Sensitive Periods Of Development
The prenatal period and adolescence are two phases of development consistently linked with adult psychiatric illness. For example, when a woman experiences extreme stress during pregnancy, her offspring have an increased risk for psychiatric problems such as anxiety, depression, and schizophrenia[1-3]. In contrast, adolescence is the time when many psychiatric illnesses tend to emerge. However, the relationship between adolescent development and psychiatric illness remains poorly understood. Therefore, an overarching goal of our laboratory is to understand how the timing of stress exposure across development determines brain and behavioral
Nicotinic Acetylcholine Receptors (nAChRs) and Mental Illness
Prenatal Stress, Behavior, and nAChRs
Behavioral effects of prenatal stress
Prenatal stress has wide-ranging effects on the behavior of rodents. Dozens of published papers demonstrate that prenatal stress increases anxiety and depressive-related behaviors, and decrease memory function. Interestingly, these effects tend to be sexually dimorphic in nature. In our laboratory, we observe prenatal stress-induced increases in anxiety-related behaviors in females but not in males, and decreased memory function in males but not in females.
Effects of prenatal stress on nAChRs
The mechanisms by which prenatal stress alters emotional and memory function appear to be complex and to involve a number of neurotransmitter systems. However, the effects of prenatal stress on the brain cholinergic system has received very little attention, despite the importance of this system for both emotional and memory function. We recently demonstrated that prenatal stress significantly increases hippocampal alpha4 beta2 receptor levels in adulthood, suggesting that prenatal stress disrupts normal cholinergic signaling.In contrast, the effects of prenatal stress on alpha7 receptors were more subtle. Specifically, prenatal stress increased alpha7 nAChRs in the dentate gyrus of females. These sex-specific effects of prenatal stress may contribute to the sex-specific nature of behavioral impairments caused by prenatal stress.
Choline as a Stress Intervention
Effects of prenatal stress on hypothalamic nAChRs
Prenatal stress is associated with reproductive dysfunctions in offspring including mating behavior, sexual orientation, female fertility, and female fecundity. Nicotinic acetylcholine receptors (nAChR) in the hypothalamus regulate these same processes, but whether the effects of prenatal stress on reproductive function are mediated by altered nicotinic acetylcholine receptors is not known. Given that prenatal stress alters levels of nAChRs in other brain regions, we are testing the hypothesis that maternal stress alters the development of hypothalamic alpha7 nicotinic acetylcholine receptor levels in offspring.
Effects of prenatal stress on basolateral amygdala nAChRs
Both human and animal studies demstrate that prenatal stress impacts basolateral amygdala (BLA) development. For example, higher maternal cortisol concentrations in early gestation are associated with larger right amygdala volumes in girls at 7 years of age. Furthermore, early gestational cortisol levels are associated with affective problems in girls, suggesting that this association might be mediated, in part, by the larger right amygdala volume . In rodents, the offspring of prenatally stressed Sprague-Dawley dams have smaller BLA nuclei volumes, smaller BLA anterior/posterior lengths, and decreased numbers of neurons and glial cells in the brain. Given that PS impacts overall BLA development, and nicotinic receptors in the BLA are important for many of the behaviors impaired by PS, we hypothesize that PS will also alter levels of nAChRs in the BLA.
Prenatal programming of the effects of adolescent stress?
From the standpoint of sensitive periods of brain development, and individual’s previous stressful experiences may alter the course of brain development in a manner that confers increased risk, or even resilience, to the impact of subsequent stressors. Although both prenatal and adolescent stress are associated with increased risk of mental illness[1-3], whether prenatal stress exposure increases sensitivity to stress during adolescence is not known. Preclinical rodent models have enormous potential for elucidating the relationships between the timing of stress exposure across development and dysfunction. Therefore, we are currently testing the hypothesis that early stress exposure modifies the behavioral impact of stress during adolescence. This hypothesis predicts that the combined effects of prenatal and adolescent stress on behavioral function will be greater than the isolated effects of stress during either time period.
1. Walker, E., V. Mittal, and K. Tessner, Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annual Review of Clinical Psychology, 2008. 4: p. 189-216.
2. Walker, E., et al., Schizophrenia: Etiology and course. Annual Review of Psychology, 2004. 55: p. 401-430.
3. Walker, E.F., Z. Sabuwalla, and R. Huot, Pubertal neuromaturation, stress sensitivity, and psychopathology.Development and Psychopathology, 2004. 16(4): p. 807-824.
4. Steinberg, L., et al., The study of developmental psychopathology in adolescence: integrating affective neuroscience with the study of context, in Handbook of Developmental Psychopathology, D. Cicchetti, Editor 2005, John Wiley & Sons: New York, NY.
5. Newhouse, P., A. Singh, and A. Potter, Nicotine and nicotinic receptor involvement in neuropsychiatric disorders. Current Topics in Medicinal Chemistry, 2004. 4(3): p. 267-282.
6. Singh, A., A. Potter, and P. Newhouse, Nicotinic acetylcholine receptor system and neuropsychiatric disorders. Idrugs, 2004. 7(12): p. 1096-1103.
7. Araki, H., K. Suemaru, and Y. Gomita, Neuronal nicotinic receptor and psychiatric disorders: Functional and behavioral effects of nicotine. Japanese Journal of Pharmacology, 2002. 88(2): p. 133-138.
8. Martin, L.F. and R. Freedman, Schizophrenia and the alpha 7 nicotinic acetylcholine receptor, inIntegrating the Neurobiology of Schizophrenia2007. p. 225-246.
9. Adams, C.E. and K.E. Stevens, Evidence for a role of nicotinic acetylcholine receptors in schizophrenia.Frontiers in Bioscience, 2007. 12: p. 4755-4772.
10. Graef, S., et al., Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings. Psychopharmacology, 2011. 215(2): p. 205-229.
11. Levin, E.D., F.J. McClernon, and A.H. Rezvani, Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology, 2006. 184(3-4): p. 523-539.
12. Mineur, Y.S. and M.R. Picciotto, Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends in Pharmacological Sciences, 2010. 31(12): p. 580-586.
13. Schulz, K.M., et al., Maternal stress during pregnancy causes sex-specific alterations in offspring memory performance, social interactions, indices of anxiety, and body mass. Physiology & Behavior, 2011. 104(2): p. 340-7.
14. Zeisel, S.H. and K.A. da Costa, Choline: an essential nutrient for public health. Nutrition Reviews, 2009.67(11): p. 615-623.
15. Buss, C., et al., Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proc Natl Acad Sci U S A, 2012. 109(20): p. E1312-9.
16. Kraszpulski, M., P.A. Dickerson, and A.K. Salm, Prenatal stress affects the developmental trajectory of the rat amygdala. Stress, 2006. 9(2): p. 85-95.