Parasite control of host behaviour: Revealing a neurobiological mechanism for active manipulation

Parasitic animals live in or on other organisms and draw all their energy and nutrients from their hosts, and often show fascinating specialisations to survive in close contact with another species' physiology and immune systems. Many species also affect the behaviour of their host in specific ways which benefit the parasite. One well documented case is seen in the shallow waters of California salt marshes, where trematode infected killifish (Fundulus parvipinnis) abandon normal caution and come up to the water surface more frequently, which in turn makes them more conspicuous to predatory birds. Such fish are in fact thirty times more likely to be eaten by birds than those which are not suffering from the parasite. The trematode then completes its development to an adult tapeworm in the bird, and is soon able to release egg thus starting the lifecycle again. We know that brain encysted trematodes inhibit brain serotonergic (5-hydroxytryptamine, 5-HT) neurotransmission in infected fish, 5-HT being most well known for its involvement in human depression. Presence of the parasites also stimulate the reward chemical dopamine (DA), which may explain the anti-anxiety effect. The NEUROPAR project performs high resolution mass spectrometry studies to identify the exact nature of the parasite derived neuroactive agents, and describes their mode of action on brain physiology and gene expression. One important waypoint has been to establish a laboratory model by recreating naturally occurring brain-encysted trematode intensities using experimental infections in California killifish. We find that infection intensities comparable to those occurring in nature can be recreated in the laboratory, and artificially infected fish show behavioral changes similar to wild infected fish. Mass-spectrometry analysis of infected brain tissue and out-dissected parasites show that the parasite release a group of signal substances known as prostaglandins, which may influence both the nervous and immune system of host animals. Further analysis of the underlying biological mechanisms are expected to open up a front of new research opportunities regarding both fundamental and applied aspects of parasite derived neuroactive substances. Understanding how parasites and pathogens alter brain function and behaviour may also help us understand the emerging links between infectious diseases and mental function in humans

Potential biomedical applications of novel substances with e.g. anxiolytic and anti-anorectic properties will be considered.

Numerous species of parasites affect the behaviour of their hosts in ways which enhance parasite fitness. Infected intermediate hosts show increased risk-taking behavior and expose themselves to enhanced predation by final hosts, or seek microhabitats suited for parasite dispersal. While long remaining only a theoretical possibility, possible examples of neurobiological manipulation by way of parasite-derived neuroactive substances are now emerging. In vertebrates, it has however so far only been indicated that parasites enhance the activity of signalling substances already produced by their hosts. One example is provided by the brain-dwelling protozoan Toxoplasma gondii, which induce production of excessive quantities of dopamine (DA). We recently employed mass-spectrometry based metabolomics and bioinformatics technology in a classic model system: The California killifish (Fundulus parvipinnis) and its brain parasite, the trematode Euhaplorchis californiensis. E. californiensis has previously been shown to inhibit brain serotonergic (5-hydroxytryptamine, 5-HT) neurotransmission in infected fish, while also stimulating DA. The results indicate that 5-HT producing cells in the raphe nuclei of infected fish contain a number of metabolites which are not observed in an uninfected control group. The structural identities of these substances remain unresolved. We will perform high resolution characterisation of metabolite composition and targeted metabolite analysis in order to identify the exact nature of the parasite derived neuroactive agents. The mode of action on the brain on the transcriptomic level will also be described. Ascertaining that hitherto unknown neuroactive agents of parasite origin do indeed alter brain function in a vertebrate model will end a century-long debate. Such a finding would also potentially open up a massive front of exciting new research opportunities regarding both fundamental and applied aspects.