The extracellular matrix glycoprotein tenascin-C promotes locomotor recovery after spinal cord injury in adult zebrafish.

Adult zebrafish, by virtue of exhibiting spontaneous recovery after spinal lesion, have evolved into a paradigmatic vertebrate model system to identify novel genes vital for successful regeneration after spinal cord injury. Due to a remarkable level of conservation between zebrafish and human genomes, such genes, once identified, could point to possibilities for addressing the multiple issues on how to deal with functional recovery after spinal cord injury in humans. In the current study, the extracellular matrix glycoprotein tenascin-C was studied in the zebrafish spinal cord injury model to assess the often disparate functions of this multidomain molecule under in vivo conditions. This in vivo study was deemed necessary since in vitro studies had shown discrepant functional effects on neurite outgrowth: tenascin-C inhibits neurite outgrowth when presented as a molecular barrier adjacent to a conducive substrate, but enhances neurite outgrowth when presented as a uniform substrate. Thus, our current study addresses the question as to which of these features prevails in vivo: whether tenascin-C reduces or enhances axonal regrowth after injury in a well accepted vertebrate model of spinal cord injury. We show upregulation of tenascin-C expression in regenerating neurons of the nucleus of median longitudinal fascicle (NMLF) in the brainstem and spinal motoneurons. Inhibition of tenascin-C expression by antisense oligonucleotide (morpholino) resulted in impaired locomotor recovery, reduced regrowth of axons from brainstem neurons and reduced synapse formation by the regrowing brainstem axons on spinal motoneurons, all vital indicators of regeneration. Our results thus point to an advantageous role of tenascin-C in promoting spinal cord regeneration, by promoting axonal regrowth and synapse formation in the spinal cord caudal to the lesion site after injury.

Individual variability in the stress response of C57BL/6J male mice correlates with trait anxiety.

Stress strongly alters the physiology and behavior of some individuals, while others are little or not affected. The causes of this individual variability have remained unknown. Here, we hypothesize that epigenetically induced levels of trait anxiety predict the stress response of individual mice in a genetically homogeneous population. Inbred C57BL/6 male mice were selected for their latency to freely enter from their home cage into an unfamiliar arena and classified as having high or low levels of trait anxiety. Mice were then exposed to acute stress (1-h olfactory contact with a rat) or control conditions. After 24 h, acute stress enhanced state anxiety measured in the elevated-plus maze test only in mice previously classified as having high levels of trait anxiety. This anxiogenic effect of acute stress was paralleled by enhanced novelty-induced plasma corticosterone secretion and increased messenger RNA (mRNA) expression for glucocorticoid and mineralocorticoid receptors in the hippocampus. No effects of acute stress were observed in mice classified as having low levels of trait anxiety. Under unstressed control conditions, mice only differed in basal levels of hippocampal mRNA for the glucocorticoid receptor, which were higher in mice with high trait anxiety than in mice with low trait anxiety. In summary, inbred C57BL/6 mice display a remarkably high interindividual variability in their trait anxiety that predicts the behavioral and neuroendocrine response to an acute stressor, indicating that expression of extremely different coping strategies can develop also between genetically identical individuals.

Ethological methods to study the effects of maternal exposure to estrogenic endocrine disrupters: a study with methoxychlor.

There has been increasing interest, both at the scientific and regulatory level, in the use of ethological methods for evaluating neural effects of endocrine disrupters. We present a series of ethological studies on the effects of maternal exposure to low, environmentally relevant doses (0.02, 0.2, and 2 microg/g mother bw/day) of the estrogenic pesticide methoxychlor (MXC) on behavior. From gestation day 11 to 17, female mice spontaneously drank oil with or without MXC; their maternal behavior was examined from postpartum days 2 to 15. MXC treatment during pregnancy produced slight changes in the expression of maternal behavior: females fed the lower MXC dose spent less time nursing the pups as compared to control dams. Their maternally exposed offspring were subjected to a series of behavioral tests at different ages. Maternal exposure to MXC affected behavioral responses to novelty in both sexes at periadolescence. The onset of male intrasex aggression was delayed in males prenatally exposed to low doses of MXC, since exposed males showed low levels of aggressive interactions during early adolescence but not after they reached adulthood. When adults, MXC-exposed females, but not males showed increased exploration in an unfamiliar open-field. While a sex difference was observed in the control group, with males being significantly more active in the open field than females, prenatal treatment with some MXC doses tended to decrease the sexual dimorphism in activity levels in the novel environment. Ethology, as the evolutionary study of behavior, may provide a framework for integrating a functional perspective (i.e., evolutionary significance) to studies on proximate mechanisms that can account for behavioral alterations induced by developmental exposure to endocrine disrupters.

Prenatal exposure to endocrine disrupting chemicals: effects on behavioral development.

Numerous chemicals released into the environment by man are able to disrupt the functioning of the endocrine system by binding to hormonal receptors. Exposure to estrogenic endocrine disruptors during critical periods in fetal life can alter the development of reproductive organs, the neuroendocrine system and subsequent behavior. We present a series of studies on the effects of exposure during fetal life to low, environmentally relevant doses of two pesticides, o,p'DDT and methoxychlor, and of low doses of the synthetic estrogen, diethylstilbestrol on subsequent neuro-behavioral development in house mice. The main findings can be summarized as follows: (1) Mice prenatally exposed to methoxychlor showed changes in reflex development. Exposure to a very low dose of methoxychlor appeared to produce an increased reactivity during early postnatal life. (2) Methoxychlor exposed periadolescent mice showed a decreased reaction time exploring both a novel environment and a novel object. (3) The onset of male intrasex aggression appeared to be delayed in males prenatally exposed to low doses of methoxychlor, since exposed males showed low levels of aggressive interactions during early adolescence but not after they reached adulthood. (4) The rate of depositing urine marks in a novel environment was increased in males prenatally exposed to DES, and also to o,p'DDT and methoxychlor. (5) The proportion of both males and females attacking a same-sex conspecific was increased in mice prenatally exposed to low doses of DES and, marginally, to o,p'DDT. This effect appeared to be related to a decreased latency to attack. However, males prenatally exposed to o,p'DDT displayed a decreased intensity of aggression. The possible implications of perturbing the hormonal milieu during fetal development on the modulation of developmental turnpoints and future behavioral responses are discussed.