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All five classes of vertebrates use the geomagnetic field for spatial orientation. The geomagnetic field can be used to derive both 'map' and 'compass' information. There is evidence for two different mechanisms used to sense the magnetic field, the radical pair mechanism (RPM) and the magnetite based mechanism (MBM). C57BL/6 laboratory mice can rely on directional information from the magnetic field to position their nests and to solve a water maze task. The primary objective of this research was to characterize the magnetic compass of C57BL/6 laboratory mice in the plus water maze task. These experiments explored sources of variation in magnetic responses and investigated the underlying magnetic compass orientation mechanism in C57BL/6 mice. The results provide evidence that the mouse magnetic compass is sensitive to low-level radiofrequency fields, consistent with the use of the RPM for magnetic orientation. Surprisingly, the results also suggest that C57BL/6 mice have a polarity sensitive compass, consistent with the use of a MBM for magnetic orientation. These experiments confirm that mice have a specialized magnetic compass sense. Furthermore, despite the controlled environment in which these laboratory experiments were conducted, a variety of factors can increase the variability in the response. Future experiments are needed to further characterize the mouse magnetic compass, as there is a possibility of a hybrid magnetic response where both magnetoreception mechanisms could be used for spatial orientation.

It is now clear that estrogen not only modulates the differentiation and function of reproductive systems, but it also profoundly regulates the immune system of normal and autoimmune individuals. An important mechanism by which estrogen regulates the immune system is by altering the secretion and/or response to cytokines. We hypothesized that estrogen may alter the levels and/or response to IFN-g, a prototype Th1 cytokine, that plays a pivotal role in immunity against intracellular infections and in many autoimmune and inflammatory disorders. We found that estrogen treatment tended to upregulate the secretion of IFN-g protein and mRNA expression from Concanavalin-A (Con-A)-activated splenic lymphocytes. Impressively, we found that splenocytes from estrogen-treated mice when activated with Con-A also resulted in increased release of nitric oxide compared to placebo-treated mice. Furthermore, Con-A-activated splenocytes from estrogen-treated mice also had upregulated iNOS mRNA, iNOS protein, and nitric oxide-regulated COX-2 protein when compared to control mice. Blocking co-stimulatory signals mediated through interactions of CD28 and B7 molecules by using CTLA-4Ig markedly decreased not only IFN-g, but also nitric oxide, thereby implying an important role for CD28/B7 interactions in IFN-g/nitric oxide. Estrogen-induced upregulation of iNOS/nitric oxide is mediated through IFN-g since: (i) Estrogen alone did not upregulate iNOS/nitric oxide in IFN-g knockout mice; (ii) addition of rIFN-g to activated splenocytes from estrogen-treated mice further upregulated nitric oxide levels. We next investigated whether estrogen also upregulated IFN-g-inducing cytokines and select IFN-g-inducing transcription factors. Estrogen treatment resulted in increased mRNA and/or protein expression of IFN-g inducing cytokines and their receptors, including: IL-18, IL-15, IL-27, IL-12Rb2, and IL-18Rb. We also found that T-bet, a critical Th1 transcription factor, and STAT-4 phosphorylation, a key molecule in IL-12 signaling were both increased, while IRF-4, an important player in Th2 differentiation, was diminished in Con-A-activated splenocytes from mice treated with estrogen. Altogether, these studies are the first to demonstrate that estrogen regulates IFN-g-dependent iNOS and describes the potential mechanisms of how estrogen alters IFN-g-inducible genes, IFN-g inducing cytokines, and transcription factors in normal C57BL/6 mice. These studies may have profound implications to many autoimmune and inflammatory disorders, where estrogen is known to regulate the course of these diseases. Since estrogen may promote inflammatory disorders by upregulating pro-inflammatory biomolecules including IFN-g, nitric oxide, and COX-2, these studies may help in the design of therapeutic agents that regulate or block secretion and/or response to these inflammatory molecules.

Drug addiction is a serious brain disease and with the rapid expansion in neuroscience research over the past few decades, great progress has been made in understanding the causes and effects of drug addiction and its relevance to basic components of human behavior. It is now accepted that drugs of abuse (DOA) act on the mesolimbic dopamine (DA) brain reward system to mimic the rewards induced by more ‘natural’ stimuli such as food and sex. Acute administrations of DOA, particularly the psychostimulant amphetamine (AMPH), and the opiate heroin, lead to increases in extracellular levels of the neurotransmitter dopamine in regions comprising the brain reward system, including the nucleus accumbens (NAc), the ventral tegmental area (VTA), the striatum, and the dorsal caudate (DC). Changes in DA levels contribute to both the rewarding properties of DOA, as well as behavioral aspects of their use. As knowledge of the molecular and behavioral effects of DOA has advanced, evidence has accumulated that opioids not only share similar rewarding properties as psychostimulants, but that the endogenous opioid system can directly modulate the mesolimbic dopaminergic system as well. However, the individual contributions of the three opioid receptors subtypes (mu, kappa, and delta) in modulating the brain reward system are still unclear. In an attempt to investigate this, we developed an animal model of acute amphetamine (AMPH) –induced behaviors and studied the effect of antagonizing the individual opioid receptors (ORs) on these behaviors. Using the induction of hyperlocomotion following a low dose (2mg/kg) of AMPH as a behavioral correlate of DA levels, we found that antagonizing the delta OR significantly attenuated behavior, antagonism of kappa ORs failed to effect behavior, and antagonism of mu ORs had a slight, but non-significant, augmentation of DA-dependent hyperlocomotion. In contrast, utilizing the induction of stereotypic behaviors with a high dose (12mg/kg) of AMPH as our behavioral correlate, antagonism of all three ORs significantly attenuated DA-dependent stereotypy. It is assumed that these OR-dependent effects are mediated through differential regulation of target neurons within the mesolimbic reward system and indicate that the endogenous opioid system can regulate behavioral responses to rewarding stimuli.

Risk assessment methodologies that can distinguish between adverse and acceptable chemical induced biological effects will provide powerful tools for environmental agencies to use in conjunction with standardised technologies to manage chemical contamination effectively. To advance this technology in New Zealand, the following research describes a step-wise approach to develop and establish a suite of biological effect tests in the indigenous shortfinned eel (Anguilla australis) and the laboratory mouse (C57BL/6 strain). Mice were exposed to polyaromatic hydrocarbons (PAHs) directly (via intraperitoneal [ip.] injection to benzo[a]pyrene [B[a]P or benz(a)anthracene [BA]), or indirectly (via clean soil spiked with B[a]P or BA and to soil from contaminated sites). Mice treated with multiple ip. doses of B[a]P (100mg/kg) had significantly increased liver microsomal ethoxyresorufin O-deethylase (EROD) activity and cytochrome P450 concentration (P450 content), and hepatic-somatic index (HSI) compared to control. In contrast, EROD activity following ip. exposure to BA (100mg/kg) was 1 0-15-fold less than for B[a]P, suggesting a higher affinity of B[a]P to the Ah receptor. When mice were exposed to soil artificially contaminated with two environmentally relevant doses of B[a]P and BA biomarker responses were not significantly different from controls. The inherent ability of soil to reduce chemical bioavailability, is probably the major contributing factor for this result. However, mice exposed to contaminated soil from a fuel loading site (MP 0) and soil, from the gasworks site (PW) resulted in a significant increase in EROD activity of 2-fold and 4-fold respectively, compared to the controls. The total petroleum hydrocarbon (TPH) concentration of MP 0 soil was two times higher than the PW soil, which also directly correlates to the difference in EROD activity between mice exposed to these two soils. Although PW soil had a total PAH loading that was two orders of magnitude greater than MP 0 soil, the body burdens in mice exposed to these two soils were similar. Eels were exposed to one of a range of compounds (B[a]P, Aroclor 1254, 17β-estradiol [E2], 4- nonylphenol [4-NP], or chlorpyrifos [CP]) via ip. injection, or caged at sites that were potentially contaminated. Liver microsomal EROD activity of eels treated with multiple doses of B[a]P (1 and 10mg/kg) and Aroclor 1254 (10 and 100mg/kg) was significantly increased compared to the controls. Total P450 levels followed similar trends to EROD activity, but were not statistically significant. The induction of eel plasma vitellogenin (Vtg) following multiple ip. doses of E2 (100mg/kg) was marked in ip. experiment 1. However, a reduction in Vtg induction following an identical E2 exposure in ip. experiment 2 suggests that other cues such as seasonal changes, and or, sexually immature dimorphism may be involved. A small increase in plasma Vtg concentration was measured following exposure to 4-NP but this was not significant. Plasma acetylcholinesterase (AChE) activity of eel was slightly inhibited following ip. exposure to CP, but brain AChE was not affected by this or any other test compound. Similarly liver glutathione S-transferase (GST) did not respond to any treatments. Eels caged at a potentially impacted site on the Heathcote River showed significantly greater levels of EROD activity compared to an upstream site on the Heathcote River. While trends in the other biomarker responses were apparent in the eels caged at the potentially impacted Heathcote site, none were significant. Similarly, no significant differences between other potentially impacted and pristine sites were observed for any of the other biomarkers tested. The sensitivity of EROD activity to a range of compounds when exposed in the laboratory and field was demonstrated in both animal models. While mixed responses were observed for the other biomarkers, it is clear that further research is required to determine their suitability as a monitoring tool in these two test species.