Grant: Discovery Grants Program - Individual

The neural mechanisms that regulate homeostasis must effectively sense perturbations and respond rapidly. This NSERC research program will provide new information about how the brain senses ascending warning signals (e.g. peripheral inflammation), and then activates the hypothalamic-pituitary-adrenal (HPA) axis, an evolutionarily conserved regulator of homeostasis. Our focus is on a key mediator of this inflammation-induced response, prostaglandin (PG)E2, which is produced through the cyclooxygenase (COX) pathway. The established view is that circulating cytokines (i.e. ascending inflammation signals) cause de novo induction of COX2, an inducible isozyme of COX, in the brain. The COX2-derived PGE2 in turn acts in the brain to elicit the response. However, COX2 induction is slow; it has become increasingly clear that COX1, a constitutive isozyme, is crucial for the early-onset of HPA axis response. This points to a biphasic mode of PGE2 synthesis and raises a question 'what are the early ascending signals for the COX1-mediated PGE2 synthesis?' Furthermore, whether produced through COX1 or COX2, it is unclear how PGE2 elicits the HPA axis response. It has been shown that two subtypes of PGE receptor, namely EP1 and EP3, contribute to the HPA axis response. It remains to be examined whether distinct EP subtypes are coupled to COX1- and COX2-derived PGE2 actions. Hypothesis: Multiple COX and EP receptor subtypes work in temporally supplementary manners to drive the HPA axis response. Long-term goal: to clarify the mechanisms underlying the biphasic synthesis and actions of PGE2 by primarily focusing on (less understood) COX1 and early onset of the HPA axis response. In order to resolve the rapid PGE2 synthesis by 'constitutive' COX1, we will use electrophysiological approaches in brain slices that contain the command neurons of the HPA axis. We will assess PGE2-dependent excitation of the command neurons as a readout for the rapid PGE2 synthesis. We will also clarify specific EP subtypes involved in PGE2 actions. Short-term goals: 1) To examine the role of ascending neural inputs (noradrenaline) in eliciting COX1-mediated PGE2 synthesis. 2) To clarify which EP receptor subtypes, and how they mediate the excitatory actions of PGE2 on the HPA axis command neurons. 3) To determine whether COX1- and COX2-derived PGE2 act on distinct EP receptor subtypes. The success of our research program will establish the basis for the biphasic mode of PGE2 function and fill the gap in our understanding of the early-onset of HPA axis response. The significance of this finding is that 'redundancy' (multiple isozymes and receptors) is instrumental for an optimal functioning of the system (the early-onset and delayed-sustained HPA axis outputs). Our research program will also provide a rich training environment in system biology and state of the art techniques (e.g patch clamp electrophysiology and optogenetics).