Brendan Chen ’22 and Kiran Kumar ’22
The raging conflict in Ukraine is creating a humanitarian crisis through denial of food, water, and housing for those caught in the crossfire. Each day, thousands of people worldwide are added to a growing number of individuals facing food insecurity. Food insecurity is a widespread problem, even during peacetime. Families in the United States cannot afford consistent access to food. We must consider the psychological consequences of food insecurity, in addition to the physiological. The immediate victims are not the only ones affected, and their offspring will suffer from ailments tracing back to starvation.
How Did We Get Here?
It is important to differentiate three key terms: famine, food insecurity, and hunger. Famine is an event where all or most of the entire population is unable to acquire enough food to sustain the human body. Famine generally describes many people, while food insecurity refers to a single individual’s unstable access to sufficient amounts of food for the body to perform basic functions. This is distinct from hunger, which is a feeling telling you the body wants food.
The link between food, genes, and brain function originated from two significant studies released after World War II: the Dutch Famine Birth Cohort Study, and the Minnesota Semi-starvation Experiment.
As punishment for Dutch resistance during the last year of World War II, food supplies to the Nazi-occupied Netherlands were curtailed up until Allied Liberation. This resulted in a 7 month famine in which food intake reached a low of 400 calories.1 For reference, experts recommend 2,000 calories as the amount necessary to sustain a healthy human body. More than 50 years later, the Dutch Famine Birth Cohort Study was conducted. In this study, scientists examined 2,414 children born before, during, and after the famine, utilizing information from interviews and medical records.1 One study from the cohort found evidence of famine-induced permanent genetic modification, persisting from fetus to adulthood. These modifications can occur in distinct brain regions, pointing to the possibility that mental disorders, such as depression, anxiety, and schizophrenia, could be caused by such genetic alterations.6 Genetic modifications lasting well beyond the end of the famine and even the end of nutritional rehabilitation give famine generational consequences.
During the Minnesota Experiment in 1944, American conscientious objectors underwent semi-starvation regimens to develop rehabilitative diets. Headed by Ancel Keys at the University of Minnesota, the study used 32 white, male objectors to war provided by the Selective Service System.5 Individuals underwent a controlled dietary protocol of 1,570 calories per day, from mostly high carb foods, and a daily exercise routine for 24 weeks.6 This was meant to replicate the conditions the starving in Europe and Asia. Individuals were subsequently rehabilitated for 12 weeks under a controlled diet of 2,000 calories, and were then monitored for 6 weeks during a non controlled diet. While it would never be conducted today due to ethical concerns, this study showed powerful mood swings, eating disorders, and compulsive behaviors resulting from starvation. Ancel Keys became one of the first scientists to suggest that rehabilitation from food deprivation needed both nutritional and mental health support.5
In recent research on the connection between starvation and mental health, scientists have come to identify a protein receptor named Dopamine Receptor D1 (DRD1) as being affected by starvation and influencing brain function.
The Basics
Our genes are encoded by DNA within cells. A gene is “expressed” when a cell reads the DNA sequence for a gene and produces the corresponding protein (Fig. 2). A single cell contains the entire human genome. Humans need specialized cells which express only a few genes. There are two types of markers controlling gene expression without changing the genetic code. Humans are born with one type, and another type is acquired throughout life due to environmental factors. The study of these acquired markers is known as epigenetics, and the study of food’s impact on acquired markers is known as nutrigenetics. Humans are a result of “nature” and “nurture”.
The gene for DRD1 is present within the genome common among all cells, but DRD1 itself is not present in all cells as DRD1 gene expression is limited mostly to cells within the brain. The type of markers we are born with ensure DRD1 is expressed in the brain instead of stomach or appendix. Environmental factors, such as food availability, can influence the acquired markers responsible for turning on or off DRD1 gene expression. DRD1 is primarily found in the brain, which suggests that it plays a role in sophisticated functions such as motivation and emotions.9
DRD-1, aka Dopamine Receptor D1 is one of many receptors for the dopamine neurotransmitter.9 Dopamine is commonly thought of as the “feel-good” neurotransmitter; the chemical that produces a rewarding sensation during activities like exercising or being lazy. Exercising naturally causes a release of dopamine. Dopamine release during laziness associates good feelings with the event, increasing memory retention. Dopamine is actually far more versatile, playing a role in learning, memory, and movement by activating neurons. Much of existing research and information comes from studying humans who donate their body to science and lab-raised rats. Surprisingly, the rat DRD1 is so similar to human DRD1 both genetically and functionally that it can be considered identical.7 Today’s scientists can study DRD1 in much greater detail without using human subjects.
Is there a link between food and DRD1?
In one study, researchers gave newly pregnant rats either a normal or malnourishing diet.7 Diets varied by amino acids consumed, with the malnourishing diet containing half the normal amount of amino acids needed for normal protein formation. Amino acids are required for human cells to make proteins. Starvation can impact DRD1 protein levels by reducing the amount of amino acids available to cells. Meats, beans, and nuts are important sources of essential amino acids because human bodies cannot produce them naturally. Reducing amino acid consumption means your cells will not make enough proteins when trying to express genes or turn markers on or off. That can be problematic if your body depends on a specific protein which cannot be produced.
These scientists hypothesized a severe reduction in amino acid consumption will affect epigenetic markers responsible for turning the DRD1 gene on or off. They will analyze the amount of DRD1 mRNA produced by cells at 16 weeks of age (the average wild rat lifespan is 18 weeks) to determine if malnourishment has an effect on cells’ desire to produce DRD1.7 Scientists use mRNA because it is a molecule cells produce if they want to express a specific gene. It contains instructions for the cell to make a specific protein, DRD1 in this case. High levels of DRD1 mRNA implies the cell is making a lot of DRD1 protein.
They found DRD1 had a 46.5% higher mRNA levels in rat pups of malnourished rats relative to the control group.7 This suggests nutrition for the mother has an impact in her pups’ nervous system development. In statistics, a 46.5% increase in DRD1 mRNA is too high to be a coincidence or random event. Scientists can reasonably conclude a malnourished pregnant rat would give birth to a pup with lifelong elevated DRD1 levels. That same study also revealed increased mRNA expression of DRD1 in the ventral striatum of the malnourished group.7 The ventral striatum (VS) is a region of the brain that is highly active in reward sensations which make it a key target for studying addiction.4 This region also receives signals from areas which process emotions and memories respectively. We hypothesize the VS associates reward with positive emotions from memories. The ventral striatum sends signals to brain regions important for movement.4 Using this knowledge, we can predict an increased expression of DRD1 could increase the strength of pleasurable sensation and increase muscle activity causing an increased likelihood for addictive behaviors or sensory disorders like schizophrenia.
The results are consistent with observations from the Dutch Famine Cohort—biological changes starting from birth and persisting into late adulthood. Pregnant American mothers who are already struggling to make ends meet also have to worry about their children at increased risk of psychological problems. Many Ukrainians could have lifelong biological changes because of how war threatens basic necessities. The next question is if human studies reflect this prediction, and what are observed differences in behavior.
What about DRD1 and Cognition?
After showing food insecurity has an effect on DRD1 expression levels, researchers need to see if that affects human behavior. In one study, scientists examined the brains of deceased bipolar patients and found elevated levels of DRD1 expression in the prefrontal cortex.5 Since genetic manipulation in humans is morally and ethically wrong, scientists must use brains donated by patients to observe natural occurrences of altered DRD1 expression. The prefrontal cortex is the same part of the brain that is not “fully developed” until adulthood and is responsible for complex decision making. That same study found DRD1 expression levels in the prefrontal cortex begin to decrease at 20 years of age. That is also the typical age where bipolar disorder is diagnosed and is one indicator of a fully developed prefrontal cortex.5
This suggests increased expression of dopamine receptors means an increase in the amount of signaling within a single neuron could contribute to bipolar symptoms, particularly the manic episodes. A consistently stronger than average dopamine signal could overload entire brain regions. Hyperactivity in a brain region responsible for decision-making could result in impulsivity, mood swings, or near-psychosis. It is like the prefrontal cortex is still developing but is competing with other developed parts of the brain influencing decision making.
Food insecurity is often a symptom of economic poverty in the United States, a problem which can last for generations. Experts already suggest there is an increased risk of psychiatric disorders in impoverished individuals. War restricts access to food by redistributing supplies to soldiers or destroying infrastructure needed to deliver food to civilians. Warfare causes long lasting mental trauma in both soldiers and civilians, both through combat and simply struggling to survive the ordeal. Identifying how food insecurity affects biology to cause mental illnesses allows scientists to develop effective rehab services.
Conclusions and Discussions
Many of us can agree being hungry affects our behavior, making us more irritable or reducing our performance in tasks. However, prolonged insecurity clearly also has effects on the human nervous system; literally affecting the design of the brain and its ability to process information. These effects can be lifelong, and could appear at any stage of life. Scientists found this intriguing eighty years ago and today’s studies are helping us understand how food affects human development and function.
With so much uncertainty in science and the scale of the problems, it seems like there is no perfect solution to the problems facing the world today. Millions of people face acute food insecurity daily. Just 13.8 million American households faced food insecurity at some point during 2020—nearly 11% of all households in the United States. The War in Ukraine is starving civilians living in besieged cities, reducing food access to those outside of combat zones, and destroying the infrastructure needed to deliver food to both Ukrainians and Russians post-hostilities. However, anyone can contribute to solving these issues; it takes a collection of scientists to solve the toughest mysteries, but a collection of ordinary people can take on the mightiest challenges. Volunteer or donate to charity organizations addressing food insecurity or mental health services. These organizations vary on scale from the local town level to the international community. Like science, real world change starts with the smallest progress.
References
- Bleker LS, de Rooij SR, Painter RC, Ravelli AC, Roseboom TJ. Cohort profile: the Dutch famine birth cohort (DFBC)- a prospective birth cohort study in the Netherlands. BMJ Open. 2021 Mar 4;11(3):e042078. doi: 10.1136/bmjopen-2020-042078. PMID: 33664071; PMCID: PMC7934722.
- Central dogma of Genetics. Ms. Jones Website. (n.d.). Retrieved April 12, 2022, from http://sciencewithmsjones.weebly.com/living-environment/central-dogma-of-genetics
- Guetzkow, H. S., & Bowman, P. H. (1946, June 25). Men and hunger: A psychological manual for relief workers . Internet Archive. Retrieved April 12, 2022, from https://archive.org/details/MenAndHunger/page/n43/mode/2up
- Haber SN. Neuroanatomy of Reward: A View from the Ventral Striatum. In: Gottfried JA, editor. Neurobiology of Sensation and Reward. Boca Raton (FL): CRC Press/Taylor & Francis; 2011. Chapter 11. Available from: https://www.ncbi.nlm.nih.gov/books/NBK92777/
- Kaalund, S., Newburn, E., Ye, T. et al. Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. Mol Psychiatry 19, 1258–1266 (2014). https://doi.org/10.1038/mp.2013.165
- Keys, A., Brozek, J., & Henschel, A. (1950). The biology of human starvation. University of Minnesota Press.
- Martimiano, P. H. de M., Silva, G. R. da, Vanessa Fernandes da Silva Almeida Coimbra, Matos, R. J. B., Souza, B. F. P. de, Silva, A. A. M. da, Diogo D’Paula Cunha Brasileiro de Melo, Souza, S. L. de, & Freitas, M. F. L. de. (2015, April 28). Perinatal malnutrition stimulates motivation through reward and enhances drd1a receptor expression in the ventral striatum of adult mice. Pharmacology Biochemistry and Behavior. Retrieved March 19, 2022, from https://www.sciencedirect.com/science/article/pii/S0091305715001252
- U.S. Department of Health and Human Services. (n.d.). Bipolar disorder. National Institute of Mental Health. Retrieved April 12, 2022, from https://www.nimh.nih.gov/health/topics/bipolar-disorder
- U.S. National Library of Medicine. (n.d.). DRD1 dopamine receptor D1 [homo sapiens (human)] – gene – NCBI. National Center for Biotechnology Information. Retrieved March 19, 2022, from https://www.ncbi.nlm.nih.gov/gene/1812