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Project 1: Goldstein (Lead Investigator)

Genes & Hormonal Fetal Antecedents to Sex Differences in the Brain in Depression

In a human in-vivo study of individuals diagnosed with major depressive disorder (MDD) and healthy controls (n=1000), Project 1 investigates associations between genetic polymorphisms, the prenatal hormonal and immunological environment, and adult brain function in these MDD subjects and controls. Genetic polymorphisms associated with brain derived neurotrophic factor (BDNF), gamma-aminobutyric acid (GABA), glucocorticoids (GLU), and nitric oxide (NO) have been implicated in depression. Abnormal development of the stress response circuitry, particularly the hypothalamic-pituitary-adrenal (HPA) axis and interactions with the hypothalamic-pituitary-gonadal (HPG) axis, has also been implicated in MDD. In this study, we examine associations between maternal-fetal stress during mid-to-late gestation, as indicated by inflammatory cytokines and HPA hormonal exposure during prenatal development, and sex differences in the development of depression in adulthood. We relate these prenatal conditions to sex differences in the stress response in the brain in the adult offspring with and without depression.

To examine these associations we analyze maternal serum obtained as part of our subjects' mothers' participation in the National Collaborative Perinatal Project (NCPP), a study of 66,000 pregnant women across the country from 1959-1973. By virtue of unique access to individuals and data from the New England NCPP participants (~17,000 pregnancies), all of the adults to be studied have already been assessed during development (beginning in fetal development) through age 7. We have followed them as adults over approximately the last 17 years.

Using these maternal serum assessments of HPA-related hormone and cytokine abnormalities during mid-to-late gestation, a period during which the sexual differentiation of the brain occurs, we explore the potential impact of these abnormalities on sex differences in stress response circuitry in the brain in adulthood in depression using functional and structural magnetic resonance imaging paradigms. The study conducts genotyping on adult blood samples to detect genetic polymorphisms in subjects diagnosed with MDD. We also test for sex differences in adult HPA-HPG hormonal abnormalities in individuals with MDD in order to assess the mediating effects of hormones on deficits in stress response activity in the brain.


  • Response to stress in the adult female brain is regulated by gonadal hormones
  • Gonadal hormone differences explain sex differences in brain activity in response to stress response to healthy adults
  • At the clinical level,  the impact of gonadal hormones has important implications for the regulation of anxiety and mood
  • Gonadal hormone deficits seen in women with Major Depressive Disorder (MDD) are significantly associated with stress response circuitry deficits in the brain compared with healthy women.
  • Gonadal and adrenal hormone deficits are significantly related to sex differences in brain activity deficits in MDD
  • Brain activity deficits in stress response circuitry regions and hormone abnormalities were also significantly associated with loss of parasympathetic regulation of the heart (particularly in women)
  • These brain abnormalities and the sex-specific risk for MDD have fetal origins, including pregnancy complications such as preeclampsia and obstetric conditions resulting in fetal growth restriction


Goldstein, JM, Jerram, M, Poldrack, R, Kennedy, DN, Seidman, LJ, Makris, N. Hormonal cycle modulates arousal circuitry in women using fMRI. Journal of Neuroscience, 2005, 25:9309-9316. PMID: 16207891

Goldstein JM, Jerram M, Abbs B, Whitfield-Gabrieli S, Makris N. (2010). Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci 30(2): 431-8. PMID: 20071507; PMCID: PMC2827936

Holsen, LM, Spaeth, SB, Lee, J-H, Ogden, LA, Klibanski, A, Whitfield-Gabrieli, S, Goldstein, JM. (2011) Stress response circuitry hypoactivation related to hormonal dysfunction in women with major depression, Journal of Affective Disorders 131: 379–387. PMCID: PMC3073153

Holsen, LM, Lee, J-H, Spaeth, SB, Ogden, LA, Klibanski, A, Whitfield-Gabrieli, S, Sloan, R., Goldstein,JM. (2012)  Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: A preliminary study. Neuroscience Letters, in press; doi: 10.1016/j.neulet.2012.02.056

Goldstein JM, Cherkerzian S, Buka S, Fitzmaurice G, Susser E, Hornig M, Gillman M, Factor-Litvak P, Sloan RP. (2012) Sex-specific impact of maternal-fetal risk factors on depression and cardiovascular risk 40 years later. J Developmental Origins of Health and Disease 2 (6): 353–364. PMCID: PMC Journal - In Process

Anastario M, Salafia CM, Fitzmaurice G, Goldstein JM. (2012) Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters. Soc Psychiatry Psychiatr Epidemiol. 47(3):455-64. PMID: 21327969

Lebron-Milad, K, Abbs, B, Milad, M, Linman, C, Rougemount-Bücking, A, Zeidan, MA, Holt, DJ, Goldstein, JM. (2012) Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry.  Biology of Mood and Anxiety Disorders, in press.

Milad MR, Zeidan, MA, Contero, A, Pitman, RK, Klibanski, A, Rauch, SL, Goldstein, JM. (2010) The influence of gonadal hormones on conditioned fear extinction in healthy humans. Neuroscience 168: 652-658. PMID: 20412837; PMCID: PMC2881679

Holsen, LM, Lancaster, K, Klibanski, A, Whitfield-Gabrieli, S, Cherkerzian, S, Buka, S, Goldstein, JM.  Steroid Hormone Modulations of Stress Response Circuitry Activity Deficits in Women with Remitted Major Depression. Under re-review.