Project Leader: Tallie Z. Baram, MD, PhD
Improving our understanding of the mechanisms by which environmental signals during sensitive early-life periods contribute to mental illness will have profound impact on human health
SIGNIFICANCE: A number of brain problems, including depression and learning/memory difficulty, arise in adolescence and affect one in five American teenagers. While we know that early-life experience might contribute to the emergence of these problems, we know little about the nature of the responsible experiences, how they enter brain cells and how they lead to adolescent problems. The Conte Center @ UCI capitalizes on a unique, large cohort of mothers and children, followed from prior to their births, to observe how patterns of maternal signals and care contribute to resilience and vulnerability to cognitive and emotional problems during adolescence. In parallel, in rodent models, cutting-edge epigenetic and cellular/ molecular methods will help figure out how brain cells change their function in response to disorganized maternal signals. Sophisticated functional and structural brain imaging will be carried out in both children and rodents, and the resulting brain maps will help translate discoveries made in rodents to our understanding of human health and disease.
Improving our understanding of the mechanisms by which environmental signals during sensitive early-life periods contribute to mental illness will have profound impact on human health.
Project 1 will focus on this important problem and will test an innovative concept, that fragmented patterns of maternal signals might be a common denominator of the established, profound influence of the mother on the emotional and cognitive outcome of her progeny. It will use innovative viral-genetic methods and epigenetic tools to probe the underlying mechanisms, and integrate single-neuron discoveries with structural and network analyses of Project 2, Project 3 and Project 4. The resulting discoveries will inform and guide behavioral and imaging studies in the other projects, contributing to identification of potential biomarkers and generation of predictive models for adolescent vulnerabilities.
The aims of Project 1 include:
The aims of Project 1
(1) A. Use mathematical tools (with the BCDM core) to analyze patterns of maternal behaviors in an established model of fragmented care.
B. Building on new data showing vulnerabilities to emotional and cognitive problems already in adolescent rats, identify the onset and trajectories of these vulnerabilities to adulthood.
Use mathematical tools (with the BCDM core) to analyze patterns of maternal behaviors in an established model of fragmented care
Building on new data showing vulnerabilities to emotional and cognitive problems already in adolescent rats, identify the onset and trajectories of these vulnerabilities to adulthood
(2) In concert with Project 4, test the hypothesis that the basis of altered emotional and cognitive functions resulting from fragmented patterns of maternal signals derives from shifts in the functional connectivity of the involved brain networks.
(3) Examine for sex dependence of the consequences of fragmented patterns of maternal care.
(4) Probe causal molecular mechanisms in defined brain regions that may underlie the emotional and cognitive consequences of fragmented maternal care patterns. Building on new data and novel technologies, we will look for mechanisms of broad enduring gene expression changes, using CRH as a marker gene. Regulating expression in space and time, we will also test if enhanced CRH expression is necessary and sufficient to mediate the effects of fragmented care; finally, we will determine identities of other involved genes, and the mechanisms regulating enduring changes in gene expression at the chromatin level.
- Hyper-excitability and epilepsy generated by chronic early-life stress. Dubé CM, Molet J, Singh-Taylor A, Ivy A, Maras PM, Baram TZ. Neurobiol Stress. 2015;2:10-19.
- Chen Y, Baram TZ. Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology. 2015. [Epub ahead of print].
- Chen Y, Molet J, Gunn BG, Ressler K, Baram TZ. Diversity of reporter patterns in transgenic mouse lines targeting corticotropin releasing hormone-expressing neurons. Endocrinology. 2015. [Epub ahead of print].
- Singh-Taylor A, Korosi A, Molet J, Gunn BG, Baram TZ. Synaptic rewiring of stress-sensitive neurons by early-life experience: a mechanism for resilience? Neurobiol Stress. 2015; 1:109-115.
- Molet J, Maras PM, Avishai-Eliner S, Baram TZ. Naturalistic rodent models of chronic early-life stress. Dev Psychobiol. 2014; 56:1675-88.
- Regev L, Baram TZ. Corticotropin releasing factor in neuroplasticity. Frontiers in Neuroendocrinology. 2014; 35:171-79.
- Maras PM, Molet J, Chen Y, Rice C, Ji SG, Solodkin A, Baram TZ. Preferential loss of dorsal-hippocampus synapses underlies memory process impairment provoked by short, multi-modal stress. Mol Psychiatry. 2014; 19:811-22.
- Baram TZ, Davis EP, Obenaus A, Sandman CA, Small SL, Solodkin A, Stern H. Fragmentation and Unpredictability of Early-Life Experience in Mental Disorders. Am J Psychiatry. 2012; 169:907-15.
You can read the Project 1 Summary for a non-technical explanation.