The major hypothesis that guides studies in this project is that early life stress leads to a reduction in the ability to respond to safety signals. Despite substantial anecdotal evidence in support of this hypothesis, direct tests in humans or animals, using well-controlled behavioral paradigms, have been limited. In both rodents and humans, we have developed a discrimination procedure, referred to as AX+, BX-, that allows for the independent evaluation of excitation and inhibition of fear conditioning measured with the acoustic startle reflex. For example, AX+ could mean that two cues, such as a light and air flow created by a quiet fan presented together, are followed by shock. If so, then BX- would mean that a second cue, such as a tone and the fan, when presented together, would not be followed by shock. In this procedure, A elicits fear, whereas B is a safety signal, because it predicts that no shock will occur. Following such training, one can test whether B, the safety cue, will reduce fear to A by presenting A and B together. We have found in both rats and humans that B comes to inhibit fear following such training and this effect is not due to external inhibition. In humans, we will evaluate effects of early life stress in this paradigm using patients with or without major depressive disorders (MDD), with or without early life stress, as well as patients with social phobia with or without early life stress. In male and female rhesus monkeys we will set up this same procedure and then evaluate effects of early life stress using normal rearing conditions or rearing with repeated maternal separation, our model of early life stress. In addition, we will use another test we believe is a more a measure of anxiety than stimulus specific fear. Both humans and monkeys startle more in the dark than in the light. In rats, a nocturnal animal, we find they startle more in the light than in the dark, and this effect depends on the bed nucleus of the stria terminalis and not the central nucleus of the amygdala. A similar effect is found in rats when startle is enhanced after intraventricular infusion of CRF. Based on the fact that dark or light-enhanced startle, as well as CRF-enhanced startle in rats, involves unpredictable threat, we have suggested these effects may be more akin to anxiety vs. stimulus specific fear. Hence, we will evaluate dark-enhanced startle in these same patient groups, as well as in male and female rhesus monkeys, following normal rearing or rearing with early life stress.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
United States
Zip Code
Goodman, Sherryl H; Bakeman, Roger; McCallum, Meaghan et al. (2017) Extending Models of Sensitive Parenting of Infants to Women at Risk for Perinatal Depression. Parent Sci Pract 17:30-50
Schechter, Julia C; Brennan, Patricia A; Smith, Alicia K et al. (2017) Maternal Prenatal Psychological Distress and Preschool Cognitive Functioning: the Protective Role of Positive Parental Engagement. J Abnorm Child Psychol 45:249-260
Houtepen, Lotte C; Vinkers, Christiaan H; Carrillo-Roa, Tania et al. (2016) Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun 7:10967
Zannas, Anthony S; Arloth, Janine; Carrillo-Roa, Tania et al. (2015) Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol 16:266
Klengel, Torsten; Binder, Elisabeth B (2015) FKBP5 allele-specific epigenetic modification in gene by environment interaction. Neuropsychopharmacology 40:244-6
Johnson, Katrina C; Brennan, Patricia A; Stowe, Zachary N et al. (2014) Physiological regulation in infants of women with a mood disorder: examining associations with maternal symptoms and stress. J Child Psychol Psychiatry 55:191-8
Rouse, Matthew H; Goodman, Sherryl H (2014) Perinatal depression influences on infant negative affectivity: timing, severity, and co-morbid anxiety. Infant Behav Dev 37:739-51
Hecht, Erin E; Murphy, Lauren E; Gutman, David A et al. (2013) Differences in neural activation for object-directed grasping in chimpanzees and humans. J Neurosci 33:14117-34
Heim, Christine M; Mayberg, Helen S; Mletzko, Tanja et al. (2013) Decreased cortical representation of genital somatosensory field after childhood sexual abuse. Am J Psychiatry 170:616-23
Miller, Andrew H; Haroon, Ebrahim; Raison, Charles L et al. (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297-306

Showing the most recent 10 out of 146 publications