NBTS 10Imaging early childhood brain development: Implicationsfor schizophrenia

John H. GilmoreUniversity of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Schizophrenia is a complex disorder with multiple genetic andenvironmental risk factors. There is growing evidence that prenataland early childhood brain development is altered in persons whodevelop schizophrenia, though it has been very difficult to study earlyhuman brain development. This talk will review the application ofmagnetic resonance imaging studies to the study of early childhoodbrain development in a cohort of over 700 normal and high riskchildren. In the first two years of life, there is enormous growth ofcortical gray matter volumes, consistent with rapid and regionallyheterogeneous development of synapses and dendritic spines duringthis time period. Diffusion tensor imaging studies find a similar rapidand tract-specific development of white matter tract microstructurein the first two years of life. Resting state fMRI studies also indicatethat most resting state networks, including the default network,are established by age two years. By age 2 years, the structural andfunctional network stage is largely set for future learning, neuro-plasticity, and “fine tuning” of major structural connections already inplace. The multiple genetic and environmental risk factors associatedwith schizophrenia likely converge on a few common neurodevelop-mental pathways. Therefore, the study of developmental trajectories inearlychildhood in childrenat riskmay identifywhat these abnormalitiesare, and when they arise, ultimately providing opportunities for earlyidentification and early intervention. Male children at high risk forschizophrenia have enlarged gray matter volumes at birth, while ourfollow-upstudies suggest thatbyage twoyears, graymatter volumesaresignificantly reduced. This indicates that the structural brain abnorm-alities observed in adults with schizophrenia may arise during the rapidbrain growth that occurs in the first two years of life. Studies in ourcohort also suggest that genes of risk for schizophrenia, as well asenvironmental risk factors, such as prenatal exposure tomaternal infec-tion, have significanteffects onneonatal brain structure, also implicatingalterations in prenatal brain development.

http://dx.doi.org/10.1016/j.ntt.2013.03.013

NBTS 11The effect of prenatal stress on behavior and cortical organizationis dose-dependent, sex-dependent, and lifelong

Robbin Gibb, Richelle Mychasiuk, Allonna Harker, Celeste HalliwellCanadian Centre for Behavioural Neuroscience, University of Lethbridge,Lethbridge, Canada

We have studied the effects of parental stress on behavioral andanatomical outcomes in rat offspring. Preconception stressing of fathersaffected early behavior (P9–15),DNAmethylation, and cortical thicknessat postnatal day 21, the effects being larger inmales. Paternally-stressedmales also show enduring behavioral effects in adulthoodwith reducedmotor performance and increased anxiousness. In addition, male off-spring with perinatal cortical injury and paternal-stress history showreduced behavioral recovery relative to unstressed males. Maternalstress in the prenatal period affects both male and female offspringbehavior and neuroanatomy but the effects are dependent on theintensity of the stress and the sex of the offspring. Mild maternal stressis associated with developmental delays in sensorimotor learningand locomotion. Analysis of the epigenome revealed increased DNAmethylation in frontal cortex and hippocampus in these animals and

area- and sex-dependent changes in gene expression. Offspring exposedto high maternal stress showed similar behavioral effects as with mildstress but the opposite effect on DNA methylation. We have studiedthe effects of indirect (bystander) maternal stress on offspring andhave observed alterations in USV's emitted by the stress and bystanderdams and changes in the epigenome and behavior of bystander stressoffspring. Both males and females showed hypermethylation of DNAfollowingbystander stressbut female-exposedoffspringshowedgreaterdevelopmental delays than males. The effects of prenatal stress onneuronalmorphologyanddensity inprefrontal cortex andhippocampuswill also be discussed.

http://dx.doi.org/10.1016/j.ntt.2013.03.014

NBTS 12Enduring consequences of stress on depressive behaviorduring adolescence

Susan Andersena,b, Nadja Freunda,b,Heather Brenhousec, Britta Thompsona

aMcLean Hospital, Belmont, MA, USAbHarvard Medical School, Belmont, MA, USAcNortheastern University, Boston, MA, USA

The neurobehavioral consequences of stress uniquely impact thebrain depending on the timing of the exposure but typically manifestduring adolescence. Rats exposed to stressors either early in postnataldevelopment or later in adolescence demonstrate depressive-likebehaviors that differ in topography as a function of timing of stressexposure and sex of the subject. Using the triadic model of learnedhelplessness, we have been able to examine issues of controllability(e.g., loss thereof), general helplessness, or motivational deficits that areoften associated with anhedonia. Early life stress (ELS) during the firstpostnatalweekof life in therat reduces controllability inmales, butnot infemales. ELS exposure during the secondweek reduces controllability infemales. Longer exposure periods (e.g., the first three weeks of life)produce motivational deficits and anhedonia. Stress during this sameperiod also selectively reduces the number of synapses within thehippocampus, whereas adolescent stress selectively reduces synapses inthe prefrontal cortex. However, as we examined the developmentaltiming of the microcircuits within the prefrontal regions, we haverecently observed that ELS selectively reduces early maturing parvalbu-min GABAergic effects in this region while relatively sparing latermaturing glutamatergic neurons. While development has uniqueperiods of vulnerability, it is important to note that windows ofopportunity for intervention also exist. One such period is the intervalafter the insult, but before development is complete. Once betterunderstood, this period may provide an opportunity to re-program thetrajectory onto a normal course and reduce the cascade of psychopathol-ogy that otherwise may exist following early adverse environments.

http://dx.doi.org/10.1016/j.ntt.2013.03.015

NBTS 13Neurobiological effects of the interactions between chronic stressand substituted amphetamines

Bryan YamamotoUniversity of Toledo College of Medicine, Toledo, OH, USA

Chronic stress and drug abuse are co-morbid events and can inter-act to augment drug abuse. To understand the possible interactionsbetween chronic stress and drugs of abuse, we examined the effects of

NBTS 2013 Abstracts 77