The observation that certain species of parasite my adaptively manipulate its host behaviour is a fascinating phenomenon. As a result, the recently established field of ‘host manipulation’ has seen rapid expansion over the past few decades with public and scientific interest steadily increasing. However, progress appears to falter when researchers ask how parasites manipulate behaviour, rather than why. A vast majority of the published literature investigating the mechanistic basis underlying behavioural manipulation fails to connect the establishment of the parasite with the reported physiological changes in its host. This has left researchers unable to empirically distinguish/identify adaptive physiological changes enforced by the parasites from pathological side effects of infection, resulting in scientists relying on narratives to explain results, rather than empirical evidence. By contrasting correlative mechanistic evidence for host manipulation against rare cases of causative evidence and drawing from the advanced understanding of physiological systems from other disciplines it is clear we are often skipping over a crucial step in host-manipulation: the production, potential storage, and release of molecules (manipulation factors) that must create the observed physiological changes in hosts if they are adaptive. Identifying these manipulation factors, via associating gene expression shifts in the parasite with behavioural changes in the host and following their effects will provide researchers with a bottom-up approach to unraveling the mechanisms of behavioural manipulation and by extension behaviour itself.

The anterior pituitary hormone prolactin exerts important physiologic actions in the brain. However, the mechanism by which prolactin crosses the blood-brain barrier and enters the brain is not completely understood. On the basis of high expression of the prolactin receptor in the choroid plexus, it has been hypothesized that the receptor may bind to prolactin in the blood and translocate it into the cerebrospinal fluid (CSF). This study aimed to test this hypothesis by investigating transport of ). Peripherally administered prolactin rapidly activates brain neurons, as evidenced by prolactin-induced phosphorylation of signal transducer and activator of transcription 5 (pSTAT5) in neurons within 30 min of administration. The transport of prolactin into the brain was saturable, with transport effectively blocked only by a very high dose of unlabeled ovine prolactin. Transport was regulated, as in lactating mice with chronically elevated levels of prolactin, the rate of 125 I-prolactin transport into the brain was significantly increased compared to nonlactating controls. There was no change in the rate of 125 Iprolactin transport into the brain in PRLR 2/2 mice lacking functional prolactin receptors compared to control mice, indicating transport is independent of the prolactin receptor. These data suggest that prolactin transport into the brain involves another as yet unidentified transporter molecule. Because CSF levels of 125 I-prolactin were very low, even up to 90 min after administration, the data suggest that CSF is not the major route by which blood prolactin gains access to neurons in the brain.-Brown, R.

Scientific and public interest in host manipulation by parasites has surged over the past few decades, resulting in an exponential growth of cases where potential behavioral manipulation has been identified. However, these studies dwarf the number of genuine attempts to elucidate the mechanistic processes behind this behavioral manipulation. Ultimately, this imbalance has slowed progress in the study of the mechanisms underlying host manipulation. As it stands, research suggests that the mechanisms of host manipulation fall into three categories: immunological, genomic/proteomic and neuropharmacological, and forth potential category: symbioant-mediated manipulation. After exploration of the literature pertaining to these four pathways, four major trends become evident. First and foremost, there is a severe disconnect between the observed molecular and behavioral shifts in a parasitized host. Indeed, very rarely a study demonstrates that molecular changes observed in a host are the result of active manipulation by the resident parasite, or that these molecular changes directly result in behavioral manipulation that increases the parasite's fitness. Secondly, parasites may often employ multiple pathways in unison to achieve control over their hosts. Despite this, current scientific approaches usually focus on each manipulation pathway in isolation rather than integrating them. Thirdly, the relative amount of host-parasite systems yet to be investigated in terms of molecular manipulation is staggering. Finally, as a result of the aforementioned trends, guiding mechanisms or principles for the multiple types of behavioral manipulation are yet to be found. Researchers should look to identify the manipulative factors required to generate the molecular changes seen in hosts, while also considering the "multi-pronged" approach parasites are taking to manipulate behavior. Assessing gene expression and its products during transitional periods in parasites may be a key methodological approach for tackling these recent trends in the host manipulation literature.

New technological methods, such as rapidly developing molecular approaches, often provide new tools for scientific advances. However, these new tools are often not utilized equally across different research areas, possibly leading to disparities in progress between these areas. Here, we use empirical evidence from the scientific literature to test for potential discrepancies in the use of genetic tools to study parasitic vs non-parasitic organisms across three distinguishable molecular periods, the allozyme, nucleotide and genomics periods. Publications on parasites constitute only a fraction (<5%) of the total research output across all molecular periods and are dominated by medically relevant parasites (especially protists), particularly during the early phase of each period. Our analysis suggests an increasing complexity of topics and research questions being addressed with the development of more sophisticated molecular tools, with the research focus between the periods shifting from predominantly species discovery to broader theory-focused questions. We conclude that both new and older molecular methods offer powerful tools for research on parasites, including their diverse roles in ecosystems and their relevance as human pathogens. While older methods, such as barcoding approaches, will continue to feature in the molecular toolbox of parasitologists for years to come, we encourage parasitologists to be more responsive to new approaches that provide the tools to address broader questions.

Mermithids (phylum Nematoda) and hairworms (phylum Nematomorpha) somehow drive their arthropod hosts into water, which is essential for the worms' survival after egression. The mechanisms behind this behavioural change have been investigated in hairworms, but not in mermithids. Establishing a similar mechanistic basis for host behavioural change between these two distantly related parasitic groups would provide strong convergent evidence for adaptive manipulation and insight into how these parasites modify and/or create behaviour. Here, we search for this convergence, and also contrast changes in physiology between hosts infected with immature and mature mermithids to provide the first ontogenetic evidence for adaptive manipulation by disentangling host response and pathology from the parasite's apparent manipulative effects. We used SWATH-mass spectrometry on brains of Forficula auricularia (earwig) and Bellorchestia quoyana (sandhopper), infected with the mermithids Mermis nigrescens and Thaumamermis zealandica , respectively, at both immature and mature stages of infection, to quantify proteomic changes resulting from mermithid infection. Across both hosts (and hairworm-infected hosts, from earlier studies), the general function of dysregulated proteins was conserved. Proteins involved in energy generation/mobilization were dysregulated, corroborating reports of erratic/hyperactive behaviour in infected hosts. Dysregulated proteins involved in axon/dendrite and synapse modulation were also common to all hosts, suggesting neuronal manipulation is involved in inducing positive hydrotaxis. Furthermore, downregulation of CamKII and associated proteins suggest manipulation of memory also contributes to the behavioural shift.

Certain species of parasites have the apparent ability to alter the behaviour of their host in order to facilitate the completion of their own life cycle. While documented in hairworms (phylum Nematomorpha), the ability for mermithid parasites (from the sister phylum Nematoda) to force hosts to enter water remains more enigmatic. Here, we present the first experimental evidence in a laboratory setting that an insect which normally never enters open water (the European earwig Forficula auricularia) will readily enter the water when infected with a mermithid nematode (Mermis nigrescens). Only adult mermithids appear capable of inducing this polarising shift in behaviour, with mermithid length being a very strong predictor of whether their host enters water. However, mermithid length was only weakly associated with how long it took an earwig to enter water following the beginning of a trial. Considering the evidence presented here and its alignment with a proteomic investigation on the same host–parasite system, this study provides strong evidence for adaptive behavioural manipulation and a foundational system for further behavioural and mechanistic exploration.