Effects of neonatal domoic acid treatment and social isolation rearing on measures of attentional processing in rats: An investigation of the “two-hit” hypothesis of psychiatric disease

摘要

Neuropsychiatric disorders affect a significant number of people across the globe and are a serious economic and social burden. As a class of diseases they are often poorly understood, difficult to treat, and can lead to a significant decline in normal function and quality of life. Recent evidence supports the notion that many neuropsychiatric disorders are neurodevelopmental in foundation, originating at least in part from abnormal activity during critical periods of brain development. Attentional processing is a higher order cognitive behaviour fundamental to many important brain processes and is known to be affected in a number of human neuropsychiatric disorders. The purpose of the research described herein was to better understand how changes in early brain development can have a long lasting effect on the central nervous system relevant to the etiology of neuropsychiatric disorders, and to utilize a novel approach to investigate the “two-hit” hypothesis of psychiatric disease by probing the effects of chemically (neonatal low-dose domoic acid [DOM] treatment) and/or environmentally (social isolation rearing) induced changes in attentional processing.First, adult untreated rats were used to develop a latent inhibition (LI) paradigm that resulted in both deficient and abnormally persistent LI. Next, utilizing both the newly-developed LI protocol and previously established protocols for prepulse inhibition (PPI), the behavioural consequences of neonatal DOM administration and social isolation housing, both alone and in combination, were measured. Results indicated a number of behavioural alterations in both sexes and across all treatment groups indicating that neonatal DOM treatment and isolation rearing affect both of these measures of attentional processing although not in identical ways. Subsequently, the regional expression profiles of various proteins involved in dopaminergic and GABAergic neurotransmission were quantified by Western blot analysis to investigate the potential molecular alterations responsible for the observed behavioural changes. No significant effects on these markers were observed in any treatment group, although large inter-individual variations were noted. A preliminary post-hoc analysis of correlations between changes in PPI and protein expression resulted in a number of significant correlations and suggested that the various experimental manipulations were differentially affecting the signalling pathways involved.In conclusion, both neonatal low-dose DOM treatment and social isolation rearing affect the development of attentional processing in rats. However, each paradigm may exert these effects through different neuronal signalling systems and these different systems may be responsible for different aspects of the behavioural changes that were observed. Finally, this work illustrates the potential of a novel “two-hit” method for studying the development of neuropsychiatric disease as well as the complex interconnected processes that are affected by altered brain development.