The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and mania-like behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian period, an effect remediated by VPA treatment. Hence, VPA may exert beneficial effects on mood by normalizing lengthened circadian rhythm period in subjects with elevated DA resulting from reduced DAT

CONSTRUCTING A HEALTH AND SOCIAL INDICATOR FRAMEWORK FOR INDIGENOUS COMMUNITY HEALTH RESEARCH

Australia, Canada, community-level indicators, indicator framework, Indigenous peoples, New Zealand, population health,

Transcending sovereignty : locating Indigenous peoples in transboundary water law

All people rely upon water for life. Indigenous peoples are especially vulnerable to water conflicts and yet lack recognition in international water law. This thesis adopts Critical Race Theory to examine the intersection between transboundary water law, the doctrine of sovereignty and the international law of Indigenous peoples. The methodology adopted in this thesis includes: (i) a deconstruction of the UN Watercourse Convention and the doctrine of sovereignty; (ii) a review of Indigenous perspectives on sovereignty; and (iii) a proposal for the reconstruction of transboundary water law in a manner that recognizes the internationally affirmed rights of Indigenous peoples. A deconstruction of the UN Watercourse Convention and related discourse reveals that state-centric approaches to transboundary water law fail to recognize Indigenous peoples’ international rights or the pivotal role that Indigenous peoples’ traditional knowledge might play in transcending conflict. Case examples are provided (Columbia River and Tsangpo-Brahmaputra River) that illustrate the vulnerability of Indigenous peoples in the face of state development agreements. The inequities that exist in international water law are rooted in the historical doctrine of sovereignty which has evolved to subordinate Indigenous peoples’ interests to state interests. Indigenous perspectives regarding sovereignty provide a counter-point to the dominant legal discourse and weave an alternate narrative that challenges the myth of objectivity and neutrality that surrounds the doctrine of sovereignty and international law generally. Once we recognize that sovereignty is a social construct, we can recognize our collective ability to reconstruct international laws in a manner that transcends the sovereign discourse and recognizes the rights of Indigenous peoples. Endorsement of the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP) is indicative of states’ commitment to recognize Indigenous peoples’ rights throughout the international legal system. This thesis concludes by offering a proposal for reconstructing transboundary water law through a return to ethics and coalition building. Future reform should be directed towards (a) articulating an international water ethic with the critical engagement of Indigenous peoples; and (b) ensuring that river basin organizations are established on every transboundary river in a manner consistent with this shared international water ethic.Law, Faculty ofGraduat