Mount Sinai researchers uncover differences in how males and females change their mind when reflecting on past mistakes

A traditionally overlooked type of RNA plays an important role in promoting resilience to depression—but only in females. According to a new study led by the Icahn School of Medicine at Mount Sinai, researchers have now discovered a novel role this molecule plays in how the female brain makes decisions. The authors revealed brain-region-specific and sex-dependent effects of this biomarker, translated from humans to animals, on how individuals make only certain types of choices. This study uncovered differences in how each sex decides whether to change their minds after making mistakes, including when to cut their losses and move on as well as how they process regrets about missed opportunities.

This research sheds important light on how specific types of decisions that could negatively impact mood engage the male and female brain in very different ways. The study, published July 11 in Science Advances, using laboratory animal models, helps uncover new biological and psychological mechanisms that may be linked to psychiatric vulnerabilities.

Women are twice as likely to develop depression than men. Furthermore, depression can manifest with different symptoms between the sexes, including alterations in negative rumination on the past. However, the neurobiological mechanisms underlying these differences remain unclear.

“Our motivation for this work stemmed from a major gap in understanding why depression is more prevalent in females and how symptoms related to negative rumination take shape in the brain,” said Brian Sweis, MD, PhD, Assistant Professor of Psychiatry, and Neuroscience, at the Icahn School of Medicine and senior author of the paper. “We set out to investigate how the brain at risk for developing depression thinks about one’s prior choices and how neural circuits that process such computations could contribute to disease burden in this way.”

This study builds on a recent breakthrough involving a traditionally overlooked class of molecules known as non-coding RNA that were found to play a pivotal role in depression pathology.

In a 2020 study that leveraged analyses of postmortem human brain tissue, researchers also involved in the current study (Issler et al.) discovered that expression levels of the long intergenic non-coding RNA termed LINC00473 were reduced, specifically in the prefrontal cortex, in the brains of women—but not men—diagnosed with major depressive disorder.

Orna Issler, PhD, Assistant Professor of Neuroscience, and Anesthesiology, at the NYU Grossman School of Medicine, lead author of that 2020 study, and co-author of the present study, said, “We translated these findings into an animal laboratory model and demonstrated a causal role of prefrontal LINC00473, when experimentally increased, in promoting resilience to stress in female mice only.”

The prefrontal cortex is a key brain region essential for integrating mood with decision-making. In a key finding of the present study, researchers demonstrated that by surgically manipulating LINC00473 in the prefrontal cortex in mice, they could enhance how females, but not males, changed their minds while foraging for rewards. By applying principles of neuroeconomics to their analyses, the authors discovered that increased LINC00473 levels drove behavioral differences in females by enhancing sensitivity to sunk costs [overvaluing lost investments] and regret [sensitivity to missed opportunities] related to change-of-mind decisions—traits that may be associated with resilience to stress. Importantly, this is the first study to show that non-coding RNA plays a functional role in cognition in any capacity.

“We were able to selectively alter decision-making behavior involved in re-evaluating a recently selected choice without altering the initial judgement itself,” said Romain Durand-de Cuttoli, PhD, Instructor in Neuroscience at the Icahn School of Medicine and first author of this study. “Choices that depend on reflecting on the past are neurobiologically distinguishable from those that involve planning for the future. These are fundamentally distinct types of decisions processed in separate circuits in the brain, differently in males and females, that could in turn affect emotions in unique and complex ways.”

The implications of this research are significant. The study points to a novel molecular target for new drug development as well as an anatomical target for brain stimulation therapeutics that could potentially treat depressive symptoms related to negative rumination, specifically for females. Furthermore, the study sheds light on psychological aspects of resilience vs. vulnerabilities to depression in females. This work offers new insights for establishing a mechanistic link between the neurobiology of stress responses and how affective states interact with our choices.

“This research helps us appreciate that sensitivity to regret may not always be a bad thing. There are many ‘flavors’ of regret that could come from different parts of the brain and that can manifest very differently in males and females. Ruminating on the past, while potentially unpleasant, can still be useful for learning and can contribute to how we process emotions, deal with stress, and grow from past experiences,” explained Dr. Sweis. “The challenge will be to disentangle what aspects of this are maladaptive and feed into worsening depressive symptoms and which are healthy, adaptive, and part of an intact coping strategy. It is also exciting that behavioral findings from an animal study can push us to ask new questions about human psychology in ways that could directly inform advances in psychotherapy tailored to the individual. This study is a step in the right direction toward these goals.”

Ongoing work from this group is beginning to both forward- and back-translate efforts between the lab and the clinic to examine the manyfold dimensions of decision-making that may be altered in depression.

“This work emphasizes the importance of interdisciplinary research at the intersection of multiple fields, including psychiatry, psychology, and neuroscience,” said Eric J. Nestler, MD, PhD, Interim Dean, Icahn School of Medicine at Mount Sinai; Chief Scientific Officer, Mount Sinai Health System; senior author of the Issler et al., 2020 study; and co-author of the present study. “Translational cross-species research that includes leveraging animal models is crucial for making unexpected discoveries and accelerating the development of richer diagnostics, innovative treatments, and improved outcomes for those struggling with mental illnesses.”

This work was supported by the National Institute of Mental Health, the National Institute on Aging, the Burroughs Wellcome Fund, the Leon Levy Foundation, the New York Academy of Sciences, the Brain and Behavior Research Foundation, the Seaver Foundation, the American Society of Clinical Psychopharmacology, and the American Psychiatric Association.

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