January 14, 2020
Written by: Greer Prettyman
How do we become who we are? The debate about “nature vs. nurture” has long sought to answer the question of whether development and outcomes in life are more dependent on our genetics or our environment. We now know that nature and nurture, or genes and experiences, interact in complex ways to influence the development of our brains, behaviors, and personalities.
One prominent example of genes and experience interacting is in a person’s risk for developing psychiatric disorders. Psychiatric conditions, including depression, anxiety, and schizophrenia, have a genetic component – that is, if someone has a certain genetic profile, their chances of getting a psychiatric disorder are increased compared to someone who doesn’t have those risk genes. However, we know from twin studies that genetics cannot completely explain whether someone will get a disorder, since the identical twin of a person with schizophrenia (who has the exact same genetic makeup) has only a 50% chance of developing the disorder. The remaining risk that is not explained by genetics is due to factors in a person’s environment that shape development.
Stress is one of the main environmental experiences that can increase the risk of developing a psychiatric disorder, particularly in individuals who might already have a genetic predisposition1. Stress and trauma, especially early in life, can alter future outcomes by changing the path of brain development. The brain has a high amount of plasticity, meaning its structure and function are molded and changed by experiences during our lives. The brain is at its most plastic during infancy and childhood, so experiences of stress during this time can have a greater effect on the course of brain development.
While we know that early life stress increases the risk of depression and other psychiatric conditions, the neurobiological mechanisms that underlie this increased risk are still being discovered. One way to study this effect in the brain is to look at cellular changes in the transcriptome. The transcriptome is the messenger RNA (mRNA) code that is created based on a person’s DNA and that leads to the creation of proteins the body uses to perform all of its cellular functions.
A person or animal’s genome, or the set of genes inherited from the parents, is stable over the lifetime, like a fingerprint. The transcriptome, however, is sensitive to differences in the environment. Levels of mRNA transcripts vary by brain region and cell type and are changed based on experiences, such as stress. RNA sequencing, or RNA-seq, is a technique that allows scientists to measure the transcripts that are being produced, often referred to as “gene expression”. Digging into changes in the transcriptome following early life stress may offer clues into the cellular components in the brain that are associated with increased risk for depression and psychiatric conditions.
Recent research in animal models of early life stress used these tools to provide new insight into how experiences of stress can shape the transcriptome of the reward system and change sensitivity to stress and rewards in the adult brain2. Alternations in the reward system, such as reduced ability to experience pleasure, are cardinal symptoms of depression. Since women are more likely than men to experience depressive symptoms after early life trauma3, it is also important for scientists to investigate sex differences during research into these processes, so researchers included and compared male and female mice in their study.
Researchers induced early life stress in mice by separating pups from their mothers soon after birth and providing them only a small amount of material to nest in. Other mice were given normal maternal care and served as a control group. Some of the mice from each group received additional stress when they reached adulthood in the form of mild foot shocks, suspension from their tails, restraints, or social defeat.
Female mice from all four conditions (early life stress alone, adult stress alone, both early life and adult stress, and no stress) were tested for behaviors associated with depression. Researchers assessed the animals’ grooming, preference for sugary drinks, willingness to eat in an unfamiliar environment, and reaction to stress during a swim test to create a composite score of depression and anxiety-related behaviors. Adult stress alone did not produce depressive behaviors, but mice that had previously experienced early life stress were more sensitive to adult stress, displaying higher depression-like behaviors than animals that did not have early life stress and animals with early life stress but not adult stress. This finding supports the idea that early life stress makes animals more sensitive to additional stress as adults in a way that likely increases susceptibility to psychiatric disorders.
To understand what changes were happening in the brain following early life stress that could help explain this behavioral finding, researchers next looked at the transcriptome. This study focused on three regions of the brain that are part of the reward circuit and are associated with symptoms of depression: the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). Male and female mice that experienced early life stress had a number of genes that were differentially expressed. The transcriptomes of mice that underwent additional stress as adults also looked different based on whether or not they had experienced stress early in life, further indicating that early stress primes the brain to respond differently to additional stressors.
Transcriptomic changes lead to alterations in biological processes, which can alter the development and function of circuitry that eventually leads to behavior. In the NAc, early life stress increased transcriptional regulators of cell differentiation, the process by which certain cells become designated for different roles, and nervous system development, suggesting a few mechanisms for how stress at a young age can lead to lasting changes in the reward system. Certain genes were primed for expression when animals experienced both early life stress and adult stress, but not either one without the other. This finding provides evidence for specific biological processes that are selectively activated by multiple experiences of stress across the lifetime.
The brain’s incredible plasticity can lead to heightened risk but can also aid in resilience, allowing us to change, heal, and grow. The ability to investigate transcriptional changes that underlie vulnerability to psychiatric disorders will provide researchers with better tools to understand what is happening in the brain and to intervene with better treatment strategies.
1. Anda RF, Felitti VJ, Bremner JD, Walker JD, Whitfield C, Perry BD, Dube SR, Giles WH (2006). The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci. 256(3):174-86.
2. Jensen Peña, C., Smith, M., Ramakrishnan, A., Cates, H. M., Bagot, R. C., Kronman, H. G., … Nestler, E. J. (2019). Early life stress alters transcriptomic patterning across reward circuitry in male and female mice. Nature Communications 10:5098
3. McGuigan, W. M., & Middlemiss, W. (2005). Sexual abuse in childhood and interpersonal violence in adulthood: a cumulative impact on depressive symptoms in women. Journal of Interpersonal Violence, 20(10), 1271–87.