Introduction to Behavioral Neuroscience: PSYC 211 Lecture PDF

Introduction to Behavioral Neuroscience PSYC 211 Lecture 22 of 24 – Schizophrenia Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  GENE-ENVIRONMENT INTERACTIONS Most of the diseases and disorders that curre...

Introduction to Behavioral Neuroscience PSYC 211 Lecture 22 of 24 – Schizophrenia Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  GENE-ENVIRONMENT INTERACTIONS Most of the diseases and disorders that currently plague humanity have a genetic basis. When we analyze people’s genomes, we see that there are a variety of alleles (different version of genes and gene promoter regions) that are common in the human population. Some common alleles increase a person’s risk of developing a specific disease, while other alleles are protective against specific diseases. Common diseases tend to show the classic hallmarks of gene-environment interactions: there is a strong genetic component, yet the prevalence of the disease varies widely across cultures and recent history (in a manner that is not fully explained by genetics). Common gene variants that are problematic today were probably neutral or beneficial in ancestral environments. In many cases, the associated diseases are linked to clear environmental risk factors that were not present in ancestral conditions.  GENE-ENVIRONMENT INTERACTIONS The prevalence rates of the following disorders vary widely across cultures and recent history. The associated environmental risk factors were not present in ancestral environments.  obesity and diabetes (the sudden abundance of cheap, unnaturally delicious food)  asthma (sudden changes in air quality with exposure to pollutants and antigens)  drug addiction (sudden abundance of highly purified synthetic drugs)  heart disease, strokes and cancer (sudden changes in lifespan, diet, and lifestyle).  late onset neurodegenerative disorders (sudden changes in lifespan, diet, and lifestyle).  depression and anxiety (sudden change in lifestyle, although exactly what is unclear) There is now strong evolutionary pressure on the gene variants that impact people’s susceptibility to these diseases. Gene variants that protect against these diseases and disorders currently exist in the human population. Across generations, if our environment, lifestyles and culture remain constant, these gene variants will increase in prevalence until everyone gets them.  MENTAL ILLNESS Some mental disorders do not show the classic hallmarks of gene-environment interactions. For example, schizophrenia and autism are clearly heritable, but prevalence rates do not vary widely across cultures or recent history (as far as we can tell). “Severe” mental disorders… – reduce reproductive success (they have half as many children as other people) – are clearly heritable (genetics explains much of the variance in diagnoses) – are very common (about 4% of the population) “Severe” mental illnesses are genetic disorders, but the associated alleles are widespread and seemingly not being eliminated through natural selection. What is going on? Why are harmful, heritable mental disorders so common and why do they persist?  SCHIZOPHRENIA SUSCEPTIBILITY GENES We have identified hundreds of relatively common gene variants that each individually confer a very small statistical increase in the risk of developing schizophrenia. Combinations of these gene variants create conditions where mental illness is likely. The concordance rate for schizophrenia among genetically identical twins is about 50% - if one twin has schizophrenia, there is a 50% chance the other twin will have it too. (In the general population, the rate of schizophrenia is less than 1%.) So there clearly can be genetic predisposition for schizophrenia, but what actually triggers the disease? An abusive childhood? A bad viral infection? To assess environmental risk factors, we often compare rates of schizophrenia among identical twins that were either raised together in the same household or separated at birth. It turns out that when one twin has schizophrenia, the other twin has a 50% chance of developing it, regardless of whether they were raised together or separated at birth. There are environmental risk factors, but they tend to exert a very small influence overall. Schizophrenia primarily reflects a genetic predisposition and bad luck.  SCHIZOPHRENIA SUSCEPTIBILITY GENES But why are schizophrenia susceptibility genes so common in the gene pool? One theory is that certain combinations of schizophrenia susceptibility genes may improve reproductive success (perhaps by making people smarter in some way). Wrong combinations of these gene variants clearly predispose people to schizophrenia, but maybe there are good combinations of these gene variants that boost reproductive success. If there are advantages to having the “right” combination of schizophrenia susceptibility genes, it should be evident in the close blood relatives of people who have schizophrenia. Do the siblings of people who have schizophrenia have tons of kids? No, the siblings of schizophrenics seem to have the same fertility rate as the general population. They also do not outperform other people (who do not have a family history of schizophrenia) on cognitive tasks, motor tasks, perceptual tasks, etc. Researchers have not yet identified an offsetting benefit of schizophrenia susceptibility genes.  MENTAL DISORDER SUSCEPTIBILITY GENES The common gene variants that are associated with an increased risk of developing schizophrenia are also associated with an increased risk of developing bipolar disorder, depression, autism, OCD, and ADHD. The risks conferred by these gene variants are not specific to traditional diagnostic boundaries. They are not schizophrenia genes, so to speak. Nor are they autism genes or bipolar genes. Rather, these gene variants reflect a vulnerability to developing some kind of mental illness, not a specific mental illness or even a specific symptom within a diagnostic category.  MENTAL DISORDER SUSCEPTIBILITY GENES The color (and size) of each box indicates the magnitude (and statistical significance) of the genetic correlations across psychiatric conditions. The gene variants associated with schizophrenia are also associated with bipolar, depression, OCD, autism, anorexia, and ADHD.  DIAGNOSTIC CATEGORIES But aren’t mental disorders discrete, unitary diseases? No, it doesn’t look like it. And, if we are being honest, there is too much… – heterogeneity within diagnostic categories, – comorbidity across categories, and – continuity with normality, for mental disorders to qualify as discrete, unitary diseases. Our diagnostic categories grew out of good faith efforts to describe clusters of symptoms that tend to appear together. They reflect historical conventions more than they reflect known biological differences. Diagnostic categories are somewhat helpful for treatment decisions, but it is increasing clear that similar behavioural symptoms can arise from completely different neural circuit disruptions.  MENTAL DISORDER SUSCEPTIBILITY GENES Many of the gene variants associated with an increased risk of mental illness regulate brain development and neural plasticity. These gene variants do not directly cause mental illness. Rather, they seem to collectively compromise the evolved interactions of various proteins and cell types in the brain, slightly altering the dynamic interactions of the thousands of proteins expressed in the brain, thus reducing the overall robustness of brain development and function. The issue is not as simple as one bad gene, one bad protein, or one dysregulated brain region. If you look closely at anyone’s brain, you are bound to find a few peculiarities in structure or function. People with mental illness tend to have more brain peculiarities overall, but few (if any) of these peculiarities are consistent across people with similar diagnoses. Moreover, people who present with seemingly similar types of mental illness rarely share the same gene variants.  BRAIN DEVELOPMENT Human brain development is highly complicated, but it is also robust. There is a certain amount of unavoidable randomness at the molecular level that impacts brain development and maturation, but our genome has evolved to buffer many insults – environmental variation, genetic variation, and molecular noise. Our genome contains redundancies, error checking mechanisms, and quality control efforts, all to ensure healthy brain development and brain function. Gene mutations can be a source of stress for the developing brain, but the robustness of our genetic instructions allows gene variations to accumulate in the population if the individual mutations are not too severe.  NEURODEVELOPMENTAL ROBUSTNESS The bodies of bilateral creatures are largely symmetrical, and the two sides develop independently from the same set of genomic instructions. Presumably, highly symmetrical bodies reflect clear genetic instructions. In contrast, random, uncommon asymmetries suggest the underlying genetic instructions are a bit confusing or open to interpretation. They may indicate some amount of developmental instability. Accordingly, body symmetry may be indicative of the robustness of the genetic instructions, which must contend with environmental variation and molecular noise. Body symmetry slightly correlates with intelligence, physical attractiveness, and physical health. All of these traits have a genetic basis. We have identified hundreds of gene variants that are associated with intelligence, and the same gene variants are associated with physical attractiveness, physical health, and longevity. Presumably, these gene variants are indicative of some kind of neurodevelopmental robustness (very clear genetic instructions that can withstand environmental variation and molecular noise).  MUTATION–SELECTION BALANCE Mental disorder susceptibility genes are surely being continually selected out through evolution, but new mutations keep arising. There are about 20,000 protein-encoding genes in the human genome. Half of our genes are expressed in the brain at some point, either during development or adulthood. Mutations in any of these genes can put a strain on brain development and brain function. Accordingly, mental illness may not result from specific gene mutations. Rather, there may just be an unfortunate combination of gene mutations (across the genome) that altogether slightly disrupt neural network dynamics. To some extent, the prevalence of mental illness and its persistence across hundreds of generations may reflect a gene mutation-selection balance. Harmful mutations get eliminated over evolutionary time via natural selection, but new gene mutations arise with each generation. There are not a few key genes that are important. Half of our genome impacts brain development and brain function. Mutations anywhere may increase someone’s risk of developing a mental illness.  SHOULD I HAVE MY GENES TESTED? The identification of gene variants that confer an increased risk of developing psychiatric illness has not been particularly helpful with regards to prevention or treatment. The issue is that for most psychiatric disorders, there are few preventive measures that can be taken beyond avoiding trauma and generally looking after oneself. The best advice for maintaining a healthy brain and healthy body, based on the available data, is to – Stay active, physically and mentally (exercise, socialize, set goals) – Eat well (more vegetables, less sugar) – Reduce stress, lower blood pressure – Maintain good sleep habits – Limit alcohol intake and avoid tobacco and hard drugs.  FUTURE DIRECTIONS By identifying gene variants and neural circuit disruptions that are associated with mental illness, researchers hope to develop new treatment and prevention strategies. One idea is to develop gene editing techniques that could be used in living people or as a part of in vitro fertilization. There is also still hope for better disease management through new pharmacological treatments, perhaps ones that directly target intracellular signaling cascades rather than neurotransmitter signaling. Researchers are also evaluating the efficacy of deep brain stimulation targeted to different areas of the brain. They are increasingly testing closed-loop stimulation strategies, in which an implanted metal wire is used to record brain dynamics and then deliver stimulation when necessary to correct neural circuit irregularities.  SCHIZOPHRENIA Schizophrenia is is characterized social withdrawal, disorganized thinking, abnormal speech, and an inability to understand reality. The prevalence is nearly 1% of world's population. Symptoms typically come on gradually, begin in young adulthood, and in many cases never resolve (although 20% of people eventually do quite well). About 30-50% of people with schizophrenia do not believe they have an illness or comply with their recommended treatment. SCHIZOPHRENIA ONSET  SCHIZOPHRENIA SYMPTOMS The symptoms of schizophrenia are often grouped into 3 categories: Negative: the absence of behaviours - social withdrawal, reduced emotional expression, poverty of speech, and reduced motivation Cognitive: disorganized and irrational thinking, deficits in learning and memory, poor abstract thinking, and poor problem solving Positive: the presence of delusions (delusions of persecution, grandeur, or control - beliefs that contradict reality) and hallucinations (perception of stimuli that are not actually present) Negative symptoms typically emerge first, followed by cognitive symptoms and, years later, by positive symptoms. Many patients with schizophrenia also exhibit neurological symptoms, such as poor control of eye movements and unusual facial expressions. The illness is also associated with subtle differences in brain structure, but these are quite variable.  SCHIZOPHRENIA HERITABILITY Estimates of the heritability of schizophrenia are around 80%. Heritability measures the fraction of phenotype variability that can be attributed to genetic variation. The concept of heritability can be expressed in the form of the following question: "What is the proportion of the variation in a given trait within a population that is not explained by the environment or random chance?" Concordance rates are generally easier to understand. Someone’s likelihood of having schizophrenia is … – 50% if their identical twin has it. – 50% if both of their parents have it. – 13% if one of your parents has it. – 8% if one of their siblings has it. 5% of cases are attributed to rare gene copy number variations (duplicated or missing genes), which often result in schizophrenia comorbid with autism and intellectual disabilities. These highly penetrant gene mutations are rare, even among people with schizophrenia. SCHIZOPHRENIA ENVIRONMENTAL FACTORS Environmental factors: – mother’s nutrition during pregnancy – mother’s stress during pregnancy – certain infections (particularly during pregnancy) – birth month – being raised in a city – childhood trauma – social isolation – perinatal hypoxia / brain damage  SCHIZOPHRENIA ENVIRONMENTAL FACTORS Schizophrenia is somewhat related to environmental factors that can affect development in utero: season of birth, viral epidemics, population density, and parental smoking. The seasonality effect: A disproportionately large number of schizophrenic patients are born in February, March, April, and May. Schizophrenia is also more prevalent in people who live in large cities as compared to those who live in rural areas. Presumably, some infectious illness that spreads easily in dense cities and cold weather (when people are indoors) contributes slightly to brain development in utero (before birth).  SCHIZOPHRENIA ENVIRONMENTAL FACTORS Prenatal environments of monochorionic twins (i.e., they share one placenta) are more similar than those of dichorionic twins. Some evidence suggests that the concordance rate for schizophrenia is higher for monochorionic twins than for dichorionic twins, which suggests that the prenatal environment is an important factor.  EVIDENCE FOR ABNORMAL BRAIN DEVELOPMENT Symptoms of schizophrenia are not normally seen in childhood, but behavioral and anatomical evidence indicates that abnormal prenatal development is associated with schizophrenia Behavioural: Children who go on to develop schizophrenia display less sociability and deficient psychomotor functioning as kids. Anatomical: Minor physical abnormalities are often seen in children who go on to develop schizophrenia, such as partial webbing of the two middle toes and a high-steepled palate.  TREATMENT OF SCHIZOPHRENIA There is no cure for schizophrenia. The main treatment is medication, often in combination with psychological and social support. Many drugs have been developed that relieve the positive symptoms of schizophrenia. They typically block dopamine D2 receptors and are called antipsychotics or neuroleptics. In contrast, dopamine receptor agonists, like crystal meth and cocaine, tend to temporarily elicit certain aspects of the positive symptoms of schizophrenia in people who do not have the disorder. Thus… The Dopamine Hypothesis: excessive dopamine D2 receptor activity, particularly in the nucleus accumbens (striatum), underlies the positive symptoms of schizophrenia.  THE DOPAMINE HYPOTHESIS Dopamine D2 receptor antagonists typically reduce the positive symptoms of schizophrenia (delusions and hallucinations) but not the negative symptoms (reductions in motivation, speech, emotionality, and sociality). These negative symptoms account for a large part of the long-term disability and poor functional outcomes in patients with schizophrenia. Some evidence suggests that the negative symptoms of schizophrenia result from abnormal activity in the prefrontal cortex. – For example, the negative symptoms of schizophrenia are similar to those produced by damage to the prefrontal cortex, and schizophrenic patients do poorly on neuropsychological tests that are sensitive to prefrontal brain damage. – In general, the negative symptoms of schizophrenia may be caused by hypofrontality, which is decreased activity of the frontal lobes, particularly the dorsolateral prefrontal cortex, which may relate to hypoactivity of local dopamine D1 receptors.  THE DOPAMINE HYPOTHESIS The negative symptoms of schizophrenia have been associated with hypofrontality, which is decreased activity of the frontal lobes, particularly the dorsolateral prefrontal cortex, which may relate to hypoactivity of local dopamine D1 receptors. So, while excess dopamine signaling in the striatum is associated with the positive symptoms of schizophrenia, it is possible that reduced dopamine signaling in the prefrontal cortex underlies some of the negative symptoms. In general, schizophrenia may be associated with too little dopamine in the prefrontal cortex and too much dopamine elsewhere. The atypical antipsychotic clozapine has been found (in monkeys) to simultaneously decrease dopamine levels in the striatum and increase dopamine levels in the prefrontal cortex  ATYPICAL ANTIPSYCHOTICS Atypical Second generation antipsychotics that aim to reduce both the positive antipsychotic symptoms and negative symptoms of schizophrenia. medications They typically influence the activity of several neurotransmitter receptors (beyond blocking the dopamine D2 receptor). Clozapine First of the atypical antipsychotic medications. It blocks dopamine D2 and serotonin 2A receptors, among other actions. Aripiprazole Another atypical antipsychotic. (also known as Abilify or Aristada) It acts as partial agonist at dopamine D2 and D3 receptors as well as at serotonin 1A receptors. It is thought to simultaneously reduce dopamine receptor activity in the striatum (nucleus accumbens) while boosting it in the prefrontal cortex. By acting as a partial agonist at dopamine receptors, the atypical antipsychotic Aripiprazole is thought to reduce dopamine receptor activity in the striatum while simultaneously boosting dopamine receptor activity in the PFC. A partial agonist is a drug with very high affinity for a receptor, but it activates it less than the normal ligand does. Because of these properties, a partial agonist can boost receptor activity in regions where there is low concentration of the normal ligand while simultaneously reducing receptor activity in regions where there is high concentration of the normal ligand.