Roles of hypothermia in response to environmental hypoxia: Behavioural and thermal modulation of the genetic and proteomic responses to low oxygen

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We will conduct the first investigation of the interdependence of hypoxia (low oxygen) induced gene expression and behavioural hypothermia. The work is best carried out in ectothermic animals, whose body temperature changes with that of the environment. We will use an invasive pest crayfish, Pacifastacus leniusculus, which is displacing the endangered native species. When faced with lowered environmental oxygen such species seek out a cooler environment, thereby lowering metabolic rate and oxygen demand. Normal physiological responses to hypoxia include underlying changes in gene expression and protein profiles. This gene transcription is regulated by a hypoxia inducible factor (HIF) which is normally degraded if sufficient oxygen is present. We will examine the exciting possibility that behavioural induced hypothermia can modulate gene expression by reducing tissue oxygen demand. Recent and tantalising evidence indicates that metabolites of energy metabolism may regulate a coordinated response in gene transcription and behaviour, or even that behaviour is a result of changes in gene expression. We will collaborate with Dr Gorr/Prof Gassmann (Zurich). The aim is to show how behaviour may modulate gene expression or, alternatively, is coordinated with gene expression. We will characterise the hypoxic gene response and the resulting changes in the protein profile of the tail muscle of animals in low oxygen, compared to normal oxygen, and determine if lowered body temperature obviates this gene and protein response. We will probe the linkage between behaviour and hypoxia induce gene transcription by a pharmacological approach. Using inhibitors that block HIF degradation, even in normoxic cells, we will establish dependent responses in; (a) gene transcription, (b) protein profiles and (c) behaviour. This latter point is near unique since it uses behaviour as assay of gene expression. We will use exogenous inhibitors (not natural to the animal) of HIF degradation, as well as metabolites of energy metabolism which inhibit HIF degradation and putatively stimulate the behaviour. Thus, effects of metabolites that promote cold-seeking behaviour and induce hypoxia responsive genes will link the two responses. Effects of exogenous compounds, that stimulate behaviour will do so as a consequence of changes in the expression of hypoxia responsive genes, that is behaviour is promoted by changed gene expression. The study will reveal if energy metabolism feeds back directly on genes in response to hypoxia and if this is modulated by behaviour. The potential implications range from environmental to biomedical. The HIF system is a target for tumour treatment and evidence as to the role of temperature and metabolites of energy metabolism is directly relevant. Should we prove that the behavioural and molecular responses to hypoxia are separate (behaviour delays the molecular response), there will be large ecological significance for animals with access to cooler habitats. Should we prove that behaviour and molecular responses are linked by metabolic signals or that behaviour is caused by molecular events then this will open new areas of ecological, environmental and biomedical investigation. Discovering new feedback (or feed-forward) systems in physiological and behavioural responses has implications for understanding species success, temporal costs in protein turnover, and the behaviour of cells, be they tumour cells or from environmentally stressed animals. Hypoxia is an important environmental factor limiting the distribution and success of aquatic species (e.g. eutrophication of rivers and lakes). The likelihood for any species survival depends significantly on the nature and extent of the hypoxic response. Variation in this response between species can lead to changes in the faunal mix, which may be of relevance for P. leniusculus in our study since it is displacing the native species, in part, due a greater hardiness and survivorship.