The """"""""stress hormone"""""""" cortisol has been studied in depression for decades. However, relatively little is known about the role of cortisol in psychological features of depression. Basic research shows that cortisol modulates brain processes that are highly relevant to depression (especially the neural substrates of negative biases in learning and memory formation). However, very few studies have directly examined the effects of cortisol on neural circuitry of learning in depressed humans. In addition, basic research shows that the effects of cortisol on the neural substrates of learning differ for males and females. The toll of depression is especially high in women, who are roughly twice as likely as men to suffer from depression. Thus, the primary goal of this project is to investigate the effects of cortisol on the neural circuitry of learning in depressed women. A secondary goal is to investigate whether early life adversity moderates cortisol's effects on neural circuitry of learning. Animal data suggests that early life adversity causes life-long biases toward learning in threatening conditions associated with elevated cortisol. In addition, new data from humans suggests that alterations in cortisol traditionally ascribed to depression may stem in part from early adversity rather than depression per se. Thus, this study will examine effects of cortisol on neural circuitry of learning in depressed and healthy women with and without history of early life adversity. The study will use pharmacological manipulation of cortisol levels (compared to placebo) during measurement of brain activity at rest and during memory encoding of emotional and neutral stimuli. The study will also measure whether cortisol exacerbates (or instills) the negative biases in emotional memory often seen in depression. In doing so, the study will examine the role of cortisol in neural networks associated with emotional learning that are often implicated in depression. Medications that target cortisol receptors in the brain may be beneficial in the treatment of depression. However, this knowledge has yet to inform clinical practice, and mechanisms of action of these medications are not well understood. This project is significant because it provides the prerequisite knowledge (and develops a paradigm) that can be used in the development of more effective targeted intervention strategies. The project is innovative because it brings the vast literature of cortisol's effects on learning to research on depression. """"""""Learning"""""""" broadly refers to acquisition of relevant knowledge and the capacity to adaptively alter one's behavior to meet demands of the environment. At the core of depression is difficulty adapting to and engaging with one's environmental context, especially in the face of stressors. Recovery from depression (whether treated medically or behaviorally) requires neural changes supporting adaptation to one's environment. Thus, the project translates information from animal to human research suggesting that recovery from depression entails amelioration of stress-related alterations in neural processes underlying learning.

Public Health Relevance

Depressive disorders are a major public health concern, and the toll of depression is especially high for women. The proposed research will 1) contribute novel information about the relation between neurophysiological and cognitive mechanisms in women with depression, and 2) contribute knowledge regarding the differentiation of depressive subtypes. The project will provide basic information and a research paradigm that can be used in the development of more effective targeted intervention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH094478-01A1
Application #
8246161
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Rumsey, Judith M
Project Start
2012-03-29
Project End
2017-02-28
Budget Start
2012-03-29
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$381,822
Indirect Cost
$120,225
Name
University of Wisconsin Madison
Department
Psychiatry
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Abercrombie, Heather C; Frost, Carlton P; Walsh, Erin C et al. (2018) Neural Signaling of Cortisol, Childhood Emotional Abuse, and Depression-Related Memory Bias. Biol Psychiatry Cogn Neurosci Neuroimaging 3:274-284
Frost, Carlton P; Meyerand, M Elizabeth; Birn, Rasmus M et al. (2018) Childhood Emotional Abuse Moderates Associations Among Corticomotor White Matter Structure and Stress Neuromodulators in Women With and Without Depression. Front Neurosci 12:256
Philippi, Carissa L; Cornejo, M Daniela; Frost, Carlton P et al. (2018) Neural and behavioral correlates of negative self-focused thought associated with depression. Hum Brain Mapp 39:2246-2257
Plante, David T; Birn, Rasmus M; Walsh, Erin C et al. (2018) Reduced resting-state thalamostriatal functional connectivity is associated with excessive daytime sleepiness in persons with and without depressive disorders. J Affect Disord 227:517-520
Gaffey, Allison E; Wirth, Michelle M; Hoks, Roxanne M et al. (2014) Circulating cortisol levels after exogenous cortisol administration are higher in women using hormonal contraceptives: data from two preliminary studies. Stress 17:314-20
van Ast, Vanessa A; Cornelisse, Sandra; Marin, Marie-France et al. (2013) Modulatory mechanisms of cortisol effects on emotional learning and memory: novel perspectives. Psychoneuroendocrinology 38:1874-82
Abercrombie, Heather C; Wirth, Michelle M; Hoks, Roxanne M (2012) Inter-individual differences in trait negative affect moderate cortisol's effects on memory formation: preliminary findings from two studies. Psychoneuroendocrinology 37:693-701