Brain Behav Evol 2002;60:370377 DOI: 10.

1159/000067790

Modulating the Modulators: Parasites, Neuromodulators and Host Behavioral Change

Shelley A. Adamo
Department of Psychology, Dalhousie University, Halifax, Canada

Key Words Parasites W Neuromodulators W Host behavior W Invertebrate W Neuroimmunology

Abstract Neuromodulators can resculpt neural circuits, giving an animal the behavioral flexibility it needs to survive in a complex changing world. This ability, however, provides parasites with a potential mechanism for manipulating host behavior. This paper reviews three invertebrate host-parasite systems to examine whether parasites can change host behavior by secreting neuromodulators. The parasitic wasp, Cotesia congregata, suppresses host feeding partly by inducing the host (Manduca sexta) to increase the octopamine concentration in its hemolymph. The increased octopamine concentration disrupts the motor pattern produced by the frontal ganglion, preventing the ingestion of food. Polymorphus paradoxus (Acanthocephalan) alters the escape behavior of its host, Gammarus lacustris (Crustacea), possibly through an effect on the hosts serotonergic system. The trematode Trichobilharzia ocellata inhibits egg-laying in its snail host (Lymnaea stagnalis), partly by inducing the host to secrete schistosomin. Schistosomin decreases electrical excitability of the caudodorsal cells. The parasite also alters gene expression for some neuromodulators within the hosts central nervous system. In at least two of these three examples, it appears that the host, not

the parasite, produces the neuromodulators that alter host behavior. Producing physiologically potent concentrations of neuromodulators may be energetically expensive for many parasites. Parasites may exploit indirect less energetically expensive methods of altering host behavior. For example, parasites may induce the hosts immune system to produce the appropriate neuromodulators. In many parasites, the ability to manipulate host behavior may have evolved from adaptations designed to circumvent the hosts immune system. Immune-neural-behavioral connections may be pre-adapted for parasitic manipulation.
Copyright 2003 S. Karger AG, Basel

Introduction

Neuromodulators [see Katz, 1999, for definition] can resculpt neural circuits enabling an animal to alter its behavioral response to its environment [e.g., see Kravitz, 1990; Harris-Warrick and Marder, 1991]. This plasticity gives an animal the flexibility it needs to survive in a complex changing world. This ability, however, comes at a cost. The animal leaves itself vulnerable to the possibility that a parasite, using the same or similar neuromodulators, will usurp control of the animals behavior. In this paper, I will present evidence suggesting that some parasites have exploited this strategy. I will focus on three invertebrate host-parasite relationships: (1) the decline in

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feeding and locomotion in the caterpillar, Manduca sexta, infested with the braconid wasp Cotesia congregata; (2) the clinging behavior observed in the amphipod Gammarus lacustris infested with the acanthocephalan Polymorphus paradoxus, and (3) the absence of egg laying in adult snails (Lymnaea stagnalis) infested with the trematode Trichobilharzia ocellata. Many parasitized animals show changes in behavior [see Moore, 2002; Horton and Moore, 1993]. For example, ants, infested with the trematode Dicrocoelium dendriticum, climb to the top of nearby plants and fix themselves there with their mandibles [Romig et al., 1980]. This behavior is thought to increase the probability that the ant will be eaten by a mammalian herbivore, the next step in the trematodes life cycle. Because some changes in host behavior appear to benefit the parasite, many researchers suspect that parasites actively alter the behavior of their hosts by secreting neuromodulators [e.g., Romig et al., 1980, also see discussion in Holmes and Zohar, 1990; Thompson and Kavaliers, 1994; Adamo, 1997; Katz and Edwards, 1999; Moore, 2002]. Despite this widespread belief, there is little evidence that parasites change host behavior by secreting any substance that acts directly on the hosts central nervous system (CNS). There is good evidence, however, that parasites secrete hormones into their hosts [e.g., see Beckage and Gelman, 2001]. The parasitic wasp Cotesia congregata, for example, secretes ecdysteroids into its host [e.g., Gelman et al., 1998, 1999]. Changes in host ecdysteroid titers alter host development, and this alteration benefits the wasp [Gelman et al., 1999]. Although some neurons are known to have receptors for ecdysteroids [Hewes and Truman, 1994; Truman et al., 1994], changes in ecdysteroid titers in parasitized hosts have not been correlated with specific changes in host behavior. Some animals have a direct effect on another animals nervous system by secreting venoms [Adams et al., 1999]. Although most venoms cause gross behavioral changes (e.g., paralysis), others are capable of more subtle influences. For example, the venom of the wasp Ampulex compressa, leaves its victim, a cockroach, incapable of spontaneous movement [Fouad et al., 1994]. The cockroach is not paralyzed, however, and will walk when led by the wasp. The wasp guides the cockroach back to the wasps nest, where it is sealed up with a wasp egg [Fouad et al., 1994]. Given the existence of hormone-secreting parasites and neuroactive venoms, a neuromodulatory-secreting parasite would seem a likely possibility [but see Adamo, 1997 for a discussion of some of the difficulties facing

putative neuromanipulative parasites]. Demonstrating that a parasite secretes compounds that alter host CNS function, however, requires disentangling the interactions between two complex organisms. Adding to this complexity, host behavior can change for reasons other than a direct effect of parasitic products on the hosts CNS. Hosts may induce their own changes of behavior in response to parasitism in an attempt to rid themselves of the parasite [e.g., behavioral fever; Adamo, 1999]. Parasites can also have indirect effects on behavior [e.g., due to destruction of sensory organs or muscle; see Holmes and Zohar, 1990]. Some of these indirect effects may be difficult to distinguish from direct effects. For example, the rat tapeworm Hymenolepis diminuta secretes substances that interfere with vitellogenin production in the fat body of its intermediate host, the mealworm Tenebrio molitor [Webb and Hurd, 1999]. Eggs do not develop normally, and egg laying behavior declines [Hurd and Arme, 1986]. However, egg laying behavior may decline because: (1) fewer mature eggs in the ovary trigger less egg laying; and/or (2) the parasite may secrete some substance that disrupts the neural circuits regulating egg-laying. Difficulties in demonstrating that a parasites secretion/excretion has a direct effect on the hosts CNS will be compounded in systems in which the parasites production of a neuromodulator and/or its effect are dependent on the developmental stage of the host and/or parasite. Many systems probably have this restriction. For example, some hosts of intermediate parasites do not show altered behavior until they reach the infective stage for the definitive host [see Moore, 2002]. In other host-parasite systems, the parasites products may not directly alter the hosts CNS, but may induce the host to release its own neuromodulatory substances in order to do so. In these more complex and probably more common scenarios, determining how parasites affect host behavior will require ingenuity. This paper does not examine whether the parasiteinduced changes in host behavior benefit host, parasite, both, or neither animal. Although it might seem that a behavior that is altered by a parasitic product must be beneficial to the parasite (because of its metabolic cost), it is possible that the host could induce the parasite to release neuromodulatory substances by stressing it, with no benefit to either animal. Also, neuroactive substances released by a parasite may have been selected to influence the hosts immune system or its intermediate metabolism, and its effect on host behavior (i.e., CNS) may be an incidental non-adaptive effect. The neuroactive compound

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Fig. 1. Response to a forcep pinch by a normal M. sexta larva (A) and one parasitized by C. congregata (B). The brown scars on the larva in (B) were created by the wasps while exiting the host.

could also be a parasitic waste product, with accidental effects on the hosts CNS. Poulin [1995] and Moore and Gottelli [1996] discuss some of the tests needed to determine whether a change in host behavior is adaptive for the parasite, and whether the parasite has been selected to manipulate its host. Below I discuss three unusual host-parasite systems. These systems are unusual because, unlike most host-parasite systems, we have some information about how host behavior is altered.

Cotesia congregata and Its Host, the Tobacco Hornworm Manduca sexta

The female wasp injects venom, polydnavirus and wasp eggs into its host, M. sexta [see review Beckage and Gelman, 2001]. The wasp larvae hatch and develop within the hosts hemocoel. They do not damage any of the hosts internal organs or physically contact the hosts CNS [Adamo et al., 1997], but absorb nutrients from the hosts hemolymph. During the wasps ecdysis to the 3rd instar, they exit through the hosts cuticle [Fulton, 1940]. They then spin cocoons, which remain attached to the host. Four to five days later the wasps emerge as adults [Beckage and Templeton, 1986], and the host typically dies about 2 weeks after wasp emergence [Beckage and Riddiford, 1978; Adamo et al., 1997]. The materials injected by the wasp exert a number of effects on the host, resulting in changes in endocrine function, intermediate metabolism, and development [see Beckage and Gelman, 2001]. Despite these physiological changes, many of which occur soon after the wasps enter the host, host behavior remains indistinguishable from non-parasitized controls for most of the wasps development [Adamo et al., 1997; Alleyne and Beckage, 1997]. However, about one day prior to the wasps exit from the host, feeding [Beckage and Riddiford, 1978; Miles and

Booker, 2000] and spontaneous locomotion [Adamo et al., 1997] decline. The host remains in a non-feeding and non-moving state until its death. The wasp larvae alone, without the polydnavirus or venom, can induce these behavioral changes [Adamo et al., 1997]. The decline in host feeding and locomotion appears to benefit the parasitoid by preventing the host from feeding on, or dislodging, the wasp cocoons [Adamo, 1998]. The decline in host feeding and locomotion does not appear to be due to debilitation of the host [Adamo et al., 1997; Beckage and Gelman, 2001]. For example, host reflexes remain intact after the wasps emerge (fig. 1) [Adamo et al., 1997]. Removal of the hosts supraesophageal ganglion results in increased host locomotion [the host becomes hyperkinetic; Beckage and Templeton, 1986], suggesting that there is neural inhibition of locomotion in parasitized M. sexta [Beckage and Gelman, 2001]. At about the same time as feeding and locomotion decline, there is a sharp increase in the amount of octopamine in the hosts hemolymph and CNS (fig. 2); [Adamo et al., 1997; Adamo and Shoemaker, 2000]. Not all compounds increase in amount during parasitism, suggesting some specificity [Adamo and Shoemaker, 2000]. The increased octopamine concentrations are not a result of the lack of feeding; food deprivation has no effect on the amount of octopamine in the CNS [Adamo and Shoemaker, 2000] and induces only a small increase in octopamine concentration in the hemolymph [Adamo et al., 1997]. The increased octopamine in the hemolymph appears to play a role in the decline in host feeding [Miles and Booker, 2000]. Injections of octopamine decrease feeding in nonparasitized M. sexta, and this decrease can be blocked by injections of phentolamine, an octopamine antagonist [Adamo et al., 1997]. Increased concentrations of octopamine in the hemolymph may depress feeding partly by suppressing normal activity in the frontal ganglion. The frontal ganglion controls peristalsis in the fore-

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Fig. 2. Feeding declines as octopamine concentration increases in

both the brain (supra- and subesophageal ganglia) and hemolymph of parasitized M. sexta. Note that the increase in octopamine in the CNS precedes the increase observed in the hemolymph. Samples were analyzed prior to wasp emergence (after the host larvae molted to 4th and 5th instars (4th Day 0, 5th Day 0)), 12 h prior to wasp emergence (12 h PreEm), at the time of wasp emergence (P Em), and 1 and 3 days after the wasps had emerged (1 Day Post Em, 3 Days Post Em). Error bars have been omitted for clarity, but can be found in Adamo et al. [1997] and Adamo and Shoemaker [2000].

time. It is also possible that the wasps induce the host to secrete octopamine, which could come from a number of sources [see Adamo et al., 1997]. For example, octopamine enhances immune responses in some insects [Baines et al., 1992; Baines and Downer, 1994] and increases in concentration in the hemolymph in response to infection with bacteria [Dunphy and Downer, 1994]. By manipulating a host immune response, the wasps may be able to induce the host to raise its octopamine levels. The increase in host octopamine concentrations is unlikely to be responsible for all the behavioral changes observed in the post-emergent host. Not surprisingly, other neuromodulators are affected during parasitism. Dopamine concentrations increase in the hemolymph just prior to wasp emergence [Hopkins et al., 1998]. There are also changes in the concentration of some neuropeptides within the parasitized M. sexta brain [supraesophageal ganglion; Zitnan et al., 1995]. Zitnan et al. [1995] found increases in immunohistochemical staining for 9 of the 10 different peptides examined in parasitized M. sexta. One peptide, proctolin, showed an increase in staining at about the same time as the hosts behavior changes. How these changes are induced is unknown, nor do we know whether they relate to the observed behavioral changes.

gut which is critical for the ingestion of food [Miles and Booker, 1994, 2000]. Patterned neural output from the frontal ganglion can be disrupted by the addition of octopamine in vitro [Miles and Booker, 2000]. Phentolamine and mianserin (another octopamine antagonist) can block this disruption. Hemolymph from non-feeding hosts also disrupts the motor pattern of the frontal ganglion, whereas hemolymph from non-parasitized M. sexta, or from parasitized M. sexta prior to wasp emergence, typically does not [Miles and Booker, 2000]. The disruption induced by the addition of hemolymph from non-feeding hosts can be prevented by the addition of phentolamine or mianserin, suggesting that the increased octopamine concentration in the hosts hemolymph is causally involved in suppressing host feeding [Miles and Booker, 2000]. Although wasp larvae secrete hormones and other compounds into their host [Beckage and Gelman, 2001], they do not appear to secrete octopamine, at least in vitro [Adamo, unpublished results]. The rate of removal of octopamine from the hosts hemolymph declines after the wasps emerge [Adamo, unpublished results], and this may partly explain why the octopamine titer increases at this

Polymorphus paradoxus (Acanthocephala) and Its Intermediate Host, Gammarus lacustris (Crustacea)

Gammarids infested with P. paradoxus have an altered escape response [Bethel and Holmes, 1977]. When disturbed, infested animals skim along the surface of the water until they encounter some solid material, then cling to it, remaining immobile in a flexed posture. When disturbed, non-infested gammarids dive towards the bottom and burrow into the mud. The altered escape response of the infested gammarids increases the probability that they will be eaten by a duck (Anas platyrhynchos), the parasites definitive host [Bethel and Holmes, 1977]. The parasite lives in the gammarids hemocoel, and does not physically damage the host or come into direct contact with the hosts CNS [Maynard et al., 1996]. This observation suggests that the parasite uses some kind of chemical interaction to influence host behavior [Maynard et al., 1996]. Injections of serotonin into the hemocoel of other crusteacea can induce a flexed posture [Livingston et al., 1980; Tierney and Mangiamele, 2001], suggesting that if P. paradoxus could increase host serotonin titers it

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could induce a flexed clinging behavior in its host. In support of this hypothesis, Helluy and Holmes [1990] found that injections of serotonin into non-infested gammarids induced the clinging response typical of parasitized gammarids. Similar doses of octopamine, noradrenalin, and GABA did not increase clinging behavior. Maynard et al. [1996] then searched for changes in the hosts serotonergic system. In neurons showing serotonin-like immunoreactivity, parasitized gammarids had an increase in the number of varicosities, suggesting either an increase in the number of varicosities (potential release sites) or an increase in the amount of serotonin stored in each varicosity [Maynard et al., 1996]. This increase in staining was not observed in gammarids infested with a related acanthocephalan, Polymorphus marilis, which does not induce clinging behavior [Maynard et al., 1996]. The presence of the parasite seems to induce a change in the hosts serotonergic system [Maynard et al., 1996]. However, if increased serotonin levels are key in altering host behavior, and if this serotonin is being produced by the host, then infested gammarids must simultaneously increase both secretion and accumulation of serotonin to account for the immunohistochemical results. It would be interesting to test whether the parasite is capable of secreting serotonin. Parasitic secretion of serotonin could also explain Maynard et al.s [1996] immunohistochemical results. If the parasite is secreting large amounts of serotonin, this release could have a negative feedback effect on the host, reducing host serotonin release, and increasing serotonin storage in the hosts CNS. Holmes and Zohar [1990], however, suggest that P. paradoxus is unlikely to secrete serotonin because of the low concentrations of serotonin found in most acanthocephalans. They favor the hypothesis that P. paradoxus secretes something that activates the hosts serotonergic system. Helluy and Holmes [1990] also found that injections of octopamine could decrease clinging behavior in infested gammarids. Could the change in host behavior be due to a decrease in octopamine release as opposed to (or in addition to) an increase in serotonin? Unfortunately, we do not know whether octopamine concentration changes during parasitism. It is possible that parasitic secretions/excretions do not have a direct effect on the hosts nervous system. The change in host behavior could be caused indirectly, by the parasite interacting with the hosts immune system. Increased serotonin concentrations in the hemolymph are known to enhance immune responses in cockroaches [Baines et al., 1992] and could be part of a host response

to infestation. Thus, the parasite may manipulate its host by activating selected components of its immune system.

The Freshwater Snail Lymnaea stagnalis Infested with the Trematode Trichobilharzia ocellata

The freshwater snail, Lymnaea stagnalis, is attacked by an avian schistosome, Trichobilharzia ocellata [reviewed in de Jong-Brink, 1995; de Jong-Brink et al., 1997]. After penetrating the snails skin, sporocysts form and migrate to the area of the digestive gland/ovotestis. The sporocysts then give rise to the final larval stage, the cercariae. The cercariae leave the snail in search of their definitive host, a duck (A. platyrhynchos). One of the most striking changes in host behavior is the cessation of egg-laying [de Jong-Brink et al., 1999], a behavior non-parasitized snails perform every 3 to 4 days [van Duivenboden, 1984]. In snails infested as adults, reproduction declines once differentiated cercariae are present [Schallig et al., 1991]. The decline in egg laying does not appear to be due to host debilitation. Infested snails continue to grow at the same rate as non-infested controls [Schallig et al., 1991]. The decline in host egg laying benefits the parasite by diverting the energy that the host would have invested in its own reproduction into the parasites reproduction [de Jong-Brink, 1995]. The parasite appears to use both direct and indirect mechanisms to inhibit host egg laying [de Jong-Brink et al., 2001]. The parasite secretes a substance that induces the host to release schistosomin from its connective tissue and hemocytes [de Jong-Brink, 1995]. Schistosomin acts as a neuromodulator, reducing the electrical excitability of the hosts caudodorsal cells (CDC) [Hordijk et al., 1992]. These cells are located in both cerebral ganglia, close to the cerebral commissure [Chase, 2002]. In normal snails, these neurons fire en masse to release peptides that result in ovulation and egg laying. In parasitized snails, the CDCs are no longer capable of the prolonged firing needed for peptide release [Hordijk et al., 1992]. Purified schistosomin and hemolymph from infested snails can induce a similar inhibition of the CDCs in normal snails [Hordijk et al., 1992]. Interestingly, neither schistosomin nor hemolymph from parasitized snails changes the resting potential of CDC neurons. Hordijk et al. [1992] suggest that schistosomin may exert its effect via an intracellular signal transduction system. Parasitic extracts can induce schistosomin production in non-infested snails both in vivo and in vitro [de Jong-

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Brink, 1995]. Although the function of schistosomin in the normal snail remains unclear, it may play a role in the snails immune system [de Jong-Brink et al., 2001]. By inducing the host to produce schistosomin, the parasite may be exploiting a host response to stress or infection [de Jong-Brink, 1995]. Although long term stressors such as starvation or cold do not increase schistosome production in non-infested snails, acute stressors such as physical disturbance during egg laying do [de Jong-Brink, 1995]. The parasite also appears to have a direct effect on the hosts CNS by altering gene expression for specific neuromodulators. For example, parasitism results in an up-regulation of the gene for neuropeptide Y (Lymnaea neuropeptide Y homologue). Infusion or injection of neuropeptide Y inhibits egg-laying, but does not reduce feeding [de Jong-Brink et al., 1999], suggesting that the treatments do not simply have an aversive effect. Neuropeptide Y does not directly interact with the CDCs (i.e., via classical synapses), but it may have an indirect effect on them [de Jong-Brink et al., 1999]. The parasite is thought to alter host gene expression in the CNS directly (i.e., via some parasitic product), because changes in gene expression are visible within 1.5 h of infection [Hoek et al., 1997]. The parasite also secretes a number of neuropeptide-like compounds; however, these appear to act on the hosts immune system, not the nervous system [de Jong-Brink, 2001]. A related schistosome (Schistosoma mansoni) attacks the freshwater snail Biomphalaria glabrata, inhibiting egg-laying in the infested host. Parasitized snails show a decrease in serotonin, dopamine and L-dopa concentrations in both plasma and CNS. The decline in serotonin in the plasma and/or CNS is linked to the decline in egg laying. Normal snails exposed to serotonin in their tank water show an increase in their egg laying. Under the same conditions, parasitized snails also show an increase in egg laying, reversing the effect of the parasite [Manger et al., 1996]. Manger et al. [1996] suggest that the parasite may alter host serotonergic function indirectly by competing for the neuromodulator and/or its precursors. This hypothesis is supported by the finding that larval S. mansoni take up serotonin through their tegument via a serotonin transporter [Yoshino et al., 2001].

to predators and mate selection; see Kavaliers et al., 1999]. Some of these behavioral changes appear to be induced by endogenous opiates [Kavaliers et al., 1999]. Interestingly, Schistosoma mansoni, a trematode, produces both -endorphin and other opioid peptides when infesting mice [Duvaux-Miret et al., 1992; Pryor and Elizee, 2000]. These peptides are thought to suppress the host immune system [Pryor and Elizee, 2000]. Because opioids can be both immuno- and neuro-modulators [Salzet, 2000], the parasite could potentially use the same compound to suppress the hosts immune system and alter its neural function. However, whether parasite-produced opioids also have direct CNS and behavioral effects is unknown [Thompson and Kavaliers, 1994; Kavaliers et al., 1999; Pryor and Elizee, 2000]. The parasites could also induce changes in host behavior indirectly by manipulating immune-neural connections in the host [Thompson and Kavaliers, 1994; Kavaliers et al., 1999; Pryor and Elizee, 2000].

Conclusions

Parasitic Manipulation in Vertebrate Hosts

In vertebrates, too, the presence of some parasites has been shown to correlate with changes in host behavior [e.g., the hosts pain response, learning abilities, response

Evidence from the examples provided suggests that parasites can manipulate neuromodulators to alter host behavior. There is little evidence, however, that they secrete these neuromodulators themselves. In 2 of the 3 examples discussed in this paper, it appears that the host, not the parasite, produces the neuromodulators that result in a change in host behavior. This arrangement may be a common one, especially for parasites that do not reside within the hosts CNS. From the point of view of the parasite, secreting substances such as biogenic amines or neuropeptides (e.g., FMRFamide) would be metabolically expensive. These substances often have short half-lives in hemolymph [e.g., Goosey and Candy, 1980]. Moreover, in many invertebrates, the parasite would need to produce high hemolymph concentrations of these substances in order for them to reach the CNS through the blood-brain barrier. For example, Helluy and Holmes [1990] needed to raise the serotonin concentration in the hemolymph of non-parasitized G. lacustris to 10 3 M to induce the clinging behavior seen in parasitized animals. To maintain this level in the host, the parasite would need to secrete large amounts of neuromodulator continuously. Although this need would be decreased for substances that are actively transported into the brain, a parasite that could produce small long-lasting compounds, capable of inducing the host to increase secretion of the necessary neuromodulators and/or inhibit their breakdown, would have an ener-

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getic advantage over a parasite producing the neuromodulator itself. In cases in which host behavior appears to be modified by a peptide or biogenic amine, the source will probably be the host. Thus, parasites appear to exploit indirect and less energetically expensive methods of altering host neuromodulators. Fortunately for the parasite, it has easy access to a host system that has modulatory connections to the hosts CNS i.e., the hosts immune system. Parasites are in intimate contact with the hosts immune system and, therefore, do not need to produce high concentrations of product in order to interact with it. Parasites are under intense selection pressure to suppress host immunity, and some parasites do this by secreting immunosuppressive

substances [e.g., de Jong-Brink, 1995]. It may be a small evolutionary step for a parasite to move from suppressing the hosts immune system, to inducing it to release its endogenous neuromodulatory contents. Neuromodulators released by the hosts immune system may serve an adaptive function in the non-parasitized animal [Maier and Watkins, 1999], but when their release is manipulated by the parasite, they could lead to changes in host behavior that are adaptive for the parasite. In many parasites, the ability to manipulate host behavior may have evolved from adaptations designed to circumvent the hosts immune system. Immune-neuralbehavioral connections may be especially susceptible to parasitic manipulation.

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