|Neurobiology of Resilience|
Stress targets everyone; but not everybody succumbs to it. Some develop stress-related psychopathology, anxiety, depression, dementia, while others weather it well and even emerge healthier. What makes some individuals resilient and others not? Comprehensive studies on 9/11 survivors and war veterans report that positive emotion helps resilient people re-route physiological resources activated by stress into successful coping strategies. Stress is known to cause brain damage, shrink neurons of hippocampus (memory center of brain) and enhance emotional learning along with neuronal growth in amygdala (emotion center of brain). Our research (@ Resilieo) is geared to find out how we can minimize and prevent brain damage caused by stress. Also, what is different and special in resilient individuals in terms of brain changes during/after stress? With this backdrop, we venture into 4 different lines of investigation.
1. Is there any difference in brains of resilient and vulnerable individuals?
Our study on rats exposed to predator stress showed distinctive pattern of neuronal branching within amygdala of resilient individuals. Well-adapted (resilient) animals had more densely packed neuronal branching and maladapted (vulnerable) animals had more spread out neuronal branching of amygdala neurons. Questions we are pursuing now include, what determines individual variation in neuronal branching? And what are the possible factors mediating this?
2. How to rescue or prevent stress-induced damages (enhance resilience)?
In addressing this question we employed gene therapy as a technique to deliver genetically altered proteins through viral vectors into specific brain regions. Targeted infusion of therapeutic molecules within amygdala rescued stressed animals from maladaptive anxiety, abnormal stress-response and neuronal over growth (hypertrophy). We continue to identify newer molecules for therapeutic intervention within amygdala and other brain regions.
3. Developing animal model of resilience
Enriched environment is known to induce positive behavior and protection against brain damage. We are testing different enrichment paradigms to develop a testable animal model of resilience. Initial results are promising. Short term enrichment rescues maladaptive fear response in stressed animals.
4. Are resilient individuals better adapted?
In an interesting new finding we showed that male rats exposed to enriched environment for a short 2 week period were more attractive and preferred as mates by females over non-enriched males. The enriched male rats also had stronger defense response against predator. Thus resilience not only makes individuals cope better with stress, but also has a bigger scope of adaptability in an ever-changing environment. Resilience triggers several physiological pathways that are directly beneficial for basic survival drives, namely, reproduction/mate-choice and protection from danger. We continue to investigate how enrichment drives basic physiology to be more adaptive? What are the pathways and molecular factors triggered by enrichment in this context?
- Rupshi Mitra and Robert M Sapolsky. (2012). Short-Term Enrichment Makes Male Rats More Attractive, More Defensive and Alters Hypothalamic Neurons. PLoS ONE, 7(5).
- Mitra, R. and Sapolsky, R.M. (2010). Gene therapy in rodent amygdala against fear disorders. Expert Opinion on Biological Therapy, 10(9), 1289-303.
- Lyons, D.M., Buckmaster, P.S., Lee, A., Wu, C., Mitra, R. (2010). Stress coping stimulates hippocampal neurogenesis in adult monkeys. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 107(33), 14823-7.
- Mitra, R., Ferguson, D., and Sapolsky, R.M. (2009). Mineralocorticoid receptor overexpression in basolateral amygdala reduces corticosterone secretion and anxiety. Biological Psychiatry, 66(7), 686-90.
- Mitra, R., Ferguson, D., and Sapolsky, R.M. (2009). SK2 potassium channel overexpression in basolateral amygdala reduces anxiety, stress-induced corticosterone secretion and dendritic arborization. Molecular Psychiatry, 14(9), 847-55,827.