direct estimate of heritability because we are only looking at genetic relatedness; suggests that there is a really high heritability for cognitive ability; twins that are 100% genetically similar living in different environments still have very high correlation in their cognitive function. Analysis of all studies suggests that 50% of the variance in cognitive ability is due to genes (50% heritable).

Groups of Genes that Contribute to Schizophrenia

1. De novo mutations/alleles: not found in a family pedigree; isolated cases of schizophrenia in a family that didn't have any previous schizophrenia cases; high number of de novo CNVs (genes that are replicated so we have multiple copies); SNVs and indels particularly in NMDA receptors and cytoskeleton proteins 2. Rare alleles: genome-wide increase in CNVs 3. Common alleles: polymorphisms that are quite common and are linked to about 50% of the variance in schizophrenia risk; shared polygenic overlap with disorders such as BD, MDD, and ASD

Prevalence of Alcohol Abuse

16.6 million adults (18+) suffer from alcohol use disorders in the US. Affects more men than women; this is starting to flip. 88,000 people die annually from alcohol-related causes. 30.8% of all driving fatalities; 3rd most preventable cause of death. Chronic use of alcohol can cause neurological, hepatic (liver), gastrointestinal, or cardiovascular problems.

Summary of Influences on Cognitive Ability in Humans

50% of the variance is due to genetic factors. 25% of the variance is due to shared environment. 17% of the variance is due to non-shared environmental influences. 8% is due to measurement error. These results are largely based on children; can this change over the course of development? The importance of our heritability usually decreases as we age; genetic differences become less important as experiences accumulate over the course of our lifetime. However, in g we find the opposite; heritability and genetics in cognitive ability plays a bigger role as we age.

Environmental Risk Factors for Schizophrenia: Preconception

A lot of the preconception factors have to do with creating a space for de novo mutations (e.g. advanced paternal age as a risk factor for schizophrenia - as males age the fidelity of DNA replication in the sperm is decreased, which can increase the number of de novo mutations in an individual and can be passed on). Preconception factors: -Advanced paternal age (55+) -Prolonged delay between pregnancies; as genotypic women get older the genome in the oocytes becomes more fragile, which leads to propensity for genetic mutations -Parental smoking, drinking, and substance abuse -Exposure to pollution

Contributions to AD

AD is a complex interplay between genetics, aging, environment, and metabolism. There are not very many good treatments for AD, most try to manage symptoms or slow progression. An interesting approach that is now starting to be taken is to use an alternative energy source in the brain; put individuals on a ketogenic diet. A ketogenic diet allows the body to create ketone bodies, which can serve as an alternative energy source to maintain normal brain energy production (especially when there's disrupted glucose metabolism). It has been shown that allowing the cells to metabolize ketone bodies does a lot of the same things glucose metabolism does to suppress the formation of amyloid plaques and neurofibrillary tangles. Early data has shown that about one third of patients tested on these ketogenic diets have shown significant clinical improvement.

Linkage Studies of Alcoholism in Humans

Additionally, linkage studies have identified a number of QTLs (e.g. ADH cluster on chromosome 4). In addition to ADH genes, polymorphisms were found in genes encoding critical components to neurotransmission (D2R dopamine receptors and GABA receptors). This makes sense because if alcohol is becoming addictive by influencing the pleasure center of the brain which is predominantly dopaminergic, we see polymorphisms in dopamine receptors that can affect risk for developing alcohol dependence; GABA receptors are also the principal substrate for alcohol in the brain.

Defining Risk Alleles of Alcoholism

Alcoholism: has been identified since 1849; chronic disease characterized by impaired control over drinking, preoccupation with alcohol, and use of alcohol despite adverse consequences. Alcohol dependence is a much more accurate description of alcohol addiction rather than just impaired control or preoccupation; it is a physiological dependence. Spans many phenotypes; individuals will engage in anything from abstinence to middle of the road alcohol use that doesn't have an ill effect to heavy drinking to addiction. Alcohol sensitivity, development of tolerance, and susceptibility to addiction vary in the population.This suggests that there are multiple interacting genes with individually small effects; expression depends on the environment; has the elements of a quantitative trait. Relatively little is known about the genetic architecture that predispoposes an individual to alcohol addiction. Risk genes are difficult to identify: -While it's easy to discriminate the extremes (e.g. abstinence vs abuser), it is challenging to precisely quantify a level of alcohol intake and the extent of dependence; difficulty obtaining unambiguous quantitative phenotypic values; a lot of this has to do with how we rely heavily on self-reporting, which sometimes makes it challenging to get an accurate picture of what their drinking and dependence is like -Confounding genotype-by-environment effects; can't isolate humans in specific environments -Insufficient sample sizes; too small

Genes for Amyloid Plaques and Neurofibrillary Tangles

Amyloid beta plaques are the result of a buildup of a peptide called A-beta peptide. A-beta peptide comes from the break down of APP protein. APP is an integral membrane protein and gets cleaved into smaller components; these smaller components are what cause the plaques by sticking together and creating aggregates. APP's normal function in the brain is unclear, but it may be a signaling molecule, particularly being cleaved or activated in the case of injury. However, we know APP is important for normal brain function because when we knock it out the animals die in utero; shows that APP is important at some level for neuronal development and survival. APP is typically cleaved throughout our lifetime; typical healthy brains will cleave APP and we will have some level of amyloid beta peptides in the extracellular space. Generally in a healthy brain these amyloid beta peptides are soluble and can be cleared and degraded; what we see in Alzheimer's is defects in the ability to clear and regulate amyloid beta peptide buildup; this allows for amyloid beta peptides to accumulate and generate plaques. Early onset AD results from dominant mutations in genes that regulate amyloid beta processing: -Presenilin 1 (PSEN1) -Presenilin 2 (PSEN2) -Beta-amyloid precursor protein (APP) Presenilins are the enzymes that cleave APP into its amyloid beta subunits. These mutations lead to increased plaques and can cause changes in cognitive function.

Phenotyping Alcoholism

Assessments of alcoholism are dependent upon self-reporting. Typically genetics studies use the "CAGE" questionnaire: -Have you ever felt the need to Cut down on your drinking? -Have people Annoyed you by criticizing your drinking? -Have you ever felt Guilty about drinking? -Have you ever felt you needed a drink first thing in the morning (i.e. Eye opener) to steady your nerves or get rid of your hangover? These questionnaires can often be confounded by other comorbid disorders (depression, anxiety, schizophrenia); may cause you to answer yes to some of these questions even though you aren't necessarily abusing alcohol. The majority of what we understand about genes related to addictive behaviors comes from animal models; animal models allow us to precisely quantify addictive drive and intake amounts, which we can't do in human studies. Frequency of drinking to develop alcoholism varies among individuals. Environmental variation and genotype-by-environment interactions can confound results.

C4 Haplotypes

C4 exists as two isotypes: C4A and C4B. These isotypes vary in structure and copy number. An isotype is a slight phenotypic variation in a gene that allows it to encode different but functionally similar proteins. Typically about 1-3 copies are present in tandem within the MHC locus. C4A and C4B bind to slightly different molecular targets. What distinguishes the long and short forms are the presence of HERV (human endogenous retroviral insertions).

C4A Protein Localization in Human Brain Tissue

C4 protein is expressed by neurons in the hippocampus. Localized specifically to both pre- and postsynapse. NeuN is a neuronal specific marker. Hoechst stains DNA. PSD95 is a postsynaptic marker. VGLUT1/2 is a presynaptic marker. Found that the greatest number of C4+ cells is in the hippocampus and it seems to be localized specifically along axons and at synaptic specializations in human brain tissue, suggesting that C4 is produced and/or deposited on neurons and synapses.

Alcohol Sensitivity in Model Organisms: C. elegans

Can use C. elegans to study some addictive behaviors C. elegans and ethanol: acute exposure causes rapid decrease in locomotion and causes loss in muscular tone (animals become more relaxed and straightened out); animals also develop tolerance with chronic exposure. While we cannot assess behavioral drives, we can assess development of tolerance within the nervous system. Study did a genetic screen to look for animals that were resistant to alcohol-induced relaxation, and found several alleles of a gene called slo-1 that confers resistance to ethanol exposure. Animals that had loss of function mutations in slo-1 were relatively unaffected by alcohol. Over-expression of slo-1 makes animals hypersensitive to ethanol.

Alcohol Sensitivity in Drosophila: Genes that Contribute to Tolerance

Catecholamines (particularly tyramine and octopamine) have been shown to play a role in sensitivity and tolerance. Tolerance is reduced in flies with mutations in tyramine B-hydroxylase (Tbh; converts tyramine into octopamine). Tyramine and octopamine are the equivalents of norepinephrine and epinephrine in the invertebrate nervous system. Stress can also affect tolerance; e.g. heat stress can elicit the induction of tolerance to subsequent alcohol exposures (exposing flies to a heat shock results in relative tolerance to ethanol exposure after), which suggests common pathways. Transcription factor "hangover" is a component of this pathway. The induction of tolerance is eliminated by mutations in hangover. Wildtype flies and flies without Tbh have typical responses to heat shock and ethanol exposure; hangover mutants seem to have reduced cross-tolerance (do not become tolerant to ethanol following heat shock). Hangover mutants have decreased tolerance to alcohol. When we do ethanol-ethanol exposure, we find that octopamine is playing a bigger role in specifically tolerance developed to ethanol; if we knockout Tbh we reduce tolerance and when combined with hangover mutant it is reduced even more. Suggests that tolerance to ethanol exposure likely requires octopamine signaling to induce transcription of genes via hangover activation. Highlights that the ability to develop tolerance to a drug of abuse can also be dependent on our environmental stressors; not only highlights possible neural correlates, but also gets to the fact that stressors can influence our genetic predisposition for developing alcohol-dependent behaviors. Catecholamines (particularly tyramine and octopamine) have been shown to play a role in sensitivity and tolerance. Tolerance is reduced in flies with mutations in tyramine B-hydroxylase (Tbh; converts tyramine into octopamine). Tyramine and octopamine are the equivalents of norepinephrine and epinephrine in the invertebrate nervous system. Stress can also affect tolerance; e.g. heat stress can elicit the induction of tolerance to subsequent alcohol exposures (exposing flies to a heat shock results in relative tolerance to ethanol exposure after), which suggests common pathways. Transcription factor "hangover" is a component of this pathway. The induction of tolerance is eliminated by mutations in hangover. Wildtype flies and flies without Tbh have typical responses to heat shock and ethanol exposure; hangover mutants seem to have reduced cross-tolerance (do not become tolerant to ethanol following heat shock). Hangover mutants have decreased tolerance to alcohol. When we do ethanol-ethanol exposure, we find that octopamine is playing a bigger role in specifically tolerance developed to ethanol; if we knockout Tbh we reduce tolerance and when combined with hangover mutant it is reduced even more. Suggests that tolerance to ethanol exposure likely requires octopamine signaling to induce transcription of genes via hangover activation. Highlights that the ability to develop tolerance to a drug of abuse can also be dependent on our environmental stressors; not only highlights possible neural correlates, but also gets to the fact that stressors can influence our genetic predisposition for developing alcohol-dependent behaviors.

Hallmarks of Addiction

Chronic and compulsive craving to continue a behavior so that it evokes an emotional response and as energy is expended seeking objects addiction this increases the addictive drive; behavior becomes incompatible with normal daily activities. Addiction: recurring compulsion by an individual to engage persistently in some specific activity. Because people who exhibit addictive behaviors become so engaged with those behaviors they often forego other daily activities, addiction has been recognized as a maladaptive psychopathology; although we have the brain centers for it and reward reinforcement is important for our survival, the enhancement of activity in this brain region is maladaptive. Dependence: presence of withdrawal symptoms upon termination. Withdrawal symptoms are produced by the body to compensate for the unusual effects of the drug; usually opposite effect. Physical symptoms: physical discomfort, intense pain, vomiting, or nausea. Psychological symptoms: cravings, irritability, and depression. Someone who is engaging in addictive behavior will continue to do so to avoid the withdrawal symptoms (remain in a normal state).

Cognitive Ability in Animal Models: Robert Tryon

Cognitive abilities in animal models are based on assays that investigate problem solving and learning. We can't directly ask animals if they remember something or how they would solve a problem, but we can have them do something like solve a maze and see how good their learning and memory is. Robert Tryon (1940s) selectively bred mice for their ability to navigate a maze to find food; this study started to highlight that there is a genetic component to problem solving. Took the mice that did very well on the maze and mated them together and took the mice that did very poorly on the maze and mated them. Ended up with a dramatic separation between these two populations that occurred relatively quickly; illustrates that there are genetic influences that underlie cognitive ability.

Does heritability change during development? - collective data

Collective data from a wide variety of studies shows that the shared environment is an important feature of cognitive ability during early developmental times, however, its importance fades during adulthood as influences outside the family increase. Heritability starts to become more important in adulthood. Why does heritability increase during the life course? -Small genetic effects "snowball" over time -As we age, intellectual experience is more self-directed; more likely that adults who have a genetic propensity towards high cognitive ability might keep up with those mental activities by reading, investigating, thinking about problems, etc.; may reinforce genetic differences

Cognitive Ability in Animal Models: Cooper and Zubek

Cooper and Zubek took the mice that Tryon had developed (dull and bright mice) and placed them in a variety of different environments. Goal was to observe the environmental influences; can cognitive influence be influenced by the environment? 3 different conditions: -Standard condition: normal laboratory setup; free access to food and water -Impoverished condition: mouse in social isolation -Enriched condition: many animals that have lots of stuff to play with and other mice to interact with Found that these enriched conditions did not have a dramatic effect on the bright mice; however, there was a dramatic difference in the dull mice. When dull mice were placed in enriched conditions it enhanced their abilities in the maze just through environmental influences. Conversely, the restricted environment is very detrimental to the bright mice; performed very poorly on the maze. This study illustrates the power of environmental influence when we think about cognitive ability; there isn't really a simple answer concerning the effect of the environment on cognitive function, but we do see genotype-by-environment interactions where different environments are affecting specific genotypes in different ways. Genotype-by-environment interactions are found in enriched and restricted environments.

Specific Cognitive Disabilities: Dementia

Dementia is typically classified as a specific cognitive disability, however, over the progression of the disease it becomes more general; some of the classic hallmarks of late stage dementia are impairments in general cognitive function. Impairment of memory, reasoning, and abstract thinking. Alzheimer's disease is responsible for over half of the reported cases of dementia. Alzheimer's is a progressive disease for which there is no cure. The biggest risk factor for Alzheimer's, specifically late onset Alzheimer's, is aging (i.e. not necessarily a genetic link but rather progressive disease that occurs with the aging process). Alzheimer's is associated with the selective damage of brain regions and neural circuits critical for memory and cognition (cortical dementia). Prefrontal cortex, amygdala, hippocampus, and the basal ganglia are the most affected brain regions. There are two different disease progressions for Alzheimer's: early vs late onset. In early onset Alzheimer's, we find most of the cases to be familial (i.e. there is a genetic underpinning). Late onset Alzheimer's is mostly sporadic cases that are related to the aging process as opposed to having a genetic correlate.

Heritability of Depression

Diagnoses of MDD are highly correlated among first degree relatives, suggesting that there is a high heritability. MZ twins have greater concordance rates than DZ twins. These correlations did not result from shared environments. Mood disorders appear to be particularly responsive to non-shared environment (specifically environmental influences that are associated with psychological and physical stress). Study looked at 2000 female twins and found that there was an increase in genetic predisposition in depression that was correlated with an increase in stressful life experience; this shows that the depressive episodes did not correlate always with the timing of the stressful life events; the overall theory that this study put out was that predisposing genes may increase psychiatric dysfunction but may also overlap in contribution of selecting more high risk/stress types of environments; genetic overlap between development of psychiatric disorders and personality traits.

Personality Traits

Distinguishing and enduring qualities or characteristics of an individual's behavior. Essentially our tendency to think or act in a similar fashion in response to a variety of stimuli. The predominant theory in behavioral genetics research is the five factor model (FFM). The FFM is a rating scale from 1 (strongly disagree) to 5 (strongly agree) that assesses personality based on self-ratings in response to questions about: -Openness -Conscientiousness -Extraversion -Agreeableness -Neuroticism Does not identify you as a specific personality type, but instead rates individuals on a continuum of each of these 5 traits. Some of the caveats to the FFM is that these are tests based on our self-ratings, so it requires that we have a deep understanding of our own personality and that we don't lie on the test. This FFM is a pretty good metric for thinking about personality traits and how we understand what types of genes are related to each of these categories.

Alcohol Sensitivity in Model Organisms: Drosophila

Ethanol is actually a normal component of the environment for drosophila; ethanol is a byproduct of fermented fruits. Exposure to high concentrations of ethanol causes: -Initial hyperactivity -Over time as alcohol concentrations increase they lose mobility and postural control -Can also become sedated over time Looks similar to what we see in humans. Inebriometer: measures intoxication in flies. Put flies in the inebriometer and expose them to alcohol and quantify the amount of time it takes for them to pass out; when they pass out they fall out of the tube and we can count how many flies fell and how long it takes for them to fall. Mean elution time: how long it takes to fall out of the device. This method is a pretty reproducible measurement of their sensitivity to alcohol. Most animals fall out/become sedated at the same time. Wildtype animals take about 20 minutes to fall out of the tube. Animals that are hypersensitive to alcohol take less time to fall out of the tube. Animals that are more tolerant/resistant to alcohol take a longer time to fall out of the tube.

Quantitative Inheritance: Behavior

Examples of human behaviors: -Mood -Personality -Cognition -Social -Instinctive Cognition falls under this category of human behaviors that are quantitative traits (explained by many genes that contribute to the development of cognitive function). Therefore, we see a wide distribution in cognitive abilities in any given population. Reminder about quantitative traits: -Influenced by multiple genes -Responsive to environmental influences -Normally distributed across a range of phenotypic expression Quantitative behavioral traits can be assessed using a standardized quantitative rating scale that produces a numerical score. For cognitive ability, this is frequently measured by using the IQ score. The IQ score is a composite of diverse tests of cognitive ability and is used to provide an index of general cognitive function. IQ scores can be quite powerful in the study of genetics.

Drosophila Model of Tau Induced Neurodegeneration

Experiment over-expressed a wildtype and mutant form of human tau protein (R406W) in the Drosophila brain. These mutations in human tau protein are found in familial cases of AD. Found that in tau mutants neurons underwent progressive degeneration. Experiment showed that the accumulation of tau protein caused neurotoxicity, but did not lead to formation of tau tangles. Therefore, it seems as though the hyper-phosphorylation of tau in transgenic flies promoted neurodegeneration, but they didn't observe the formation of tau tangles. This suggests that the formation of tau tangles and neuronal cell death in AD are not necessarily linked (i.e. aggregate is not necessary for neurotoxicity). There is still fuzzy evidence that links the AB peptides and tau tangles to neurodegeneration in AD, but there is no hard evidence for direct causation (i.e. these tangles and peptides are directly impacting neuronal survival).

Mouse Models for AD

Experiment where mouse expressed human APP gene that has a mutation that's found in familial early onset AD. Two cohorts of mice: -Mice that were expressing mutant APP -Mice that were over-expressing APP Found that in either case, these mice accumulate plaques and cognitive impairments (impaired memory).

Alcohol Sensitivity in Drosophila: Forward Genetic Screenings

Forward genetic screen isolated a mutant named cheapdate that is hypersensitive to alcohol exposure. Isolated mutant flies by putting them in the inebriometer and selecting flies that were hypersensitive to alcohol exposure. Cheapdate is an allele of amnesiac. Amnesiac is a gene that is involved in cAMP signaling principally in memory formation.

C4 Expression and Schizophrenia Risk

Found highest risk for schizophrenia with the AL-AL haplotype. C4A expression is highest in the AL-Al haplotype. Schizophrenic patients had 1.3X more brain C4A expression than control individuals. Absolute risk is your risk of developing a given disease over a period of time; for example, if you have a 1 in 10 chance of developing diabetes in your lifetime you have a 10% absolute risk. A relative risk is used to compare risk between two groups of people; a relative risk of 1 means that there is no difference in risk between the two groups. If the relative risk is greater than 1 it means that their risk of developing disease is higher than the other group. If the relative risk is lower than 1 it means that they have a lower risk of developing disease than the other group. A relative risk of 1.5 is equivalent to a 50% increase in risk. Relative risk of 1.3 means that someone carrying the C4A AL-Al haplotype is 30% more likely to develop schizophrenia than someone who does not have that risk variant.

Cognitive Disabilities: Genetics

Four levels of general cognitive disability: -Mild: IQ 50-70 -Moderate: IQ 35-50 -Severe: IQ 20-35 -Profound: IQ <20 Sibling study suggests that moderate, severe, and profound cognitive disability may be due largely to non-heritable factors. Studies looked at IQ scores siblings of children with mild or severe cognitive disability. Found that siblings of individuals that are severely disabled tend to have average IQ scores. On the other hand, siblings of individuals that are mildly disabled tend to have lower than average IQ scores. These results suggest that mild cognitive disability is genetically heritable whereas severe cognitive disability is not heritable. Typically, the severe/profound categories of cognitive disability are usually attributed to environmental trauma (e.g. teratogens in prenatal environment, malnutrition, brain trauma, oxygen deprivation, etc.). We also tend to find de novo genetic mutations in severe/profound categories.

Genes Controlling 5HT Receptor Localization

Genes controlling 5HT receptor localization affect mood. Calpactin I light chain protein (CLP11, p11 protein) functions in localizing 5HT to the cell surface. CLP11 has been shown in mice as well as in humans that lower levels of its expression can contribute to depression. In a depressed mouse model, we see lower levels of p11 as well as reduced 5HT receptor expression. In postmortem brain tissues of individuals with depression, this gene has also been shown to be under-expressed.

Alcohol-Associated Phenotype: Drosophila

Genome wide transcriptional response to ethanol shows: -Downregulation of genes affecting olfaction -Upregulation of biotransformation enzymes (metabolism) Additionally, when we look at gene regulation during tolerance we can see another set of genes that is changing. During tolerance development, genes related to biosynthesis and regulation of pyruvate metabolism increases; also get increase in malic enzyme. Malic enzyme converts malic acid into pyruvate; generates NADPH as a byproduct which is an essential co-factor for fatty acid biosynthesis; this is equivalent to what we see in humans suffering from alcoholism. The upregulation of genes that lead to increases in fatty acid biosynthesis is similar to the metabolic changes seen in humans suffering from alcoholism and develop fatty liver syndrome. This underscores that there is an evolutionary conservation in function in a number of these genes; genes that affect alcohol sensitivity and development of tolerance in flies may have similar orthologues in humans and contribute to alcoholism associated phenotypes. Therefore, we can use genes identified in drosophila as candidate genes to guide association studies in humans.

Tolerance Effects

Graph shows tolerance to cocaine. Initially, a small amount of cocaine produces an intense high and then when the drug wears off the amount of withdrawal (or depression) is not very severe. Over time, taking repeated doses of the same amount of cocaine produces less and less high and withdrawal becomes more sever. Generally in this scenario people who are engaging in the addictive behavior end up chasing a high; take increasing amounts of a drug more frequently in order to achieve the same level of pleasurable feeling that they did the first time they took the drug. The fact that they're left with very intense withdrawal symptoms is very motivating for them to take drugs so they won't feel those symptoms.

Cognitive Ability in Animal Models: g Factor

Groups have done diverse learning tasks in rats and mice; there are a collection of learning tasks in rats in mice that we can use to estimate their cognitive ability (similar to g factor in humans). Intercorrelations among diverse learning tasks in rats and mice indicate that g accounts for ~30% of the variance in performance; shows that g is not all of cognitive ability, but is a fairly decent chunk. Collectively, data from animal models suggests a genetic factor to cognitive ability. Inbred laboratory strains also show a genetic component to learning/cognitive abilities. Allows for functional genomic investigation of brain pathways between genes and g; good setup for a QTL because we have two strains that vary in their SNPs and have opposite behaviors. This suggests that over time when we inbreed these animals we change their genetic makeup, and this allows for shifts in their cognitive function.

Support and Contradictions of the Dopamine Hypothesis for Schizophrenia

Historically, there have been two hypotheses for what is happening in schizophrenia; much of it is based on drug treatments, which is one of the things that has always been a problem in understanding psychopathology; in reality, we don't always know why those drugs are treating a particular disorder. One of these hypotheses is the dopamine hypothesis. The dopamine hypothesis contends that positive symptoms of schizophrenia occur due to increased levels of dopamine at the synapse or increased sensitivity to dopamine at the post-synaptic receptors. Support for the dopamine hypothesis: -Drugs that increase dopamine levels (e.g. agonists such as cocaine and amphetamines) can produce positive symptoms of schizophrenia -Drugs that block dopamine receptors (antagonists) sometimes reverse the symptoms of schizophrenia Therefore, essentially all of the support for this hypothesis comes from looking at the effects of psychopharmacology. Contradictions to the hypothesis: -Schizophrenics do not show increased dopamine metabolites in their cerebrospinal fluid -Dopamine antagonists act within hours, but symptoms take weeks to go away For a long time, people focused on dopamine when studying schizophrenia because drugs that we gave to schizophrenic patients that were dopamine antagonists worked to affect symptoms.

IQ Test

IQ test is the most common measure of cognitive ability. Most common IQ test is the Wechsler adult intelligence scale; uses 10 different subsets of analyses to measure cognitive ability; provides measurements for all of the different broad cognitive abilities. In a research context, we derive the value of g through factor analysis where the IQ tests are weighted differently; the contribution to how we calculate g is related to the complexity of the cognitive operation that the question on the IQ test assessed (i.e. a question that is more complex is weighted more than a straightforward question). g accounts for 40-50% of the variance among IQ tests; this indicates that there's more to the IQ test than just our cognitive ability (i.e. variance occurring among individual IQ tests that is due to reasons outside of our general cognitive function). This g value does not always explain all of our cognition, intelligence, or achievement in general (could have things to do with emotional sensitivity, social abilities, musical/artistic abilities, etc.). Although we see that there are multiple factors that go into our overall cognitive ability, the measurement of general cognitive ability (i.e. measurement of g) is a very reliable measure and is probably the most reliable behavioral domain and has long-term stability after childhood (has greater stability long-term than any other human behavioral trait and appears to have a genetic component). The IQ test historically has been quite controversial; it is a very broad construct and has a wide range of definitions; it is risky to associate individuals' success with IQ (e.g. separating children into different classes based on IQ); however, it has long been shown that the test scores are a reasonable indicator of general cognitive ability and these scores have been generally consistent across various studies.

Tolerance and Sensitization

In addition to addictive drive, dependence, and withdrawal there are other physiological occurrences that happen with drug abuse (namely tolerance and sensitization). Tolerance and sensitization are manifestations of learning and memory; they have similar molecular underpinnings to habituation and sensitization (decreases and increases in strength of response to a stimulus induced by past experience). Repeated administration of a drug can alter its subsequent effectiveness. Tolerance: repeated drug administration results in diminished drug effect (or requires increased dosage to maintain constant effect in the nervous system); tolerance can reflect decreased drug-receptor binding or reduced postsynaptic action of the drug; in the presence of high amounts of drugs of abuse the brain is trying to compensate for the presence of all of this extra signaling by reducing postsynaptic receptors (tolerance usually reflects decreased receptor efficacy or concentration). Sensitization: repeated drug administration results in heightened drug effectiveness. Tolerance and sensitization do not develop to the drug itself; it is really the drug effects (what is happening in the brain) that elicit sensitization or tolerance. Drugs can produce many different effects with repeated administration; some effects might show sensitization while others show tolerance or some might not change; largely dependent on what drug is administered, how often it's administered, concentrations, and the behavioral effect we're talking about. An animal that's sensitized for one particular behavior might become tolerant for another. Therefore, when we think about these two phenomena it's important that we define which behaviors we're talking about and which neural circuits we're considering.

Primary Brain Regions Involved in Cognitive Ability

In both men and women, the volume of the frontal lobe, hippocampus, superior temporal lobe (language), and cerebellum (motor skill learning) positively correlates with g. Focus is on the frontal lobe; association with reasoning, problem solving, and abstract thinking. NMDA-R expression in frontal lobe enhances learning in mice.

Breeding for Temperament: Traits in Dogs

In dogs, we can quantify 13 distinct behaviors that can generate a temperament profile; this is similar to the 5 traits measured in the FFM. It has been shown that these temperaments are remarkably consistent over generations. Some of these traits roughly parallel shared traits that are seen in humans. Consistent expression of temperament traits in inbred breeds suggests strong genetic component that is unaffected by environment. Traits: excitability, general activity, snapping at children, excessive barking, affection demand, territorial defense, watchdog barking, aggression to dogs, dominance over owner, obedience training, housebreaking ease, destructiveness, and playfulness.

Disordered Hippocampal Pyramidal Cells

In patients with schizophrenia the apical dendrites are pointed in different directions and so these arrangements in the hippocampus and other areas of the limbic system is important for the formation of the correct synaptic connections. If our dendrites are pointed in the wrong direction we can't receive appropriate input. It is thought that some of this is due to deficits in axon guidance cues that occur during development.

Role of C4 in Synaptic Refinement

In the immune system, C4 promotes C3 activation. C3 attaches to targets and signals for engulfment. In developing mouse brain C3 tags synapses for pruning by microglia. Examined synaptic refinement in the lateral geniculate nucleus (mouse). Undergoes activity-dependent synaptic refinement (inputs from two eyes remain segregated). In C4 knockout mice, there was reduction in C3 recruitment and deposition to synapses (lower amounts of C3 in knockouts compared to wildtype controls). This suggests that C4 plays a role in C3 deposition in the brain, so we can deter the microglia in the brain from pruning synapses; if we don't have a lot of C3 at synapses then we may not prune away the right ones. C4 knockout mice exhibit a greater overlap between retinal ganglion cell inputs from the two eyes than the wildtype controls. Suggests reduced pruning and that C4 mediates synaptic refinement in the developing brain. If C4 is important for pruning, then in a case where it's overexpressed we might get excessive pruning.

Early Brain Development

In utero, the brain develops extensively. Most of the gross brain structure is in place by week 11. Weeks 13-27 (second trimester) is a period of neural wiring and migration; greatest period of synaptic refinement that continues to occur as we age. It is likely that maternal infection is so impactful during the second trimester because this is the time when things like synaptic pruning, plasticity, and glutamate signaling is really important for making synaptic contacts. The brain continues to develop after we're born until about age 25, which is why infections or stress during childhood can also impact brain development.

Dopamine Hypothesis of Schizophrenia

It was theorized that positive symptoms of schizophrenia are due to over or hyperactivity of the mesolimbic dopamine system (release of dopamine from the VTA into areas of the limbic system such as the hippocampus, amygdala, and nucleus accumbens). Negative symptoms were associated with reduced activity of the mesocortical pathway (VTA to prefrontal cortex). Getting hyperactivity in one area and reduced activity in another area suggests that it's likely more genetically on the end of the receptor; getting polymorphisms in different receptors that are expressed in these different areas that can be influencing these different regions in different ways. It's not a simple answer like schizophrenics don't make any dopamine or have too much dopamine; there seems to be this fine balance in activity of the dopaminergic system in different areas.

Does heritability change during development? - adopted siblings

Looked at adoptive siblings that were not genetically related but lived in the same environment. During childhood, the siblings have some correlation for cognitive ability. However, this correlation disappears when they reach adulthood. The correlation of IQ in adoptive siblings as children suggests that the environmental influence is important during the early developmental years, but as adults this correlation disappears suggesting that the shared environment now has little influence over the variance in cognitive ability we see in adults.

Genetic Factors that Contribute to Schizophrenia

MZ twins have a very high concordance rate of 48%; while there is a strong genetic component, it also indicates that there is some environmental influence. Family studies also show concordance for schizophrenia; overall, about 70% of people who develop schizophrenia have a genetic basis for it (i.e. they have a relative who also has the disease); the risk decreases as the relationship becomes further (the closer the relative the higher the risk). The general population risk for schizophrenia is ~1%. There have been adoption studies done that suggest that shared environmental influences have little to no contribution; there is no reported decrease in the rate of schizophrenia for offspring who are adopted away from parents with schizophrenia. There is no evidence that children who have no genetic underpinning for schizophrenia who come from families that don't have schizophrenia in their lineage; if these children are adopted by parents who have schizophrenia there is no increased risk. Non-shared environments have a stronger influence on the development of schizophrenia. One particular environmental influence may be what the fetus is experiencing during prenatal development. Overall, the data suggests that schizophrenia is functioning like a polygenetic trait or multifactorial disease; there are risk alleles for many genes and traits are expressed in varying degrees based on allelic composition and there is an important environmental influence.

Cognitive Disabilities

Many single genes and chromosomal abnormalities are known to contribute to general cognitive disabilities. If we see polymorphisms in genes contributing to disability it's likely that they are polymorphisms that contribute to higher cognitive functioning. Rare genetic changes, but account for a substantial amount of cognitive disability - particularly severe cognitive deficits. According to the DSM, cognitive disability is sub-average intellectual functioning that is onset before the age of 18. Severe cognitive disability is an IQ of less than 50. Specific types of cognitive disabilities: -Reading disability -Dementia

Genes Contributing to g

More than 250 single gene disorders that include cognitive disability; many are involved in growth, development, and neuron function. Candidate gene approaches have not been fruitful; focus on genes involved in brain function; no real hypothesis as to which are true candidates; most candidate gene associations cannot be repeated. QTL linkage reports indicate linkage to short arm of chromosome 6 (among other linkage regions). Most GWAS studies have not identified replicable associations; strongest associations explain less than 1% of the variance in cognitive ability; one large GWAS identified FNBP1L, which is important for actin polymerization and critical for regulation of neuronal morphology during development. We don't really have a clear picture what the genes are that contribute to cognitive function, but we do know that there is a genetic underpinning. While this is scientifically exciting to think about (identifying genes that contribute to cognitive ability will give us a lot more insight into how our brain functions), understanding genetic correlates to cognitive ability also has a big ethical component (e.g. prenatal screenings, discrimination in education or employment, etc.).

Mood, Anxiety, and Personality Disorders

Much like our general personality traits, there are quantifiable tests that we can use to score and evaluate traits that are exclusively associated with psychopathology. For these traits, we find a normal distribution in the population, with patients falling at the tail ends of the distribution. Patient symptoms can also fall within a normal distribution ranging from weak to severe symptoms. These types of disorders are often multifactorial; they have variability in inheritance and we get manifestations of symptoms based on specific allelic combinations as well as environmental influences. Disorders of mood, anxiety, and personality are often comorbid (i.e. occur together) and frequently share symptoms. There is large overlap in genetic correlates in these disorders. More individuals tend to fall outside the normal range than we would predict due to shared symptoms between multiple types of disorders.

NMDA Receptors and Cognitive Ability

NMDA receptors are important for cognitive function/ability in rats and mice. In the Morris water maze, animals over-expressing NR2B (subunit of NMDA receptors) in the forebrain learned better than non-transgenic animals. Reduction of the NR2B gene as you age positively correlates with memory loss. Suggests a candidate gene/neural system that provides a neurological basis for some features of intelligence. From animal studies a lot of what has been identified has been genes that work within this glutamate system (NMDA receptors, enzymes that break down glutamate, reuptake transporters, etc.).

Evidence for Other Genes Involved in Depression

Norepinephrine: -Depressed patients respond positively to drugs that affect NE signaling -Ryu identified that an allele of the norepinephrine transporter gene occurs more often in depressed individuals CREB: -Allele of CREB1 has been linked to a highly heritable form of early onset major depression in females Shows that there seems to be a variety of biogenic amine systems that can be dysregulated in depression. The genetic underpinning of depression may be broad, but we're starting to find evidence to support dysregulation of biogenic amine signaling such as NE and 5HT.

Alcohol Sensitivity in Drosophila: Re-Exposure

Once the flies fall out of the tube they can recover and we can test what happens with re-exposure to alcohol. Re-exposure within several hours can create a tolerance, so mean elution time shifts; mean elution time peaks about 2 hours after first exposure and dissipates after 24-36 hours; animals become tolerant if we do re-exposures every 2 hours. Scientists investigated differences in particular genetic backgrounds and found that this ability to become tolerant is highly dependent on both the age of the animals and their genetic background. Canton S-B and Canton S-E are two strains of wildtype flies (usually used as negative controls). When we compare these two strains of flies their ability to become tolerant to the second ethanol exposure differs. Canton S-B animals become more tolerant whereas Canton S-E are not quite as tolerant to the second exposure.

Genetic Contribution to AD: Apolipoprotein E (ApoE)

One of the earliest links that bridges this gap between brain metabolism (i.e. ability to process glucose in the brain) and AD is apolipoprotein E. ApoE is a carrier protein produced in the nervous system by astrocytes ApoE directly involved in transporting cholesterol and other essential lipids to neurons; cholesterol is an important part of our cell membranes, so we need ApoE to bring cholesterol into the cell. ApoE interacts with a group of low density lipoprotein (LDL) receptor genes; ApoE binds to cholesterol, interacts with these receptors, and then enters the brain. ApoE has been shown to be involved in other types of regulation and brain metabolism. In the population, the ApoE gene has four polymorphisms. The ApoE(E4) allele is the polymorphism most highly associated with late onset AD (increased risk); usually most cases of late onset AD are not familial, but in the case of ApoE(E4) there is an increased genetic risk. ApoE(E4) allele diminishes protection from AB plaque formation and augments neurotoxicity. ApoE(E4) has a quantitative effect; individuals that carry one of the alleles have about 3-4X increased risk for AD development. If you are homozygous for the ApoE(E4) allele your risk for developing AD is 15X the general population. 20% of the population are carriers for the ApoE(E4) allele; 2% of the population are homozygous for the ApoE(E4) allele. One of the main receptors for ApoE in the brain is called LRP1. LRP1 has also been shown to be associated with glucose metabolism.

Selective Breeding for Ethanol Sensitivity in Drosophila

One of the ways we can assess heritability is by taking animals with varying sensitivities and breeding them together to see if we can generate a line of animals with specific behavioral phenotypes. We can selectively breed for ethanol sensitivity in drosophila. Drosophila were bred based on their mean elution time from inebriometer. Over time, three lines of flies were developed; one line was highly tolerant to ethanol, one line was very sensitive to ethanol, and one line was somewhere in the middle. Squares = low sensitivity. Circles = high sensitivity. Response to selection was rapid; started to separate flies out after about 7 generations and they were maintained over time. This suggests that there is a genetic underpinning for this type of sensitivity to alcohol in drosophila. This is also a good basis for a QTL analysis where we could mate these two lines of flies and look for linkages to particular SNPs in the population.

Breeding for Temperament: Study on Risk-Taking Behavior

One personality trait that seems to have an underlying genetic component is the propensity for risk-taking behavior. Study used selective breeding to create lines of song birds that were high-risk and low-risk taking song birds. Quantified the latency to go after food after a startle experience; lower risk taking birds took longer to go after the food after being scared away while high risk taking birds quickly approached the food after being scared away. This is analogous to human personality characteristics such as extraversion and openness to new experiences. The premise and design of this experiment is much like the idea of the maze bright and maze dull mice and aggressive flies where we take animals that have similar phenotypes and breeding them together to show that they have heritability for a particular temperament. The results of this study suggests that there is a high heritability component to some of these aspects of personality.

Mood Disorders

Predominant and persistent mood disturbance that disrupts normal daily activities: -Major depression -Dysthymia -Bipolar disorder 11.5% of US residents between 17 and 35 meet diagnostic criteria for at least one mood disorder. We find these diagnoses more frequently under certain environmental conditions. Mood disorders are more frequent in individuals with less education, lower income, and poorer health. Increased reporting in individuals who were going through divorce, cigarette smoking, or had asthma or hypertension.

Presenilins

Presenilins are crucial components of the enzymes (gamma secretase) that cleave APP into amyloid beta proteins. Mutations in presenilins 1 and 2 cause the overproduction of insoluble forms of AB peptides. In 30-70% of cases of familial onset Alzheimer's there are mutations in PSEN1. Mutations in PSEN2 are more rare (observed in <5% of cases). Like mutations in APP, mutations in presenilins are associated with increased plaques and impaired memory.

C4 Protein Localization in Culture

Primary cortical neurons in culture show localization primarily to dendrites. Also co-localizes with synaptic specializations. In culture, we see slightly different distribution but still shows that C4 is localized to two synapses. MAP2 stains microtubules found in the dendrites. Neurofilament stains all regions of the neuron. Synaptotagmin is for presynapses. PSD-95 is the postsynaptic marker. DAPI stains for cell bodies (cDNA).

Alcohol Related Phenotypes in Mice: D2R

QTL mapping paired with expression data implicates the same genes involved in variation in D2 dopamine receptor expression and ethanol-induced behaviors. Variations in D2R expression correlate with the same QTLs on chromosome 9 as Etoh induced behavior. Blue line in graph is the odds ratio and yellow bars are bootstrap data; yellow bars give us a more accurate picture of the genomic location. Ethanol-conditioned place preference and ethanol-induced open-field activity have overlapping QTLs. Chromsome 9 is associated with all 3 traits: ethanol-conditioned place preference, ethanol-induced open-field activity, and DRD2 dopamine receptor expression. Suggests that there could be something about shifting the expression of this gene that relates to these ethanol-induced behaviors.

Alcohol Related Phenotypes in Mice: Mpdz

QTL mapping studies of mice have indicated large regions of the genome. QTLs have been associated with withdrawal were found on chromosomes 1, 4, 11, and 9. This is not super informative. However, one particular QTL study identified a gene called Mpdz, which is a protein that is implicated in the synaptic organization of GABA receptors; allows for GABA receptors to be localized to the synapse (similar to SHANK3). Expression of Mpdz is correlated with severities of withdrawal symptoms from alcohol as well as pentobarbital among inbred mouse strains (wildtype). Animals that have high-expressing Mpdz have low levels of withdrawal.

Single Gene Disorders in Cognitive Ability

Rare single gene disorders count for a very small proportion of cognitive disabilities. The range of cognitive functioning for disorders is very wide; defective alleles shift the distribution of IQs downward, but there is a wide range of individual IQs. There are more than 250 other single gene disorders whose primary defect is something other than cognitive disability, but also shows effect on IQ; some examples include Duchenne muscular dystrophy, Lesch-Nyhan syndrome, and neurofibromatosis. Many cases are not familial.

Insulin Signaling and AB Peptides

Reduction of insulin receptors can cause an increase in AD pathophysiological hallmarks: -Decreases vasodilation -Decreases expression of AB degrading enzyme (IDE) -Causes increased tau phosphorylation -Decreases glucose transporter expression Insulin is important for many cognitive functions in the brain; it is less involved with direct glucose transport and metabolism; does a lot of other intracellular signaling jobs that can change synaptic plasticity, affect neurotransmitter function, etc. Not only does ApoE(E4) affect insulin receptor expression, but glucose metabolism itself can change the expression of insulin receptors. Shows that there is a link between these important molecules of metabolism and the typical pathological hallmarks of AD.

C4A Expression

Retroviruses (i.e. HERV) can function as enhancers; they can change gene expression levels. There are 4 common haplotypes in the population; of the 222 individuals sampled for the study, 90% of them had one of these four haplotypes. Four haplotypes: AL-BL, AL-BS, AL-AL, and BS. When we look at mRNA expression levels of these different versions of C4, we find that the concentrations of C4A and C4B increase proportionally with copy number (i.e. the more copies we have the more expression we get). C4A is more highly expressed in the brain; C4A expression was 2-3X higher than C4B. C4-HERV (individuals expressing the long form of C4A) increased the C4A:C4B ratio.

Risk for Schizophrenia

Risk for schizophrenia is a combination of genetics and environmental factors. The more risk alleles you inherit and the more risky your environment is, the more likely it is that you will develop schizophrenia or schizophrenia related disorders. Genes that favor schizophrenia intersect with environmental stressors = increased likelihood of schizophrenia.

Genes that Contribute to Schizophrenia: Schizophrenia Working Group

Schizophrenia Working Group is a collection of scientific labs across the globe who took data on psychiatric patients and performed a GWAS of 37,000 cases of schizophrenia and 113,075 controls. Found 108 schizophrenia associated genomic loci. Of these 108 loci, 83 of them had not been previously identified in association with schizophrenia. 75% of these genomic loci include protein coding genes; a small number of these instances cause functional protein changes, which suggests that polymorphisms affect expression. 8% of these genomic loci are within 20kb of a gene, which suggests that there are some mutations/polymorphisms in gene regulatory regions (e.g. promoters). Found that these genes are highly expressed in brain tissues and immune cells. Found associations with: -DRD2: D2 dopamine receptor -GRM3 (mGluR), GRIN2A (NMDAR), and GRIA1 (AMPAR): glutamate signaling -CACNA1C, CACNB2, and CACNA1I: voltage gated calcium channel subunits -NRXN1: neurexin 1, role in synaptogenesis We expected these results.

Demographics of Schizophrenia

Schizophrenia affects ~1% of the world population. Schizophrenia is a disorder in which we detect the development of behavioral changes relatively late; onset of symptoms is typically between the ages of 16-25 (3/4 of people with schizophrenia develop symptoms between these ages). There is a slight onset difference between genotypic males and females. For genotypic males, the age of onset is skewed slightly earlier than it is for women. There is no evidence to suggest that there is a difference in the severity of the disorder in males vs females, just a slight difference in timing.

Heritability of Schizophrenia and Related Disorders: Pedigree

Schizophrenia and schizophrenia-related disorders are often intermingled in family pedigrees. Pedigrees highlight that there's likely genetic influences that underlie many personality disorders in milder subclasses (e.g. schizophrenia-related disorders) as well as the more severe psychopathology (e.g. schizophrenia). Represents how we get variable inheritance of multiple contributing alleles; family members who inherit fewer alleles have the related disorder whereas family members who inherit a greater number of risk alleles develop the more severe psychopathology. Common theme: genes that underlie various human behaviors can be common among different pathologies; the severity of the disorder depends on the number of contributing alleles and the environmental influence.

Structural Differences in Brains of Schizophrenics

Schizophrenic patients have enlarged sulci (especially in temporal and frontal lobes) and ventricles (especially lateral and 3rd ventricles), which suggest that there is loss of brain tissue. It's not really a lot of brain matter loss (cell bodies remain intact), but instead a change in dendrite structure; losing dendrites as opposed to neuronal cell death (i.e. losing synaptic connection). We particularly see these changes in the frontal and temporal lobes; when we think about the symptoms of cognitive dysfunction (e.g. disordered sensory experiences) this makes sense.

ApoE Study

Showed that ApoE(E4) impairs neuronal insulin signaling by trapping insulin receptors in the endosomes. Therefore, it seems as though the polymorphism of the ApoE gene functions to block the neuron's expression of insulin receptors. Insulin works a bit differently in the brain than the rest of the body. Found that insulin signaling was specifically impacted when animals were fed a high fat diet. Graphs show presence of ApoE(E4) allele and phosphorylated Akt. Phosphorylated Akt is a classic way to monitor insulin receptor activity. Found that over-expression of ApoE(E4) allele in the mouse brain was associated with reduced insulin receptor activity; also showed that this reduced insulin receptor activity was due to the lower surface expression of insulin receptors (i.e. looked to see if insulin receptors were being trapped in intracellular compartments). This effect is exacerbated by animals that are fed a high fat diet (graph B). This study is a good example of how in a disease model we see a genotype-by-environment effect, where a particular genotype is contributing to receptor dysfunction and we can get an even bigger effect based on environmental regulation. This study also showed that ApoE(E4) is directly interacting with insulin receptors and causing their internalization; showed that these insulin receptors remained trapped in the endosome and don't ever repopulate the cell surface. This finding highlights the interplay between Alzheimer's pathology and glucose metabolism.

Genes for Dyslexia: QTL Studies

Sibling-pair linkage studies (essentially doing a QTL with twins) identified a region on chromosome 6 to be linked to dyslexia among siblings and fraternal twins. Separate GWAS studies done of populations in the US, UK, and Germany identified two genes in the same region of chromosome 6: -DCDC2: role in neuronal migration -KIAA0319: role in neuronal migration

Single Gene Disorders: Similarities to Autism

Single gene disorders such as PKU, Fragile X, and Rett Syndrome that were shown to cause symptoms similar to Autism also cause changes in cognitive function. PKU: causes developmental delays, seizures, microcephaly, and learning disabilities (range of IQs often <50). Fragile X: neurological disorder causing intellectual disability, cluttered and nervous speech, stereotypic movements, and atypical social behavior (IQ ~70). Rett Syndrome: causes seizures, microcephaly, autistic-like symptoms (stereotypic movements), motor deficits, and language deficits (IQ ~55).

Slo-1 Gene

Slo-1 encodes a BK potassium channel. BK potassium channels are voltage-gated potassium channels that have a high potassium conductance, so they're responsible for hyperpolarization after an action potential; also play a role in smooth muscle contraction because we find these channels in neurons, heart, and stomach. Looked at electrophysiological data and found that ethanol affected the opening probability of slo-1. A wildtype slo-1 gene makes the potassium channel work better; channel opens more frequently and leads to increased levels of hyperpolarization. If we give C. elegans ethanol we get more hyperpolarization of neurons and so they relax and stop moving because they can't depolarize anything to engage in any behavior. It has been shown that orthologues of this gene have been implicated in acute alcohol exposure also in flies and mice; we see conservation of this particular effect across evolutionary time, which indicates that alcohol's influence on K+ conductance could be part of the way its affecting the nervous system.

Specific Cognitive Disabilities: Learning Disability

Some of the places we can get the most information is by looking at a specific cognitive disability. Dyslexia entails difficulties in understanding or using spoken or written language. Restricted capacity to concentrate, listen, speak, read, write, or use mathematical calculations. Specifically, dyslexia affects the ability to acquire and consolidate written information. Not always associated with low IQ scores; dyslexic IQ scores typically fall within a normal range. 5-15% of the general population meets diagnostic criteria for one or more learning disability. Dyslexia accounts for more than 50% of all diagnosed cases of learning disabilities. Heritability of dyslexia is 40-70% based on twin studies; small influence of shared environment. Family association studies have identified candidate genes that contribute to dyslexia. Children of a dyslexic parent have an increased risk for developing dyslexia, and the risk and severity of the impairment is increased if both parents are dyslexic.

Environmental Risk Factors for Schizophrenia at Different Life Stages

Stressors that occur during youth are some of the most influential. Things like experiencing child abuse or neglect, sexual abuse, witnessing domestic violence, brain hypoxia (low oxygen levels), shorter gestation periods, low birth weight, and severe childhood illness can all play a role in increasing the risk of developing schizophrenia. Even something like living in a large city where the environment is physically more stressful can also increase the risk of schizophrenia. Severe childhood illness has been shown to highly increase the risk for developing schizophrenia; during these severe illnesses there is an increase in serum concentration of pro-inflammatory cytokines; these severe increases in cytokines during youth is associated with a 2-fold increase in the risk of development of schizophrenia by the age of 18.

Genes that Contribute to Schizophrenia: Chromosome 6

Strongest association is on chromosome 6 and it spans the entire major histocompatibility complex (MHC) locus, which is about 8Mb (hundreds of genes). The MHC locus is comprised of proteins that present antigens to T cells to initiate an immune response and can help us distinguish between self and non-self cells. Encodes 18 human leukocyte antigen (HLA) genes. This data provides a real genetic link between the immune system and development of schizophrenia. This may explain why environmental insults (e.g. maternal infection) are a big risk factor.

Genes for Dyslexia: Family Association Studies

Study done on a large Finnish family identified two more genes: -DYX1C1: expressed by radial glia -ROBO1: axon guidance cue DYX1C1, KIAA0319, and DCDC2 all play a role in neural migration during cortical development. ROBO1 plays a key role in axon pathfinding, which is important for axons to reach their appropriate targets. It seems that there are alterations in axon pathfinding and neural migration to the appropriate place in the cortex in individuals who have dyslexia. Some dyslexic patients also show cortical malformations. At this point, it is unclear if mutations in these genes are predictive (e.g. it's unclear if a mutation in ROBO1 would lead to dyslexia). However, this highlights that the brain development axon guidance and neural migration are important for the development of appropriate cognitive function. These genes are also important for developmental states throughout the brain, which raises an interesting point that our ability to communicate through writing may have not come from new genes but rather neural circuits are recruited in a different way.

Does heritability change during development? - adoption studies

Study looked at correlations for general cognitive ability in three different cohorts: -Biological mothers and children who were adopted away -Adoptive parents and their adopted children -Birth parents who live with their biological children (controls) Cognitive testing occurred at various ages. The control group and the biological mothers with their adopted children show the same trend; heritability increases as children get older. Adoptive parents with their adopted children show that heritability hovers around 0, suggesting that family environment shared by parents and offspring doesn't contribute importantly to the parent-offspring resemblance for g. Suggests a strong genetic factor and reducing environmental influence as we age.

What Causes Addiction?

Substances are not what cause addiction because the likelihood of becoming addicted to any drug varies widely within the population. The genetic underpinnings of drug abuse are clear; we see that in twin studies for drug/alcohol abuse that MZ twins have a higher concordance rate than for DZ twins, suggesting a heritability for addictive behavior. Comparatively, the concordance rates are relatively low (e.g. compared to behaviors like cognition); therefore, these studies have also illuminated that the environment has a very significant influence on addictive behaviors, particularly shared environmental factors during early adolescence. Some of these shared environmental factors include neighborhood where you grew up, parental attitude towards substance abuse, school environment, and sibling influence. Although the exposure to these shared environmental factors may be restricted to a limited period during adolescence, it has been suggested that the initiation of abuse patterns that are stimulated by these factors precede an enduring behavioral phenotype in adulthood; some of the things we experience as adolescents become quite engrained in our psychology. Addictive behaviors are often comorbid with other psychopathologies. There is phenotypic variability in susceptibility as well as environmental influence; addiction is therefore a polygenetic trait.

Personality vs Temperament

Temperament: enduring qualities of an animal's behavior; innate factors that shape emotional and cognitive expression; characteristics of behavior that are not influenced by the environment. Personality: distinguishing and enduring qualities or characteristics of an individual's behavior; biologically based, environmentally shaped traits. When we talk about young children, we usually use the word temperament because they are not old enough for their traits to have been impacted by the environment yet. Some of the earliest experiments to try to examine the genetics of personality were done in dogs; wide variety of dog breeds that were bred specifically based on particular temperaments; some of the things we understand about the genetics underlying personality traits or temperaments comes from work done analyzing different dog breeds.

Personality Disorders

The NIH reported that in 2004 ~15% of US residents met the diagnostic criteria for at least one personality disorder. OCD is the most common subtype of personality disorder in the population and is characterized by compulsion to strive for perfectionism that produces anxiety. A lot of these personality disorders (e.g. OCD and antisocial) have dysregulation in common neurotransmitter systems. In OCD we find dysregulation in 5HT system; genes related to 5HT reuptake, biosynthesis, and reception have all been linked to OCD. In antisocial personality disorder we see more genes related to dopamine biosynthesis, reception, and reuptake than we do with OCD, but similarly antisocial personality disorder genes overlap with other types of personality disorders (particularly schizophrenia). The genes that pop up in depressive and anxiety disorders as well as personality disorders all have the same common thread. The biogenic amine systems in our brain are very important for modulation, and particularly important for modulation activity that produces our most important behaviors (e.g. ability to function as part of a society).

General Cognitive Ability (g)

The concept of intelligence is somewhat of an abstract term; it refers to the ability to reason, solve problems, comprehend ideas, and learn effectively. Researchers often use tests of tangible skill as a means to measure intelligence; intelligence and cognitive ability are closely intertwined with each other. Cognitive ability = tangible skills that include mathematical ability, reading ability, memory, spatial ability, and production and comprehension of language; one of the most well-studied domains in behavioral genetics. Based on a model that cognitive abilities can be organized hierarchically (shown in figure): general cognitive ability --> broad abilities --> narrow abilities (tests). These broad abilities can intercorrelate with each other; for example, individuals who do well on tests of verbal ability tend to also do well on tests of spatial ability; this is what the g factor is. g is referred to as the measure of general cognitive ability; variable that essentially summarizes positive correlations among different cognitive tasks (i.e. a measure of correlation among all of our broad cognitive abilities).

Genetic Influences on Depression

The earliest understanding we have of the neural systems that are impacted during depression come from our understanding of psychotherapy that works. For example, drugs that were designed to enhance 5HT neurotransmission have been shown to be effective in treating symptoms, so the focus has always been on regulating the 5HT system in depression. The issue with these psychotherapy treatments is that a lot of times we treat a psychopathology with a drug and don't completely understand what it's doing or why it's having an effect. Classically, drugs that increase 5HT in the synapse have been used to successfully treat depression. SSRIs (e.g. Prozac) treat symptoms of depression by blocking 5HT reuptake (increases 5HT in the synapse). Because these drugs worked, this prompted the study of the 5HT transporter gene (5HT-T).

Glutamate Hypothesis and Schizophrenia

The glutamate hypothesis contends that schizophrenia results from under activation of glutamate receptors; correlates well with some fo the things we see changing as a result of inflammation (e.g. cytokines produce kynurenic acid, which lowers NMDA function). Support for the hypothesis: -Drugs that block NMDA receptors can produce positive and negative symptoms of schizophrenia; hallucinogenics like PCP and ketamine can create both positive and negative symptoms and these are both NMDA receptor blockers -Anti-NMDA antibodies found in some patients with some schizophrenic symptoms -Some evidence suggests that drug treatments that we give to schizophrenic patients are atypical neuroleptics, which also impact NMDA receptor function All of the evidence for this hypothesis has been pharmacological.

Environmental Risk Factors for Schizophrenia: Prenatal

The greatest environmental risk factor for developing schizophrenia is a prenatal risk factor where during the mother's gestation they become exposed to infections. Prenatal factors (during gestation) include: -Mother's exposure to viral/parasite infections such as influenza, rubella, and polio -Inflammation caused by infection may create dysregulation of neurotransmitter systems -Inflammation can also release cytokines, which can cross the placenta and enter into the developing fetus and change neural structures -Cytokines increase the concentration of kynurenic acid (metabolite of tryptophan), which is a natural NMDA antagonist; blocking NMDA receptors can have high impacts on plasticity and development in the early fetal brain Brain is especially vulnerable to infections during second trimester.

Why Does Addiction Occur?

The major neural pathway in addiction is the mesolimbic dopamine pathway, which is a collection of neurons in the hindbrain (VTA); VTA releases dopamine into the NA. VTA also sends dopamine inputs to other areas of the brain (e.g. amygdala, hippocampus, and PFC). The evolutionary purpose of the mesolimbic pathway is to provide pleasurable sensation associated with behaviors that we want to continue to do; mediates positive/reinforcing sensations for things like food and sex that are beneficial behaviors for our species. Function of the NA is to mediate pleasure sensations associated with beneficial behaviors. The activity of the NA is regulated by the VTA via dopaminergic input. The NA sends GABAergic output to the orbitofrontal cortex, where there is a lot of integration between sensory and affective input; the function of the orbitofrontal cortex is still poorly understood, but it is thought to integrate pleasure sensation or emotional reactions with a sensory experience; helps us in decision making by triggering decisions that reinforce or avoid a particular behavior. Individuals that have lesions to the orbitofrontal cortex have increased compulsive behaviors like excessive drug use, compulsive gambling, more violent, etc.; seems as though orbitofrontal cortex helps regulate compulsive behaviors.The connections between the VTA and NA are inhibitory, so dopamine is functioning to suppress NA activity; projections from the NA to orbitofrontal cortex are also inhibitory; overall a disinhibitory neural circuit where the NA is always inhibiting the orbitofrontal cortex, and dopamine input into the NA will relieve the inhibition of the orbitofrontal cortex.

Alcohol Related Phenotypes: Rodent Models

The most common behavioral assay for ethanol intake in mice is the two bottle preference test. Mice are presented with either water or ethanol and they choose between the two bottles. Mice prefer ethanol over a particular range of concentrations; there is a point where the concentration of ethanol is too high and they don't like the taste. Some of the behavior is driven by gustatory preference for ethanol; T1R3 receptor mediates the taste sensation for ethanol and when we knock it out we see that their preference for ethanol drops. Different wildtype strains of mice differ in their preference for alcohol intake; gives us founder strains for recombinant inbred lines - QTL mapping. Loss of righting reflex: good assessment for intoxication; put mice on their back (they do not like this and try to flip over); when mice are given ethanol they don't flip over quickly. Mice do develop physiological dependence to alcohol and exhibit withdrawal symptoms when it's removed.

Actions of Alcohol

The most genetic information we have about genetics linked to addictive behavior is looking at alcohol. Alcohol is a CNS depressant, which can cause visual impairment, lack of motor coordination, increased reaction time, euphoria, and release from inhibitions. Alcohol acts within the brain to: -Potentiate GABA receptors (increases Cl influx); strongly inhibits neurons -Inhibits glutamate NMDA receptor (decreases Ca influx) -Increases dopamine release from the VTA and nucleus accumbens (pleasurable aspects of intoxication) -Increases serotonin levels

Self-Stimulation of the Nucleus Accumbens

The stimulation of the NA is very powerful. Rats will self-stimulate the mesolimbic pathway via electrical stimulation. Rats quickly make the association between the lever press and pleasurable feeling; will continue to press the lever and forego other vital functions like eating, drinking, and sex. This pathway has a real governance over our behavior. There is a learning component here; the rat must make the association between the pleasurable feeling and lever press; therefore, there is an underlying learning and memory component to addictive behavior. We find some genes related to addictive behavior that are also associated with learning and memory.

Positive and Negative Symptoms of Schizophrenia

The word schizophrenia means "split mind." Patients with other types of personality disorders, particularly those that involved multiple personalities, tended to get lumped together with schizophrenia. However, we now know that schizophrenia is its own collection of symptoms. Schizophrenia is a disease of cognitive abnormality, particularly underscored by abnormal sequential thoughts (i.e. individuals with schizophrenia have a hard time holding on to the logical sequence of a story; can get tripped up by things like loose associations); e.g. if you're talking about a boxer as in the dog breed they may think you're talking about a boxer as in the sport. Schizophrenics also have a hard time with abstraction; thoughts are grounded in the concreteness of a story; can't make judgements about how concrete or abstract a story is; take things very literally and can't abstract meaning beyond the literal sense. Schizophrenia can be manifested with positive or negative symptoms (or alternating between both). Positive symptoms usually occur during psychotic episodes. Positive symptoms include auditory hallucinations that occur in the absence of stimuli, disordered thought processes, and bizarre behaviors often relating to delusions; their delusions or thoughts are beliefs that are contrary to reality and typically center around delusions of grandeur, persecution, or paranoia. Negative symptoms usually occur during non-psychotic episodes. Negative symptoms are things where our behavior is relatively suppressed. There are many subtypes of schizophrenia, and each of them can have different symptoms. For example, individuals with paranoid schizophrenia mainly experience positive symptoms; individuals with catatonic schizophrenia experience only or longer periods of negative symptoms.

Structural Changes in Brains of Schizophrenics

There are some structural abnormalities specifically in the hippocampus. One of the areas where we see physical developmental deficits is in the limbic system. During the development, it has been shown that the hippocampus is smaller in patients diagnosed with schizophrenia. There is also disordered arrangement of hippocampal pyramidal cells. There is a correlation between how disordered the cells are and the severity of schizophrenia. Some evidence suggests that there is a link between how disordered the cells are and how the infection of pregnant person to influenza during the second trimester. Normal control: pyramidal cells are organized in a single layer.

AD and Glucose Metabolism

There has been a lot of data from how aging subjects perform in memory tasks. Even in non-AD patients, part of the deficit for aging individuals in memory task performance is due to the fact that they have insufficient cerebral glucose supply (i.e. their brain is not metabolizing enough glucose - our neurons are metabolically activating ATP and without glucose they start to lose function). It has been shown that aging individuals are at increased risk for glucose deprivation; decreased glucose transport and ability to metabolize glucose seems to be aberrant, especially in AD. These metabolic changes can influence the pathophysiology of plaque and tau tangle formation. The dysregulation of glucose metabolism has been shown to be a relatively invariant feature of AD; it seems that across the board AD patients all have deficits in the ability to metabolize glucose in the brain.

Polymorphism in 5HTT

There has not been much of a genetic link to genes involved with 5HT signaling in depression. However, one variation (polymorphism) in the promoter region for 5-HTT is associated with depression in individuals who report stressful life events. Polymorphisms found in the promoter for 5-HTT result in different promoter lengths; short "s" promoter is less efficient than the long "l" promoter. Individuals that are homozygous for the short promoter (s/s) have lower levels of expression of 5-HTT than individuals who are homozygous for the long promoter (l/l). Individuals that were s/s had more significant changes in their depressive symptoms only when there were stressful life events. The probability of developing a major depressive episode typically only happened if there was severe maltreatment during development in s/s individuals. This is a good example of how a reaction norm can be informative (i.e. conditional neutrality). This example exemplifies the complex interactions between genes and environment; also highlights that there's little evidence to support this direct association between promoter variants and depression. If s/s have lower expression of 5-HTT then we would expect them to have more serotonin in the synapse and thus less depressive symptoms but we see the opposite; indicative of the fact that it's not too much or too little serotonin, but really imbalances in serotonin signaling that can lead to depression (hence why sometimes SSRIs are not effective for certain individuals). This experiment underscores the importance of thinking about genetic contributions and how different polymorphisms can affect people differently based on the environment.

Neuropathology of AD: Neurofibrillary Mutations

There have been some mutations shown to create destabilization of proteins that form the neurofibrillary tangles. AD patients show increased neurofibrillary tangles intracellularly, and this is composed of cytoskeletal proteins (especially proteins that are associated with microtubules called tau). Tau proteins bind to microtubules and stabilize them; they can become disassociated and start to aggregate and form sticky plaques inside the cell. Many of the tau tangle associated proteins are heavily phosphorylated; phosphorylation of tau causes it to fall off the microtubule. Can also create a protein environment where it makes it more attractive to other proteins; phosphorylation can contribute to the aggregation and precipitation of cytoskeletal proteins, which is what leads to the neurofibrillary tangles. Not only do we destabilize the microtubules (which is important for intracellular trafficking), but we are also growing an aggregate of protein inside the cell that can sequester other proteins and prevent them from doing their normal functions. Although rare, there have been mutations in MAPT that cause accumulation of tau, which destabilizes neurons and displaces cellular components; quite rare and found most often in Eastern European groups (two haplogroups). In addition to AD, we see that these mutations in MAPT can also contribute to Lewy body dementia and Parkinson's disease.

A Gene for Personality: D4DR

Took two dog breeds that had fairly opposite temperaments (golden retrievers and shiba inus). Golden retrievers exhibit personality traits where they are very amenable to being trained and are playful and friendly in nature; shiba inus are more difficult to train and can be territorial and aggressive. Using genomic experiments, the researchers found that the DRD4 gene was only expressed in golden retrievers and not shiba inus. DRD4 gene encodes a dopamine receptor protein, specifically an inhibitory dopamine GPCR expressed in the prefrontal cortex. Golden retriever DRD4 is orthologous to alleles of DRD4 identified in humans who score high on personality tests for novelty seeking. Suggests that something about dopamine reception in the frontal lobe (or inhibition of neurons that express dopamine receptors) are suppressing our propensity to be more reserved. This work tells us three things: -It identifies a candidate gene for the novelty seeking temperament -It suggests that this candidate gene can be used to identify temperament in a variety of dog breeds (i.e. do these animals express DRD4 or not) -Shows homology with human personality traits based not only on behavioral observation but a shared genetic factor; might provide insights into personality development in humans as well as psychiatric disorders (dysregulation of DRD4 has been linked to psychiatric disorders such as addictive behavior, eating disorders, and schizophrenia)

Alcohol Related Phenotypes in Mice: Transgenic Studies

Transgenic approaches (knock out or knock in) look at candidate genes for alcoholism in mice. Transgenic studies have implicated that GABA receptors and D1/D2 dopamine receptors in the behavioral drives for addictive behavior in mice. D2R knockout animals have a lower level of alcohol consumption in comparison to the wildtype or heterozygous animals. A lot of these transgenic studies have been inconclusive: -Effects can be different based on genetic background -Functional redundancy/alternative pathways -Diversive effects of alcohol on the nervous system Suggests that there are alternative ways alcohol can be affecting addictive behavior outside of dopamine or GABA receptors.

Association Studies of Alcoholism in Humans

Twin studies estimate the heritability of alcoholism at 50-60% (genes and environment). Adoption studies suggest cultural and social factors can increase risk. For example, in countries where the use of alcohol is limited or illegal alcoholism is nonexistent. From these studies, it is clear that alcohol dependence is a cumulative effect of many genes. However, there are a few genes that have been identified in linkage studies and GWAS that have identified major contributions to predisposition for alcoholism. One of these alleles is alcohol dehydrogenase (ADH). ADH converts ethanol into acetaldehyde; acetaldehyde is responsible for the feeling of a hangover and causes dehydration. ADH genes have a number of alleles in the population and the polymorphisms in these genes cause different enzymatic effectiveness, which correlates with extent of tolerance to alcohol; high tolerance = increased risk; low tolerance = decreased risk. For example, individuals that carry the ADH2(2) allele have a non-functional ADH and can't metabolize alcohol; drinking causes a swift and immediately strong dysphoria, tachycardia, or extreme nausea; this causes negative reinforcement; low tolerance to alcohol creates a decreased risk for developing alcoholism. Individuals with highly functioning ADH genes can metabolize alcohol quickly and feel the effects of alcohol less strong; these individuals are at an increased risk for developing alcoholism. Study looked at the global distribution of these alleles and found that there is a high concentration of the ADH2(2) alleles in asian populations; this correlates with the fact that asian populations have the lowest risk for developing alcoholism.

Human Personality Traits

What we see in animals is based on observation; in humans, personality traits are largely based on self-reporting so there could be some lack of validity and reliability. However, if we measure personality traits at multiple points over time it seems as though they remain relatively stable. Twin and adoption studies have helped determine the level of influence genes have on particular personality traits; 30-50% of variation in trait expression is due to genetic influence. Many MZ twin adoption studies suggests that there is not a significant difference in concordance rates between twins raised apart and twins raised together; this had led scientists to think that there is not much environmental influence on our personality, but it's possible that MZ twins that have been adopted apart share more environmental factors than we think (e.g. age, genotypic sex, gender, and prenatal environment). Borkenau study tried to take a broader look at twins from a wider variety of backgrounds (e.g. SES, culture, etc.) and found that there is an environmental contribution that weighs more heavily on the non-shared environment; the one exception to this was the temperament trait of extraversion; extraversion seems to be completely genetic and unaffected by environment. In the typical range of personality traits we find that we have a significant contribution by genetics (i.e. genes play a big influence on how we develop our personality). Personality disorders are extreme variations of normal personality traits; learning about the genetic underpinnings of a personality disorder may give clues to how normal personality traits develop.

Sensitization Effects

When mice are given repeated doses of cocaine, over time they display a more robust locomotor response to the presence of cocaine than they did initially. Locomotor response was how much they ran around the cage. Sensitization is the enhancement of a directly elicited drug effect that is adaptive; appears to represent facilitation within the system, making an effect easier to elicit on a future occasion. In a human sense, sensitization often becomes linked with a co-occurrence, meaning that there is a particular stimulus or environment that heightens the sensitivity to the drug (or can prompt/trigger a craving); e.g. people who smoke say that it's hard to forego a cigarette in the morning because they're so used to pairing a cigarette with a cup of coffee (cup of coffee triggers craving); two behaviors go hand in hand sensitizing a response.

Sex Differences in Mood Disorders

Women are 2X more likely to develop a mood disorder. This is likely because estrogen can raise levels of the stress hormone cortisol by activating the HPA axis. Cortisol can have a negative effect on the brain: -Decrease in 5HT receptors and dendritic spines in the hippocampus; may explain higher rates of mood disorder Also thought to be because there is a higher rate of reporting among women vs men.

Alcohol Sensitivity in Drosophila: cAMP

cAMP production and PKA activity influences sensitivity to alcohol. Mutations in other genes involved in cAMP signaling also confer hypersensitivity to alcohol similar to the cheapdate mutants. Also shown that CREB activation may facilitate the expression of ADH genes in drosophila; ADH genes have CREB response elements in their promoters; it seems that activating CREB is an important driver for ADH gene expression. CREB activation may also facilitate expression of slo-1 BK channels in drosophila. We see a lot of convergence of genes between memory as well as the expression of genes that are important for alcohol metabolism and neuronal function. However, cAMP and PKA play fairly generic roles in various cell types; here we see that the things that are generically important in neuronal signaling play a role in development of sensitivity to alcohol.