Maternal Programming Of Behavior

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While development is fundamentally determined and regulated by genetics, it is also substantially modified by environmental influences, particularly those originating from the mother; a phenomenon known as “maternal programming”. Factors such as nutrition, genetic perturbations, infection, and psychiatric conditions can all contribute to the development of specific, adverse conditions in the offspring. In many cases, the effects of the maternal environment extend beyond the first generation of offspring, to the grand- and even great-grand-offspring. The mechanisms underlying maternal programming are poorly understood, but are believed to involve non-genetic stimuli such as immunological molecules and epigenetic signatures. The central nervous system is particularly sensitive during gestation, and abnormalities during fetal development could contribute to altered brain-behavior circuitry. In this dissertation, two maternally-programmed conditions are dissected into their underlying transmission mechanisms. A partial/complete maternal tumor necrosis factor (TNF) deficiency results in augmented postnatal offspring hippocampal proliferation, and ultimately, atypical adult spatial memory. This occurs via a TNF-dependent “lactocrine” pathway, in which the levels of specific chemokines are reduced in the mother’s milk. Because TNF levels can be regulated by lifestyle, it is possible that this maternal TNF-milk chemokine pathway evolved to promote offspring adaptation to the post-weaning environment. Maternal serotonin 1A receptor (5-HT1AR) deficiency programs a multi-symptom psychiatric-like phenotype in genetically wild-type offspring. The symptoms are not inherited together, but rather propagated to consecutive generations by separate, parallel mechanisms, producing varied offspring emotional phenotypes. Some symptoms are transmitted somatically via a neuro-immune pathway, while others are depend on a gametic mode of transmission. Both maternal programming scenarios in this dissertation describe non-Mendelian inheritance of neurodevelopmental and behavioral phenotypes across generations. Understanding non-genetic inheritance mechanisms is becoming increasingly important, as it is apparent that most complex diseases are the result of a combination of genetic and environmental influences. The development of neurodevelopmental diseases may not be inevitable. In fact, the work presented here suggests it could be possible to anticipate, and even prevent, some disorders through revised diagnostic approaches and more personalized therapeutic applications.

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