Grant: Discovery Grants Program - Individual

The overarching goal of my research program is to understand the biological underpinnings, development, and lasting consequences, of fear. The effects of a fearful event on an individual are well known, and the ability of such events to affect future generations, through biological and/or social transmission is increasingly recognized. Indeed, we have recently shown that an ecologically realistic degree of predator stress (PS) prior to conception causes lasting changes in the first filial (F1) and second filial (F2) generations. Adult F1s from preconception PS parents responded to a mild stressor with an altered behavior phenotype, increased neuronal activity in the hippocampus, and elevated plasma corticosterone as compared to F1s from control parents. The effects of preconception parental PS were also unexpectedly persistent and produced a similar behavioral phenotype in the F2s. Our data illustrate that a surprisingly small amount of preconception PS alters the brain, physiology, and behavior of future generations. My first objective is to expand these initial results to understand the maternal versus paternal contribution to the offspring phenotype, and examine the timing of the fearful in the parental generation on changes in the offspring. In part one of this objective, predator stressed males will be bred to control females (and vice versa) and behavior (e.g. anxiety-like behavior, social behavior, learning and memory, startle response), brain (e.g. FKBP5), and physiology (e.g. plasma corticosterone) will be assessed in offspring (F1 and F2 generations). In part two, PS exposure timing will be varied (e.g. 1 or 3 months) prior to breeding, and brain, behavioural and physiological changes will be assessed in offspring (F1 and F2 generations). Objective two investigates possible epigenetic changes occurring in the parents, and whether these changes persist into the F1 and F2 generations. We will use a targeted approach based on preliminary data indicating increased FKBP5 protein expression in the F0 and F1 generations. Chromatin Immunoprecipitation will be used to investigate whether FKBP5 is epigenetically modified by a fearful event (to the parent and transmission to the offspring). Finally, objective three will examine the effects on offspring of attenuating or preventing (via blocking memory consolidation) the predator stress-induced changes in the parents. To block consolidation of the PS memory, mice will receive an intra-hippocampal injection of a protein synthesis inhibitor following exposure to the predator or control condition. Mice will be bred and brain, behavior, and physiology will be assessed in offspring (F1 and F2 generations). My program of research affords a better understanding of the basic mechanisms underlying the  transmission of fear effects across generations. Ultimately, my research will have important implications for biologists, psychologists, neurobiologists, and ecologists.