David R. Riddle - US grants

Aging is associated with progressive declines in a variety of biological functions, often reflecting local responses to system-wide physiological changes. The overall goal of this Program Project is to investigate the effects of the age-related decline in growth hormone and resultant decline in insulin-like growth factor 1 (IGF-1) on the brain. IGF-1, like several other growth factors, influences the growth and differentiation of both neurons and the microvasculature that supports the tremendous metabolic demand within neural tissue. The large decrease in IGF-1 that occurs with senescence is likely to result in significant changes in neuronal form and function within the brain. The temporal correlation of the decrease in IGF-1 levels with a general decline in cognitive abilities, and the recent observation that administration of e exogenous IGF-1 to aged animals increases cognitive abilities, makes the factor an important candidate for further study. This project will test the hypothesis that IGF-1 influences the development and maintenance of neuronal architecture and metabolism such that the age-related decrease in IGF-1 levels significantly affects neurons structure and activity. The experiments are predicated on the idea that the cognitive deficits associated with aging must result, at least in part, from an age-associated change in neuronal architecture and/or a loss in ability to regulate and maintain neuronal connectivity and signaling. To examine the specific relationship between IGF-1 and neuronal form and function we will quantify age-related changes in the extent and complexity of dendritic processes of cortical neurons, as well as changes in metabolism and vascularization, within well-defined regions of the cerebral cortex. We will determine whether those changes are the result of the age-related decrease in IGF-1 levels by testing whether they are reversed by exogenous IGF-1 delivered to aged animals, prevented by maintaining IGF-1 levels in aging animals, and elicited by an earlier than normal decrease in IGF-1 in young adult animals. Finally, we will examine specific mechanisms by which IGF-1 may regulated neuronal structure and function by measuring the effects of IGF-1 on developing dendrites, examining the interaction of IGF-1 with other neurotropic factors that influence neuronal growth and differentiation and quantifying the effects of IGF-1 signaling on calcium homeostasis, a key regulator of the neuronal development and function. These studies will provide a greater understanding of the effects of age on the brain and of the role of one critical factor in regulating those changes.

[unreadable] DESCRIPTION (provided by applicant): Understanding the regulation of dendritic growth is essential to understanding how neural circuits form and function. Dendrites are the targets of 90% of all synapses, and both the extent and pattern of dendritic branching critically influence the integration of synaptic inputs. The cognitive impairments that accompany many developmental disorders are likely to result in part from inappropriate regulation of dendritic growth and plasticity in the developing CNS. One significant challenge currently is elucidating the molecular mediators that control of how much and where dendrites elaborate during development. [unreadable] [unreadable] Recent evidence suggests that neural activity influences dendritic growth through the actions of trophic factors, which focally promote formation and elaboration of new branches. It is likely, however, that one or more factors promote dendritic elaboration more generally and thereby prime neurons for the focal regulation of development and plasticity that is mediated by factors with more restricted actions. With respect to agents that might provide a broad but critical stimulus for dendritic elaboration, insulin-like growth factor 1 (IGF-1) is of particular interest. IGF receptors are widely expressed in the developing brain. IGF-1 can cross from the plasma into the brain as an endocrine factor, and also may act in a paracrine and/or autocrine fashion following production by cells of the cerebral vasculature and by neurons and glia within the brain. Several laboratories have reported that IGF-1 promotes dendritic elaboration by neurons in vitro. [unreadable] [unreadable] Moreover, the growth of neuropil in the cerebral cortex appears to be increased in transgenic mice in which IGF-1 is overexpressed and decreased in mice in which IGF-1 activity is decreased. Significantly, human studies and clinical cases indicate that abnormal IGF-1 signaling during development can result in intellectual impairment, which may arise in part from dysregulation of dendritic development. Building upon such studies, the experiments proposed will test key predictions of the hypothesis that IGF-1 modulates the growth of neuropil and provides a critical stimulus for dendritic elaboration in the developing cerebral cortex. IGF-1-dependent regulation of dendritic development will be tested in vitro, using organotypic slices of the developing cerebral cortex, and also in vivo, using transgenic mice in which IGF-1 signaling is increased or decreased specifically within the brain. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Whole brain irradiation (WBI) is an effective treatment for brain tumors and metastases but 50% or more of the long-term survivors treated with WBI suffer cognitive deficits attributed to radiation-induced injury to normal brain tissue. The cellular and molecular mechanisms underlying the deficits are not well understood, but it is clear that radiation kills proliferating cells and also induces acute and chronic oxidative stress and inflammatory responses that alter the function of surviving cells. Although investigations of the mechanisms of radiation-induced brain injury in animal models have begun to reveal key pathways and mediators, translating the knowledge gained from these studies to the clinic is difficult since experimental studies of radiation-induced brain injury in adult rodents have used, almost without exception, very young adults. In contrast, in the clinical population, the majority of adult patients treated with WBI are 50 years of age or older. Since brain aging is accompanied by changes both in proliferating cell populations and in basal levels of inflammation and oxidative stress, the effects of WBI on the older brain are likely to be substantially different from the effects in young adults. This expectation is supported by our preliminary studies and by epidemiological evidence that aging increases the likelihood and the severity of radiation-induced cognitive decline. Treatment of radiation-induced cognitive dysfunction would benefit tremendously from a better understanding of the cellular and molecular responses that follow WBI, but it is critical to test radiation-induced changes in neurobiological measures and cognitive functions following a clinically relevant regimen of WBI and in animals that best model the relevant clinical population. The experiments proposed here will i) provide the first direct test of the effects of aging on radiation-induced deficits in a range of cognitive functions, ii) clarify the key cellular and molecular events that contribute to those functional changes, and iii) test whether treatment with the peroxisomal proliferator-activated receptor (PPAR)? agonist, pioglitazone, an anti-inflammatory agent, prevents radiation-induced cognitive dysfunction in old rats. The information that will be provided by this quantitative analysis of radiation-induced injury in young and old rats is critical to translational efforts to develop therapies to prevent or ameliorate radiation-induced cognitive dysfunction. In the absence of such studies, one runs the significant risk of targeting mechanisms of injury that may be of lesser significance in the primary clinical population. PUBLIC HEALTH RELEVANCE: This research is relative to public health because it will test the effects of a clinically relevant radiation treatment on the development of brain injury and cognitive deficits in an animal model that is amenable to experimental manipulation and that appropriately reflects the primary clinical population, middle age and older adults. Such studies will facilitate the development of new and more efficacious treatments to prevent or reduce radiation-induced brain injury and thereby provide benefits to cancer patients.