Effects of maternal hypothyroidism during pregnancy on learning, memory and hippocampal BDNF in rat pups: Beneficial effects of exercise
Introduction
Thyroid hormones are essential throughout life for normal brain development and function (Aranda and Pascual, 2001, Williams, 2008, Giné et al., 2013). These hormones enhance neurogenesis and the maturation of new neurons in the brain during its development (Ambrogini et al., 2005). The expression of thyroid hormone receptors in the brain in early gestation suggests that thyroid hormones play a crucial role in the body during this period (Perez-Castillo et al., 1985). The lack of thyroid hormones during this period can have dramatic effects on the proper functioning of many regions of the brain, including the hippocampus (Bernal, 2007). The structural integrity of the hippocampus is crucial for some types of learning and memory processes, which, in turn, depend on the sufficient intake of thyroid hormone supplements during the stage of development (Madeira et al., 1991). Thyroid hormone deficiency during the critical period of brain development is therefore associated with morphological, electrophysiological and biochemical alterations in the hippocampus (Gilbert et al., 2007), resulting in severe cognitive and neurological disorders (Desouza et al., 2005). Prenatal hypothyroidism is reported to decrease neuronal survival, the density of the dendritic spines and the functioning of the synapses, thus leading to learning and memory impairments (Wang et al., 2010).
The results of recent animal experiments suggest that exercise increases learning and memory abilities within a variety of behavioral tasks (Cotman and Berchtold, 2002, Swain et al., 2012). Moreover, exercise up-regulates the expression of growth factors, including the nerve growth factor (NGF) and the brain-derived neurotrophic factor (BDNF) in the hippocampus, which comprise a key brain structure in the medial temporal lobe and are essential for activity-dependent learning and memory (Neeper et al., 1996, Lynch, 2004). The hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition (Vaynman et al., 2004). Exercise also increases neurogenesis in the hippocampus (Helfer et al., 2009) through BDNF and NGF-mediated mechanisms (Baek et al., 2012). In addition, exercise delays neuronal apoptosis in the dentate gyrus of the hippocampus (Kim et al., 2010b). The results of cross-sectional and longitudinal intervention studies on humans have shown that physical activity helps attenuate the memory and cognitive decline associated with normal aging and caused by neurodegenerative diseases such as Alzheimer’s disease (Kramer et al., 2004, Bherer et al., 2013). In children, aerobic fitness is associated with a better neuroelectric responsiveness and a faster cognitive processing (Hillman et al., 2005). A meta-analysis confirmed the positive relationship between physical activity and cognitive and academic performance in school-aged children (Sibley and Etnier, 2003).
BDNF and its high-affinity receptor, namely TrkB, are widely expressed in the mammalian brain (Lewin and Barde, 1996) and play a crucial role in the development, maintenance and functioning of the CNS (Huang and Reichardt, 2003). In adolescence, BDNF affects almost all the aspects of development, such as the differentiation of neural stem cells into neurons and stimulating the growth and improving the survival of newly-generated cells and synaptogenesis (Tapia-Arancibia et al., 2004). In addition, neuronal activity regulates BDNF transcription, transport of BDNF mRNA and protein into dendrites and the activity-dependent secretion of BDNF, which, in turn, modulate synaptic plasticity, synaptogenesis and memory formation (Bekinschtein et al., 2008).
Developmental thyroid hormone insufficiency reduces cognitive functions and neural development in both humans and experimental animals (Chakraborty et al., 2012). In rats, maternal thyroidectomy significantly reduces BDNF expression in the brain of developing rat pups (Liu et al., 2010). Prenatal exposure to PTU also leads to reduced hippocampal BDNF in neonatal rats (Chakraborty et al., 2012). BDNF is known to be directly regulated by thyroid hormones and play essential roles during the critical period of fetal brain development (Wang et al., 2006). These findings suggest that reduced hippocampal BDNF during early development may contribute to the adverse functional and structural events in the CNS induced by lack of thyroid hormones during pregnancy.
A review of literature suggests that studies have not yet examined how physical activity helps reverse the behavioral and biochemical alternations induced by developmental thyroid hormone insufficiency. Therefore, we investigated whether both voluntary and mild treadmill exercise would restore cognitive deficits, and reduced hippocampal BDNF in both male and female hypothyroid rat pups. We used both voluntary and forced exercise because different kinds of physical activity induce different effects on neuronal adaptations in different brain regions, and cognitive functions (Liu et al., 2009, Lin et al., 2012).
Section snippets
Experimental animals
Female Wistar rats were obtained from the breeding colony of the Semnan University of Medical Sciences Semnan, Iran and housed in cages for a 12 h light/dark cycle at 22–24 °C, where they had ad libitum access to food and water. All experimental procedures were conducted in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.
Experimental design
Female rats were mated with normal males. Day of conception was confirmed by observation of vaginal plug and was designated
Discussion
The present study demonstrates that developmental hypothyroidism impairs spatial learning and memory and reduces hippocampal BDNF levels in male and female rat pups. These cognitive and biochemical alterations can be reversed in both genders through short-term exercise programs carried out during adolescence. Proper physical activity can thus be used as a therapeutic intervention against hypothyroidism-induced behavioral and biochemical deficits.
Conflicts of interest
We attest that we have herein disclosed any and all financial or other relationships that could be construed as a conflict of interest and that all sources of financial support for this study have been disclosed.
Acknowledgements
This work was supported by a grant (478) from Semnan University of Medical Sciences to Dr. Abbas Ali Vafaei and Dr. Ali Rashidy-Pour. We would like to thank Dr. A. Bandegi for his help in BDNF measurement and Dr. K. Sedaghat for her critical reading and editing the paper. This article is extracted from the student thesis of Mr. S. Morteza Shafiee for PhD degree of Physiology.
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Equal contribution with the first author.