Academic journal article Environmental Health Perspectives

Diminished Experience-Dependent Neuroanatomical Plasticity: Evidence for an Improved Biomarker of Subtle Neurotoxic Damage to the Developing Rat Brain

Academic journal article Environmental Health Perspectives

Diminished Experience-Dependent Neuroanatomical Plasticity: Evidence for an Improved Biomarker of Subtle Neurotoxic Damage to the Developing Rat Brain

Article excerpt

Millions of children are exposed to low levels of environmental neurotoxicants as their brains are developing. Conventional laboratory methods of neurotoxicology can detect maldevelopment of brain structure but are not designed to detect maldevelopment of the brain's capacity for plasticity that could impair learning throughout life. The environmental complexity (EC) paradigm has become classic for demonstrating the modifications in brain structure that occur in response to experience and thus provides a set of indices for plasticity in the healthy brain. In this study, we have tested the hypothesis that if degradation of experience-dependent cortical plasticity is used as a biomarker, then developmental neurotoxic effects will be detected at doses below those that alter cortical morphogenesis overtly. Pregnant Long-Evans hooded rats received a single injection of either saline vehicle or 1, 5, 10, or 25 mg/kg of the well-characterized developmental neurotoxicant methylazoxymethanol acetate (MAM) on the 16th or 17th day of gestation. On postnatal days 35-39, male offspring were assigned to either a complex environment (EC) or an individual cage (IC) for 28 days to stimulate neuroanatomical plasticity. This response was measured as the difference between the thickness of visual cortex of IC and EC littermates at a given dose. The threshold dose for significant reduction of cortical thickness was 25 mg/kg, but the threshold dose for failure of plasticity was much lower and could be detected at 1 mg/kg, the lowest dose used. No other method of assessment has detected lasting effects of prenatal exposure to MAM at such a low dose. These data suggest that this simple test of plasticity could be an efficient way to detect subtle neurotoxic damage to the developing brain. Key words: biomarker, complex environment, cortical plasticity, developmental neurotoxicology, methylazoxymethanol.

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The development of the human nervous system is an extended process. It begins during early embryogenesis with the specification of neural epithelium; it requires that complex synaptic circuits be established [reviewed by Pomeroy and Kim (2000); Volpe (2000)], and it may never truly end in that synaptic connections continue to be modified throughout life, presumably as a mechanism of brain information storage (Black et al. 1998). Therefore, intrusion of a neurotoxicant could produce different defects depending on the timing and level of exposure (Spencer 2000) because it might disrupt populations of neurons engaged in cellular proliferation, migration, differentiation, or maturation (Jensen and Catalano 1998; Rodier 1995). This timing issue alone makes assessing the risk of even a single compound at a single dose a complex task, even discounting individual differences in response. Ideally, a biomarker would assess an important brain function with broad sensitivity. In this study, we questioned whether measuring experience-dependent brain plasticity late in development can reveal subtle lasting deficits caused by exposure to a neurotoxicant early in development.

By late embryogenesis, cortical neurons have been intrinsically programmed to form dendrites of the appropriate architecture (Banker and Waxman 1988). However, dendrites continue to grow into the postnatal period (Becker et al. 1984; Juraska 1982) and remain "plastic," such that extrinsic factors, notably, the unique behavioral experience of the individual, can induce readily quantifiable modifications in dendritic structure throughout life [reviewed by Kolb and Whishaw (1998)]. The therapeutic potential of behavioral stimulation is well established (e.g., Walsh and Greenough 1976), and recent animal studies demonstrate positive plastic changes in brain structure or physiology following housing in a broadly stimulating environment (e.g., Rema and Ebner 1999) or regimens of training designed to address specific functional deficits (Klintsova et al. 1999). …

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