Leaving Your Mark on the World

By Danielle Gerhard


The idea that transgenerational inheritance of salient life experiences exists has only recently entered the world of experimental research. French scientist Jean-Baptiste Lamarck proposed the idea that acquired traits throughout an organism’s life could be passed along to offspring. This theory of inheritance was originally disregarded in favor of Mendelian genetics, or the inheritance of phenotypic traits isn’t a blending of the traits but instead a specific combination of alleles to form a unique gene encoding the phenotypic trait. However, inheritance is much more complicated than either theory allows for. While Lamarckian inheritance has largely been negated by modern genetics, recent findings in the field of genetics have caused some to revisit l’influence des circonstances, or, the influence of circumstances.


Over the past decade, efforts have shifted towards understanding the mechanisms underlying the non-Mendelian inheritance of experience-dependent information. While still conserving most of the rules of Mendelian inheritance, new discoveries like epigenetics and prions challenge the central dogma of molecular biology. Epigenetics is the study of heritable changes in gene activity as a result of environmental factors. These changes do not affect DNA sequences directly but instead impact processes that regulate gene activity such as DNA methylation and histone acetylation.


Epigenetics has transformed how psychologists approach understanding the development of psychological disorders. The first study to report epigenetic effects on behavior came from the lab of Michael Meany and Moshe Szyf at McGill University in the early 2000s. In a 2004 Nature Neuroscience paper they report differential DNA methylation in pups raised by high licking and grooming mothers compared to pups raised by low licking and grooming mother. Following these initial findings, neuroscientists have begun using epigenetic techniques to better understand how parental life experiences, such as stress and depression, can shape the epigenome of their offspring.


Recent research coming out from the lab of Tracy Bale of the University of Pennsylvania has investigated the heritability of behavioral phenotypes. A 2013 Journal of Neuroscience paper found that stressed males went on to produce offspring with blunted hypothalamic pituitary (HPA) axis responsivity. In simpler terms, when the offspring were presented with a brief, stressful event they had a reduction in the production of the stress hormone corticosterone (cortisol in humans), symptomatic of a predisposition to psychopathology. In contrast, an adaptive response to acute stressors is a transient increase in corticosterone that signals a negative feedback loops to subsequently silence the stress response.


The other key finding from this prior study is the identification of nine small non-coding RNA sperm microRNAs (miRs) increased in stressed sires. These findings begin to delve into how paternal experience can influence germ cell transmission but does not explain how selective increases in these sperm miRs might effect oocyte development in order to cause the observed phenotypic and hormonal deficits seen in adult offspring.


A recent study from the lab published in PNAS builds off of these initial findings to further investigate the mechanisms underlying transgenerational effects of paternal stress. Using the previously identified nine sperm miRs, the researchers performed a multi-miR injection into single-cell mouse zygotes that were introduced into healthy surrogate females. To confirm that all nine of the sperm miRs were required to recapitulate the stress phenotype, another set of single-cell mouse zygotes were microinjected with a single sperm miR. Furthermore, a final set of zygotes received none of the sperm miRs. Following a normal rearing schedule, the adult offspring were briefly exposed to an acute stressor and blood was collected to analyze changes in stress hormones. As hypothesized, male and female adult offspring from the multi-miR group had a blunted stress response relative to both controls.


To further investigate potential effects on neural development, the researchers dissected out the paraventricular nucleus (PVN) of the hypothalamus, a region of the brain that has been previously identified by the group to be involved in regulation of the stress response. Using RNA sequencing and gene set enrichment analysis (GSEA) techniques they found a decrease in genes involved in collagen formation and extracellular matrix organization which the authors go on to hypothesize could be modifying cerebral circulation and blood brain barrier integrity.


The final experiment in the study examined the postfertilization effects of multi-miR injected zygotes. Specifically, the investigators were interested in the direct, combined effect of the nine identified sperm miRs on stored maternal mRNA. Using a similar design as the initial experiment, the zygote mRNA was collected and amplified 24 hours after miR injection in order to examine differential gene expression. The researchers found that microinjection of the nine sperm miRs reduced stored maternal mRNA of candidate genes.


This study is significant as it has never been shown that paternally derived miRs play a regulatory role in zygote miR degradation. In simpler terms, these findings contradict the conventional belief that zygote development is solely maternally driven. Paternal models of transgenerational inheritance of salient life experiences are useful as they avoid confounding maternal influences in development. Studies investigating the effects of paternal drug use, malnutrition, and psychopathology are ongoing.


Not only do early life experiences influence the epigenome passed down to offspring but recent work out of the University of Copenhagen suggests that our diet may also have long-lasting, transgenerational effects. A study that will be published in Cell Metabolism next year examined the effects of obesity on the epigenome. They report differential small non-coding RNA expression and DNA methylation of genes involved in central nervous system development in the spermatozoa of obese men compared to lean controls. Before you start feeling guilty about the 15 jelly donuts you ate this morning, there is hope that epigenetics can also work in our favor. The authors present data on obese men who have undergone bariatric surgery-induced weight loss and they show a remodeling of DNA methylation in spermatozoa.


Although still a nascent field, epigenetics has promise for better understanding intergenerational transmission of risk to developing a psychopathology or disease. The ultimate goal of treatment is to identify patterns of epigenetic alternations across susceptible or diagnosed individuals and develop agents that aim to modify epigenetic processes responsible for regulating genes of interest. I would argue that it will one day be necessary for epigenetics and pharmacogenetics, another burgeoning field, to come into cahoots with one another to not only identify the epigenetic markers of a disease but to identify the markers on an person by person basis. However, because the fields of epigenetics and pharmacogenetics are still in the early stages, the tools and techniques currently available limit them. As a result, researchers are able to extract correlations in many of their studies but unable to determine potential causality. Therefore, longitudinal, transgenerational studies like those from the labs of Tracy Bale and others are necessary to provide insight into the lability of our epigenome in response to lifelong experiences.

Neurodevelopment and the Health-Wealth Gap


By Danielle Gerhard


The famous Roman poet Virgil said that the greatest wealth is health. But what if your actual wealth affects your access to health?


It is estimated that more than 45 million Americans, or 14.5% of the population, live below the poverty line, according to the most recent Census Bureau survey. Although slightly lower than previous years, the poverty rate for children under 18 is still startlingly high: 19.9%. Poverty dictates how an individual lives their life and most importantly, what resources they have easy access to. Proper nutrition, environmental stimulation, basic healthcare, and family nurturing are all resources shown to aid healthy development yet are lacking in low-income communities.


An individual’s zip code is considered to be as much of a risk to one’s health as their genetics. Dr. Melody Goodman of Washington University in St. Louis researches the contribution of social risk factors to health disparities in local communities. One particular area in St. Louis, known as the Delmar Divide, is a stark example of how location is predictive of education and health. To the south of Delmar Boulevard is a largely white community with an average income of $47,000 and 67% of residents having a bachelor’s degree. Directly north of Delmar Boulevard is a predominantly African American community with a lower average income of $22,000 and only 5% of residents have a bachelor’s degree. In addition to income and education following the so-called Delmar Divide, health is also negatively affected. Higher rates of cancer, heart disease and obesity are only a few of the diseases plaguing these neglected, low-income neighborhoods.


Because our brains are rapidly developing during childhood, this leaves them more vulnerable to stress and environmental changes. Recently scientists have extended their efforts to better understand the long-lasting effects of income and environment on the brain and behavior. There have been a number of studies that look at the behavioral consequences of growing up in disadvantaged families, including increased risk for behavioral disorders, developmental delays, and learning disabilities. Fewer human studies have looked into the long-lasting effects of childhood poverty on brain regions known to be critical for executive function, attention and memory. Two studies published recently attempt to investigate this very question using a large-scale, longitudinal design in children between 3 and 20 years of age coming from different socioeconomic backgrounds.


One longitudinal, multi-site study published in JAMA Pediatrics investigated whether or not childhood poverty caused significant structural impairments in brain regions known to be important for academic performance. Key regions targeted in the study include the frontal lobes, involved in behavioral inhibition and emotion regulation, the temporal lobes, important for language and memory, and the hippocampus, a region shown to be critical for long-term memory as well as spatial and contextual memory. Demographic information and neuroimaging data was collected from nearly 400 economically diverse participants who were controlled for potential confounding factors such as health problems during or after pregnancy, complicated medical histories, familial history of psychiatric disorders, and behavioral deficits.


As hypothesized, children raised in low-income families had lower scores on the Wechsler Abbreviated Scale of Intelligence (WASI), which measures intelligence via verbal and performance IQ, and the Woodcock-Johnson III Tests of Achievement (WJ-III), a test for math skills and reading comprehension. Anatomically, children raised in low-income families showed reductions in gray matter (or volume – where most of the brain’s cells are housed), in the frontal and temporal lobes as well as in the hippocampus, with the largest deficits seen in children living well below the federal poverty line.


Another study recently published in Nature Neuroscience reported similar findings. The authors investigated whether poverty, defined by a parent’s education level and income, is predictive of neurodevelopmental deficits in key brain regions. As hypothesized, income is related to structural impairments in brain regions important for reading, language, and other executive skills. Similar to the study published in JAMA Pediatrics, this study found the strongest interaction in children from the poorest families.


These studies highlight the importance of access to beneficial resources during childhood and adolescence and how income and environment can drastically affect the trajectory of health and development of brain regions key to success into adulthood. A number of different programs for social change that are guided by empirical data and public policy are being implemented in disadvantaged communities. Sending healthcare workers out of the clinic and into these communities is a step in the right direction. However, some clinicians argue that this is unsustainable and instead advocate taking further steps towards training individuals who live in these communities and/or have healthcare providers move into these communities.


Furthermore, initiatives focusing on children and adolescents, in particular, could prevent more problems, possibly irreversible ones, from occurring down the road. Interventions directed towards reducing income inequality, improving nutrition, and increasing access to educational opportunities could drastically redirect a child’s trajectory into adulthood. Early education programs targeting children aged 3-5 years of age have been shown to improve future education attainment and earnings as well as reduce crime and adult poverty.


An unhealthy, broken social support system nurses an unhealthy, broken environment in disadvantaged regions lacking basic resources. Scientific knowledge can help direct public policy initiatives towards programs that could have greater impacts on society. A continued dialogue among scientists, politicians, and community activists is vital to the health not only of the children growing up in low-income communities but arguably to the health of our society as a whole. Solely placing funds and resources towards ameliorating adult poverty is akin to placing a band-aid on the problem. Today’s children are tomorrow’s adults, thus helping today’s children help’s tomorrow’s adults.

Electric Kool-Aid Acid Therapy?


By Danielle Gerhard

[quote]When the light turns green, you go. When the light turns red, you stop. But what do you do when the light turns blue with orange and lavender spots?[/quote]

– Shel Silverstein, A Light in the Attic


Research and development of drug therapies for treating mental illnesses burgeoned in the early to mid-20th century, coinciding with a more permissive public sentiment on the origins of psychological disorders.  Gradually, psychopharmacological discoveries shifted from serendipitous findings to rational drug design to target specific chemical systems in the brain. However, many treatments, such as selective serotonin reuptake inhibitors (SSRIs) for depression or atypical antipsychotics for schizophrenia and bipolar disorder, can take weeks to months to be effective and require chronic treatment. This often results in undesirable, and sometimes permanent, side effects as a result of the drug’s unintended off-target effects. Therefore, many researchers have directed their studies towards rapid-acting, acute treatments, particularly psychedelics.


Psychedelics entered the experimental world due to subjective reports of not only sensory hallucinations but importantly the expansion of consciousness experienced following use. Popular psychedelics include MDMA, LSD, ketamine, peyote, psilocybin (magic mushrooms) and marijuana. Like many drugs used to treat mood disorders, psychedelics also increase neural levels of the neurotransmitter serotonin. The general American public stance on legalization of illicit drugs has become more lax since the days of prohibition and “reefer madness.”


One example of societal shifts can be seen with the most popular illicit drug in the US: marijuana. Marijuana legalization has attracted a lot of attention lately, so much so that it has entered daily political rhetoric.  The Gallup Poll on Illegal Drugs  found that the percentage of individuals in favor of legalizing marijuana has risen from 12% in 1969 to 51% in 2014. The percent of individuals who report having tried marijuana has surged from 4% in 1969 to 38% in 2013. While only 38% of those polled have tried marijuana, 70% approved of the drugs use to alleviate pain and suffering.


Given increasing public support for the legalization of marijuana, why is it still considered illegal at the federal level and furthermore, why is it still classified as a Schedule I drug under the Controlled Substances Act that was enacted in 1970? Schedule I drugs are characterized as having a high potential for abuse, no medical use, and a lack of accepted safety. Other drugs in this category include heroin and methaqualone but also other psychedelics like MDMA, LSD, and psilocybin. Advocates of marijuana legalization and individuals urging for a revised categorization of psychedelics are calling on Congress to revise the CSA classification of these drugs to correspond with their science-based scheduling process.


There has been a lot of stigma and misconceptions circulating about the effects of psychedelics, which largely stem from conservative backlash to Vietnam-era rebellion in the youth who were reported to be using psychedelics. Three main concerns raised by the opposition regarding psychedelics include: safety, addiction and the long-term effects on mental health. While drug safety should be a concern regardless of its legal state, two legal drugs in particular, alcohol and tobacco, have been shown to be more harmful and dangerous to the brain and body than psychedelics. Recent reports by government agencies concerned with drug safety reported that only 0.005% of hospitalizations in 2013 were related to LSD or psilocybin, significantly lower than alcohol or non-medical abuse of prescription pills. Furthermore, psychedelics have very low levels of abuse when compared to alcohol and tobacco.  The National Institute for on Drug Abuse (NIDA), a government funded research agency, describes LSD as a non-addictive agent.


While there is a growing push to grant doctors the ability to prescribed marijuana for the purposes of treating the symptoms accompanying chronic and painful diseases like cancer or multiple sclerosis, there have been fewer studies investigating the use of other psychedelics to treat another chronic disease: mental illness. This is largely due to the third concern mentioned above. Many individuals who are opposed to loosening the restrictions on psychedelics worry that drugs like LSD, which transiently mimic aspects of schizophrenia, could independently instigate the onset of a mental illness.


A group from Norway has recently published a paper in the Journal of Psychopharmacology presenting data from a large-scale US population study to examine the relationship between psychedelic use and mental illness or suicidality within the year following use.  Lead authors Johansen and Krebs randomly surveyed data from 139, 095 individuals, approximately 20,000 of which were psychedelic users. After controlling for potentially confounding factors like childhood mental illness, demographics and other drug use, they failed to find any link between mental illness and psychedelic use.  There is a need for more studies like this to further benefit research, policy and the scheduling of psychedelic drugs.


A few interesting and promising clinical studies are currently underway to investigate the therapeutic potential of difference psychedelics for individuals who have failed to respond to mainstream treatments. The non-profit organization Multidisciplinary Association for Psychedelic Studies (MAPS) recently gained attention for a study that has successfully crowd-sourced funding to investigate the additive effects of MDMA-assisted psychotherapy in treating posttraumatic stress disorder (PTSD). Other large ongoing studies through MAPS include LSD-assisted psychotherapy for anxiety, ibogaine (from the West African shrub iboga) therapy for drug addiction, and a handful of studies using psilocybin in cancer patients or individuals diagnosed with obsessive-compulsive disorder.


The purpose of this article is not to advocate for the widespread use of psychedelics but to discuss key empirical findings that support a reclassification of these drugs to make it easier for scientists to more effectively study their potential benefits in treatment resistant patients. While the study by Johansen and Krebs found no link between psychedelic use and mental health or suicide risk, many researchers are interested in focusing on their potential to treat mental illnesses. It is important to remember that there are still potential risks of taking psychedelics that should be taken into consideration.


As with all prescribed or non-prescribed drugs, there are individual differences in the pharmacokinetics and pharmacodynamics, or how our body affects the drug and how the drug affects our body. While many users may experience an expansion of consciousness and feel as if they have benefited from taking these drugs, others may have a very negative subjective experience that can have lasting negative effects. Another risk to consider is that because these drugs are illegal and therefore unregulated, they can be laced with harmful or more addictive drugs. For the most part, the studies discussed in this article are investigating the use of these drugs not in healthy individuals but rather in patients who are suffering from a mental illness and have failed to respond to any other commercially available treatments.




A Micro Solution to a Macro Problem?


By Danielle Gerhard

Recent estimates by the National Institute for Mental Health (NIMH) have found that approximately 25% of American adults will experience a mental illness within a given year. Individuals living with a serious mental illness are more likely to develop a chronic medical condition and die earlier. In young adults, mental illness results in higher high school drop out rate. A dearth of effective medications leaves many individuals unable to hold a job, causing America a $193 billion loss in earnings per year. These saddening statistics shed light on the need for better drugs to treat mental illness.


Traditionally, treating a mental illness like depression, anxiety or schizophrenia involves a delicate and perpetually changing combination of drugs that target levels of neurotransmitters in the brain. Neurotransmitters are chemicals produced by the brain and used by cells to communicate with one another. Drugs used to treat mental illness either increase or decrease the release, reuptake or degradation of these chemicals from the cell. The current paradigm is that the disease solely results from neurotrasmitter imbalance. Therefore, research has predominantly focused on the specific types of cells that release them. However, neurons make up approximately 50% of all cells in the human brain. The other 50% of brain cells are glial cells and are responsible for maintaining and protecting the neurons in the brain and body.


One type of glial cell, microglia, are specialized macrophage-like immune cells that migrate into the brain during development and reside there throughout life. Microglia are the primary immune cells in the brain and act as first-responders, quickly mounting responses to foreign pathogens and promoting adaptive immune actions. Microglia can adapt to changes in their microenvironment by protracting or retracting their processes to maintain neuronal health, scavenging their surroundings for dead neurons and cellular debris. Moreover, it has been shown that microglia are involved in the induction and maintenance of long-term potentiation, an event that is critical for synaptic plasticity underlying learning and memory. Only in the past decade or so has this cell type begun to surface as a potential mediator in the development and continuation of mental illness. As a result of decades of neuron-focused experiments, the function of microglia have either been misunderstood or over-looked all together. Two recently published experiments contradict our conventional understanding of the etiology of mental illness.


A new study published in the January 29th issue of the scientific journal Nature Communciations by Dr. Jaime Grutzendler’s team at Yale University highlights a novel role for microglia in Alzheimer’s Disease (AD). Late-onset AD is thought to result from the accumulation of the protein β-amyloid (Αβ). This process is referred to as plaque aggregation and results from reduced Aβ plaque clearance. Because microglia with an activated morphology are found wrapped around areas of high Aβ accumulation, it has been hypothesized that they actually contribute to weakened neuronal projections by releasing small neurotoxic proteins, cytokines, that affect cell communication. Aβ can exist as mature and inert fibrillar Aβ but can also revert back to an intermediatary state, protofibrillar Aβ, which is toxic to neurons.


Dr. Grutzendler’s lab set out to to further investigate the role of microglia in Aβ plaque expansion with respect to the different forms of Aβ. Using two-photon imaging and high-resolution confocal microscopy, the team at Yale was able to show that, for the most part, microglia formed tight barriers around Aβ plaques with their processes, but in some instances microglia left plaque “hotspots” exposed. These plaque “hotspots” were associated with greater axonal and neuronal damage.


These findings indicate that microglia generated protective barriers around Aβ plaques that served to protect neurons from the neurotoxic effects of protofibrillar Aβ. Of note, studies using aged mice revealed that microglia were less effective at surrounding plaques leading to increased neuronal damage. Microglia regulation decreases with age thereby rendering neurons more vulnerable to environmental insults. This cell type is therefore a likely key mediator of neuronal death that leads to cognitive decline and emotional distrubances in patients suffering from AD and other neurogegenerative diseases.


Another recently published study highlights a novel role of microglia in addiction, a chronic disease that afflicts many individuals with mental illness, comes from Dr. Linda Watkins, of the University of Colorado, Boulder. The study, published in the February 3rd issue of the scientific journal Molecular Psychiatry, examines the role of microglia in the rewarding and reinforcing effects of cocaine.


It has long been understood that drugs of abuse cause activation of the dopamine (DA) system in the brain, with increased DA release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), a brain region important for their rewarding effects. Cocaine achieves this effect by blocking dopamine transporters (DATs) on the cell, resulting in increased levels of synaptic DA and sustained neuronal activity. Therefore, efforts have focused on targeting DATs to prevent the rewarding effects of cocaine and ultimately reduce addiction.


In addition to these established dogmas, recent studies have shown that cocaine also activates the brain’s immune system. Microglia express Toll-like receptor 4 (TLR4) and its binding protein MD-2, which are important for reconizing pathogens and activating the release of pro-inflammatory molecules such as interleukin-1β (IL-1β). Using an animal model of addiction in combination with in silico and in vitro techniques, Dr. Watkin’s team found that cocaine activates the TLR4/MD-2 complex on microglia, resulting in an upregulation of IL-1β mRNA in the VTA and increased release of DA in the NAc. Administration of the selective TLR4 antagonist (+)-naloxone blocked the cocaine-induced DA release and the rewarding effects of cocaine administration in the rodent self-administration behavioral models. Overall, the study concludes that TLR4 activation on microglial cells contributes to the rewarding and reinforcing properties of cocaine. Thus, drugs targeting this system could provesuccessful in treating addiction.


Through these studies and similar reports, it is becoming apparent that mental illness is more than a chemical imbalance in the brain and therefore shouldn’t be studied as such. The two studies highlighted in this article show the diverse role of microglia in the development and maintenance of mental illnesses. A more in-depth understanding of how this cell type interacts with already identified neural systems underlying mental disorders could result in the development of better-tailored drug design.