Research-Occupational Therapy Program
Prenatal Alcohol Exposure|Sensory Processing Disorder: Primate Model
Mary Schneider, Ph.D., OTR
schneider@education.wisc.edu
Primate Models of Developmental Disabilities
- How does alcohol exposure during pregnancy affect the developing brain?
- How can we disentangle the effects of prenatal alcohol exposure from the effects of prenatal stress, since they tend to go hand-in-hand in real life?
- Is there a window of vulnerability for prenatal alcohol effects?
- Does prenatal alcohol exposure interact with genetic endowment?
- Does prenatal alcohol exposure and/or prenatal stress alter the development of the dopamine system and the behaviors dependent on dopaminergic function?
- Can we characterize the changes in neurotransmitter function that sub-serve the behavioral effects of prenatal alcohol exposure?
- What are the effects of prenatal stress and/or prenatal alcohol exposure on sensory processing function?
- What neurobiological correlates are associated with sensory processing disorder?
The University of Wisconsin-Madison has a long and distinguished history of contributions to understanding human psychological disorders using a primate model. Today, Dr. Schneider and colleagues have the largest study of non-human primate model of fetal alcohol exposure, prenatal stress, and sensory processing disorder at any university.
We believe that nonhuman primate studies provide an important bridge between rodent studies and human studies, in that nonhuman primate studies afford the controlled investigation of critical windows of fetal development in a species that shares more than 95% gene homology with humans. Also, nonhuman primates have the capacity for complex social relations and cognitive function. Even with the best statistical analyses it is difficult, if not impossible, to separate completely the effects of variables associated with alcohol use, such as psychological stress, tobacco use or chaotic home life, from the effects of fetal alcohol exposure per se. Nonhuman primates also have the advantage of gestation characteristics and early development similar to the human, and their shorter life span makes longitudinal studies somewhat easier to conduct. Rhesus monkeys are used because of the large amount of available data on their behavior and development in laboratory settings (Harlow & Harlow, 1969; Suomi, 1997).
Our primate model also enables us to conduct non-invasive neuroimaging studies using positron emission tomography (PET). Dr. Schneider collaborates with faculty from other departments, including faculty from Psychology (Professor Colleen Moore) and from Medical Physics (Professor Onofre DeJesus, Brad Christian, James Holden, and Jerry Nickles) and the Waisman Center Laboratory for Brain Imaging and Behavior.
Prenatal Alcohol Exposure
Dr. Schneider and colleagues are actively studying this issue using the latest technological advances. See UW-Madison press release. The questions being investigated pertain to separating the effects of alcohol from other life-style factors, such as stress during pregnancy, and examining the effects of exposure during specific gestation periods. It is particularly important to examine exposure during early pregnancy, when pregnancy might not yet be detected. In humans, fetal alcohol exposure is associated with deficits in learning, memory, attention, impulsivity, school achievement, adaptive social behaviors, and depression. In the United States, 60% of women of childbearing age consume alcohol and many women are unaware of their pregnancy until 6-8 weeks gestation.
We produced a cohort of monkeys whose mothers consumed moderate level alcohol during: 1) early gestation (0 – 50 days); 2) middle-to-late gestation (50 – 135 days); 3) both periods (0 – 135 days) or 4) sucrose-consuming controls. These monkeys have been well characterized since birth with respect to their neurobehavior, temperament, stress reactivity (HPA axis), cognitive function (executive function), genealogy (kinship coefficients and genotyping), sensory processing function, and brain DA function (DA synthesis and D2R binding) using PET technology.
During the first two phases of our study we detected a profile of prenatal alcohol-induced impairments that included: 1) reduced early attention and motor maturity (Schneider et al., 1997; 2001a); 2) dysregulated stress response system (Schneider et al., 2004); 3) impaired cognitive function (Schneider et al., 2001b); 4) unusual sensory sensitivities (Schneider et al., in press) and 5) altered DA system function, which depends on gestational timing (Schneider et al., 2005). Early gestation exposure and continuous exposure throughout pregnancy was found to be a period of vulnerability for down-regulation of D2R availability, which may be a risk factor for excessive alcohol consumption (Volkow et al., 2004). This contrasts with middle-to-late gestation, which showed up-regulation of D2R binding, which may be protective against alcohol abuse (Volkow et al., 2004).
Moreover, genetic endowment interacts with prenatal alcohol exposure. Prenatal alcohol-exposed carriers of a short length polymorphism in the serotonin transporter gene promoter region exhibited increased neonatal irritability and increased stress hormones (cortisol and ACTH) compared to fetal alcohol exposed monkeys homozygous for the long allele and monkeys not fetal alcohol exposed regardless of genotype (Kraemer et al., in press).
Dr. Schneider (PI) and colleagues recently received 5 years of funding from the National Institute of Alcohol Abuse and Alcoholism to extend this research program. A series of experimental studies will determine whether prenatal moderate level alcohol exposure during a specific window of fetal development increases an individual’s risk for excessive alcohol consumption during adulthood. The model of oral alcohol self-administration established by Kathleen Grant and colleagues that reliably produces a pattern of excessive alcohol consumption in monkeys will be employed (Vivian et al., 2001). It is hypothesized that monkeys exposed to alcohol during early pregnancy or throughout pregnancy will consume greater amounts of alcohol during adulthood then monkeys from mid-late-gestation alcohol-exposed pregnancies or controls. This hypothesis is based on previous findings of down-regulation of D2R binding in early gestation exposed offspring and in monkeys exposed throughout pregnancy, which may be a risk factor for predisposition to alcohol abuse (Volkow et al., 2004). This compares with up-regulation of D2R binding in those monkeys exposed later in pregnancy, which may be a protection against alcohol abuse (Volkow et al., 2004).
Monkeys will be induced to consume water, then ethanol (4% w/v) under a fixed-time (FT) schedule of pellet delivery in 16-hour sessions. The amount of alcohol consumption induced will be increased gradually over several months (to avoid conditioned aversions) and monkeys will eventually self-administer alcohol “ad libitum” for 16 and 22 hours per day for 3 months each.
Studies are underway to determine whether prenatal alcohol exposure reduces DA transporter (DAT) binding availability, D2-type (D2R) and D1-type (D1R) receptor binding in prefrontal cortex, caudate, putamen, and ventral striatum under baseline conditions. We will also assess DAT, D2R and D1R binding before and after chronic alcohol self-administration to determine whether excessive alcohol consumption alters DA system function.
A series of studies will also determine whether prenatal alcohol exposure reduces prepulse inhibition (sensorimotor gating) and tactile habituation (assessing well characterized neural circuit connecting limbic cortical regions and sub-cortical DAergic systems involved in inhibitory control).
Related publications:
Kraemer, G.W., Moore, C.F., Newman, T.K., Barr, C.S., Schneider, M.L. (2008). Moderate level fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and LHPA axis regulation in monkeys. Biological Psychiatry, 63, 317-324.
Schneider, M.L., Moore, C.F., DeJesus, O.T., Converse, A.K. (in press). Prenatal stress influences on neurobehavior, stress reactivity, and dopaminergic function in rhesus macaques. In T. Burbacher, G. P. Sachett, & K. S. Grant (Eds.), Primate models of children's health and developmental disabilities (pp.213-258). New York: Elsevier Inc..
Schneider, M.L. Moore, C.F., Gajewski, L.L., Larson, J. A., Roberts, A. D., converse, A. K., et al. (2008). Sensory processing disorder in a primate model: Evidence from a longitudinal study of prenatal alcohol and prenatal stress effects. Child Development, 79 (1), 100-113.
Moore, C.F., & Schneider, M.L. (2006). Prenatal development. In N.J. Salkind (Ed.), Encyclopedia of Human Development, pp. 1018-1020. Thousand Oaks, CA: Sage.
Schneider, M.L., Champoux, M. & Moore, C.F. (2006). Neurobehavioral assessment of nonhuman primate neonates. In G.P. Sackett, G.C. Ruppenthal, & K. Elias (Eds.), Nursery Rearing of Nonhuman Primates in the 21st Century (pp. 215-247). Springer Science-Business Media, Inc., New York.
Schneider ML, Moore CF, Barnhart TE, Larson JA, DeJesus OT, Mukherjee J, Nickles JR, Converse AK, Roberts AD, Kraemer GW (2005). Moderate level prenatal alcohol exposure alters striatal dopamine system function in rhesus monkeys. Alcoholism: Clinical and Experimental Research, 29(9), 1685-1697.
Roberts, A. D., Moore, C. F., DeJesus, O. T., Barnhart, T. E., Larson, J. A., Mukherjee, J., Schneider, M.L. (2004). Prenatal stress, moderate fetal alcohol, and dopamine system function in rhesus monkeys. Neurotoxicology and Teratology, 26, 169-178.
Schneider, M. L., Moore, C. F., & Kraemer, G. W. (2004).
Moderate level alcohol during pregnancy, prenatal stress, or both and limbic-hypothalamic-pituitary-adrenocortical axis response to stress in rhesus monkeys. Child Development, 75(1), 96-109.
Schneider, M.L., Moore, C.F. (2003). On the relevance of prenatal stress to developmental psychopathology. A primate model. In D. Cicchetti (Ed.) Neurodevelopmental mechanisms in psychopathology. (pp. 155-186) Cambridge University Press.
Schneider, M.L., Moore, C.F., Kraemer, G.W., Roberts, A.D., DeJesus, O.T. (2002).
The impact of prenatal stress, fetal alcohol exposure, or both on development: Perspectives from a primate model. Journal of Psychoneuroendocrinology, 27, 285-298.
Schneider, M.L., Moore, C. Kraemer, G.W. (2001) Moderate alcohol during pregnancy: Learning and Behavior in adolescent rhesus monkeys. Alcoholism: Clinical and Experimental Research, 25 (9), 1383-1392.
Schneider, M.L., Moore, CL, & Becker, EF (2001). Timing of moderate alcohol exposure during pregnancy and neonatal outcome in rhesus monkeys (Macaca mulatta), Alcoholism: Clinical and Experimental Research, 25, 1238 -1246.
Schneider, M. L., Moore, C.F., Roberts, A.D., & DeJesus, O.T. (2001). Prenatal stress alters early neurobehavior, stress reactivity and learning in nonhuman primates: A brief review. Stress, 4, 183-193.
Schneider, M. L. & Moore, C.F. (2000). Effect of prenatal stress on development: A nonhuman primate model. The Minnesota Symposia on Child Psychology (pp.201-243), Lawrence Erlbaum, New Jersey.
Schneider, M. L., Roughton, E. C., Koehler, A. J. & Lubach, G. R. (1999). Growth and Development Following Prenatal Stress Exposure in Primates: An Examination of Ontogenetic Vulnerability. Child Development, Volume 70, Number 2, 263-274.
Roughton, E. C., Schneider, M. L., Bromley, L., & Coe, C. L. (1998). Maternal endocrine activation during pregnancy alters neurobehavioral state in primate infants. American Occupational Therapy Journal, 52, 90 - 98.
Schneider, M. L., Roughton, E.C., & Lubach, G. (1997). Moderate alcohol consumption and psychological stress during pregnancy induces attention and neuromotor impairments in primate infants. Child Development, 68 (5), 747-759.
Sensory Processing Disorder: Primate Model
Dr. Schneider and colleagues have recently expanded their research program to investigate a primate model of sensory processing disorder. Sensory processing disorders, characterized by under or over-responsiveness to sensory stimulation that most individuals perceive as harmless have been estimated to occur in 5% of the general population (Ahn, et al, 2004) and seem to pose a unique challenge for people with developmental disabilities. Understanding the neurobiological processes associated with sensory processing disruptions is important to developing appropriate preventative and intervention approaches.
Dr. Schneider is examining whether disrupted sensory processing occurs in monkeys as a result of prenatal exposure to alcohol and/or stress, and if so, whether it would be associated with dopamine functioning in the striatum assessed with positron emission tomography (PET) neuroimaging. A primate model is used for these studies because in human studies causal conclusions are difficult to reach due to confounding variables. Nonhuman primates also have the advantage of gestation characteristics and early development similar to the human, and their shorter life span makes longitudinal studies somewhat easier to conduct. Rhesus monkeys were used because of the large amount of available data on their behavior and development in laboratory settings (Harlow & Harlow, 1969; Suomi, 1997).
Schneider, M.L., Moore, C.F., Gajewski, L. L., Larson, J.A., Roberts, A. D., Converse, A.K., DeJesus, O.T. (in press). Sensory processing disorder in a primate model: Evidence from a longitudinal study of prenatal alcohol and prenatal stress effects. Child Development.
Schneider, M.L., Moore, C.F., Gajewski, L., Laughlin, N., Larson, J., Gay, C., Roberts, A., Converse, A., DeJesus, O.T. (2007). Sensory processing disorder in a nonhuman primate model: Evidence for occupational therapy practice. American Journal of Occupational Therapy.61, 247-253.
Jacobs, S. E., & Schneider, M. L. (2001). Neuroplasticity, and the Environment: Implications for sensory integration. In S Smith, E. Blanch & R Schaaf (Eds.) Understanding the nature of sensory integration with diverse populations (pp. 29-42). Therapy Skill Builders.