Neurobiological and Metabolic Embedding of Early Life Adversity

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GENERAL BACKGROUND While mammalian development begins at conception and proceeds throughout the lifespan, the most dramatic period of change occurs during the early life segment (that is, the pre-natal and early post-natal periods). In addition, a growing body of epidemiological and experimental literature has shown that an organism’s developmental trajectory is most susceptible to disruption (i.e., adversity) during the earliest parts of the lifespan. To date, the majority of work has examined how an animal’s environment during early development affects either its endocrine physiology (e.g., glucose regulation), or its tendency to develop metabolic disease (e.g., diabetes). In comparison, very little has been done to determine the influence that early life environment can have upon brain development, particularly in relation to learning and memory. For the past four years, the focus of my research has been an NSERC-funded project examining the role that one form of pre-natal adversity (maternal obesity) can have upon brain development and metabolism in offspring. A number of important observations have been made, including the discovery that offspring of obese mothers show a significant impairment in synaptic plasticity (specifically, long-term potentiation, which is believed to be a cellular correlate of memory), but do not display changes in the expression of several important synaptic proteins. RESEARCH OBJECTIVES My long term objective is to continue building a research programme that examines how early life adversity becomes embedded during animal development. The short term objectives that will guide the current proposal are: 1) Exploring the mechanisms underlying how diet-induced maternal obesity affects both synaptic function and obesity-related metabolism in the female parent and her offspring. 2) Examining the influence that early life psychosocial stress (in the form of post-weaning social isolation) may have upon brain development and obesity-related metabolism. 3) Investigating how pre-natal adversity (in the form of maternal obesity) and early post-natal adversity (in the form of social isolation) interact to affect brain development and obesity-related metabolism. SUMMARY OF PLANNED EXPERIMENTS Experiments in the grant proposal will be developed along three lines: 1) Determining the changes in synaptic signal transduction that explain the reduced plasticity displayed by both obese mothers and their offspring. Specifically, we will focus on leptin signalling, given that this hormone participates in synaptic function and experiences altered signal transduction during obesity. 2) Characterising the effects that chronic, early-life social isolation has upon both brain development and general metabolism. In particular, we will study changes in protein expression and distribution, look for differences in synaptic plasticity, and examine signal transduction of hormones related to both obesity and synaptic function. 3) Completing a broad survey of the effect that a “two-hit” model of early adversity (that is, combined pre and post-natal disruption) can have upon brain development and general metabolism. In particular, animals born from obese mothers will be stratified into either normal, or isolated housing conditions for an extended period of time during early post-natal development (from the point of weaning to early adulthood). The results and technical approaches from the previous two phases of the study will be used to guide the experiments that will be completed. EXPECTED SIGNIFICANCE The proposed study will clarify the magnitude of change that early life adversity can have upon formation of both the nervous and endocrine systems, and help to demonstrate the nature of their developmental plasticity