The role of parasites and pathogens in influencing generalised anxiety and
predation-related fear in the mammalian central nervous system
Maya Kaushik, Poppy H.L. Lamberton, Joanne P. Webster⁎
Department of Infectious Disease Epidemiology, School of Public Health, Imperial College Faculty of Medicine, St Mary's Hospital Campus, Norfolk Place, London, W2 1PG, UK
a b s t r a c t a r t i c l ei n f o
Available online 11 April 2012
Central nervous system
This article is part of a Special Issue “Neuroendocrine-Immune Axis in Health and Disease.”
Behavioural and neurophysiological traits and responses associated with anxiety and predation-related fear
have been well documented in rodent models. Certain parasites and pathogens which rely on predation for
transmission appear able to manipulate these, often innate, traits to increase the likelihood of their life-
cycle being completed. This can occur through a range of mechanisms, such as alteration of hormonal and
neurotransmitter communication and/or direct interference with the neurons and brain regions that mediate
behavioural expression. Whilst some post-infection behavioural changes may reflect ‘general sickness’ or a
pathological by-product of infection, others may have a specific adaptive advantage to the parasite and be
indicative of active manipulation of host behaviour. Here we review the key mechanisms by which anxiety
and predation-related fears are controlled in mammals, before exploring evidence for how some infectious
agents may manipulate these mechanisms. The protozoan Toxoplasma gondii, the causative agent of toxoplas-
mosis, is focused on as a prime example. Selective pressures appear to have allowed this parasite to evolve
strategies to alter the behaviour in its natural intermediate rodent host. Latent infection has also been associated
with a range of altered behavioural profiles, from subtle to severe, in other secondary host species including
humans. In addition to enhancing our knowledge of the evolution of parasite manipulation in general, to further
our understanding of how and when these potential changes to human host behaviour occur, and how we may
prevent or manage them, it is imperative to elucidate the associated mechanisms involved.
© 2012 Elsevier Inc. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Parasitic manipulation of rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hormonal and neuromodulatory mechanisms involved in generalised anxiety in rodents . . . . . . . . . . . . . . . . . . . . . . . . . .
Hormonal and neuromodulatory mechanisms involved in feline aversion in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Manipulation by parasites and pathogens on hormonal and neuromodulatory levels in anxiety-related behaviours in rodent hosts
Parasitic impact on the human CNS and behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Case study: Toxoplasma gondii and altered mammalian host behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Specificity of behavioural manipulation by T. gondii. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Potential mechanisms of action of T. gondii. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Implications of latent toxoplasmosis in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Overall conclusions and implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . .
of transmission is by inducing behavioural changes in the infected host
that can positively affect the probability of transmission to a subsequent
Hormones and Behavior 62 (2012) 191–201
⁎ Corresponding author.
E-mail address: email@example.com (J.P. Webster).
0018-506X/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
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host. Certain species of parasite which are transmitted via predation,
where a definitive or secondary host is infected through consuming
infected prey, could be expected to evolve such behavioural changes,
but only where such parasites possess the appropriate mechanisms
with which to achieve this. It appears that several parasite species are in-
deed associated with a range of behavioural alterations likely to enhance
transmission through increased predation (Barber and Dingemanse,
2010). Whilst the majority of these experimental and field studies con-
cern parasites of invertebrate hosts (Moore, 1983; Pasternak et al.,
1995; Poulin et al., 1992), there are a notable few of such cases occurring
amongst parasites of vertebrate hosts also. Such parasites appear to
tract predation in some manner, and/or, perhaps more sophisticatedly,
through altering the infected host's sensory perception of the predation
risk and its subsequent fear response—hence effectively manipulating
the ‘mind’ of the infected host. The precise mechanisms by which such
parasites alter host behaviour, particularly those involving the more sub-
cidated. These may, however, be plausibly predicted to involve complex
and complement with the mammalian brain and central nervous system
We consider here, with a focus on those, albeit rare, potential
‘manipulatory’ parasites and pathogens infecting the mammalian
CNS, why and how parasites might achieve host manipulation. One
parasite of particular interest, in terms of both its impact on the
infected host and the potential mechanisms involved, is the protozoan
Toxoplasma gondii, which frequently has a high prevalence across its
intermediate (predominantly rodent, 27-35%; (Dubey, 2010; Webster,
1994a, 1994b), definitive (feline 7-74%; (Tenter et al., 2000), and a
full spectrum of other mammalian secondary hosts (Tenter et al.,
2000) including human (4%–92%) populations around the world
(Dubey, 2010; Flegr, 2007). T. gondii will thus be a key, but not
exclusive, model example within this review. Our focus will be directed
towards the potential mechanisms involved in the innate aversion of
rodent prey to feline predators and how certain parasites may alter
or even specifically manipulate this aversion (Fig. 1).
Parasitic manipulation of rodents
The manipulatory effect of parasites on the behaviour of rodents is
of importance in both evolutionary and medical fields. Rodents are the
main natural intermediate hosts of several potential ‘manipulatory’
parasites, and the rodent CNS and immune system are often used as
an experimental model for humans, sharing many structural and
neurochemical similarities. There are several parasitic species that
appear to alter their host's anxiety levels in a manner which may
enhance their transmission success. The behavioural alterations
induced by this spectrum of parasites have some similarities, but the
physiological mechanisms involved may be quite different. These
or multicellular, is a ‘microparasite’ (viruses, bacteria, protozoa) or
‘macroparasite’ (helminths and arthropods), has a direct or indirect
life-cycle, and its host range and/or route of transmission. Parasites that
alter host behaviour can also be enteric or neurotropic. Certainly, whilst
parasites withinthe CNS would appear tobe situated in anideal location
with which to specifically alter or manipulate host behaviour, it must
also be acknowledged that many parasitic species have a tropism for
the CNS simply due to this region representing a ‘privileged site’, being
somewhat protected via the blood–brain barrier from the full attack of
manipulation. Likewise, when considering purely enteric parasites, even
consequent events throughout the host system as the host attempts to
Fig. 1. Potential mechanisms utilised by the protozoan Toxoplasma gondii to alter intermediate host behaviour.
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
maintain homeostatic equilibrium (Lederberg, 2000; Nicholson et al.,
2002; Saric et al., 2010a, 2010b). Thus, the effects of a parasitic infection
are rarely confined to a single target tissue and instead a network of
molecular events can generally be detected throughout the host system,
be associated with subsequent behavioural alterations. When we are
considering parasite ‘manipulation’, however, such alterations are likely
(but not necessarily) to be highly specific and only predicted to evolve if
there is a selective advantage to the parasite to achieve such manipula-
any such behavioural alterations observed amongst infected hosts result
ina selective benefittotheparasite or not, and/or whether suchchanges
are a consequence of simple generalised pathology (defined here in
terms of a behavioural alteration induced in the host as a side-effect/
by-product of infection not under (current) selective pressure to en-
hance parasite transmission nor that of a host response aimed to inhibit
straightforward. One initial step towards such elucidation may be pro-
vided by considering the potential routes and mechanisms that may be
both available and susceptible to modification by parasites of vertebrate
Hormonal and neuromodulatory mechanisms involved in generalised
anxiety in rodents
A number of neuromodulators appear to be involved in the
mechanisms of anxiety within the mammalian CNS, in particular
γ-aminobutyric acid (GABA) and serotonin (5-HT). GABA is an
inhibitory neurotransmitter which interacts with other neurotransmit-
ters in the brain. It acts by binding with GABA-A and GABA-B receptors
in regions of the brain thought to be important in the control of fear
and anxiety, such as the amygdala, the hippocampus, and the frontal
cortex (Kalueff and Nutt, 2007). 5-HT cell bodies are located predomi-
nantly in the raphe nuclei of the midbrain, and the axons project to
these regions of the brain (Barker, 2008). The role of 5-HT in anxiety
is complex: it is thought that it may enhance conditioned fear but
inhibit innate fear (Graeff et al., 1997). In the case of conditioned fear,
the animal learns to fear an aversive stimulus, whilst innate fear is a
genetic trait that has been selected for independent of individual
experience. The serotonergic system has at least 14 5-HT receptor sub-
types, e.g. 5-HT1A (Barnes and Sharp, 1999). Both agonists and
antagonists of the 5-HT1A receptor modulate anxiety behaviour in
animals (Toth, 2003). Rats exposed to the elevated plus maze test
(Walf and Frye, 2007), a test for assessing generalised anxiety levels,
showed decreased cortical GABA function and increased hippocampal
5-HT function (File et al., 1993a, 1993b, 1993c). Changes in uptake of
5-HT after the anxiety test were greater than changes in release,
although the two were not independent of each other. Increased
hippocampal 5-HT function was observed after withdrawal of benzodi-
azepine (an anxiolytic (anxiety reducing) drug), and after handling
habituation. This suggests that an increase in hippocampal 5-HT
function occurs in a variety of situations that lead to anxiogenic (anxi-
ety increasing) responses in animal tests. Exposure to the elevated plus
maze has also been shown to cause a decrease in GABA function in the
cortex, via decreased basal and K+stimulated release of GABA, and
hence it seems that presynaptic changes in the cortex can occur rapidly
in response to tests of anxiety amongst mammals (File et al., 1993a,
tohave ananxiogenic effect(Barker, 2008). Inmammals, the endocrine
stress response is mediated through the hypothalamic–pituitary–
adrenal (HPA) axis. During stress, the synthesis of CRH in the paraven-
tricular nucleus increases. When the CRH neuropeptide reaches the
anterior pituitary gland, it binds to a CRH receptor which leads to the
release of other neuropeptides such asβ-endorphin and adrenocortico-
tropin (ACTH). ACTH in turn can induce the synthesis and release of
glucocorticoids, principally the steroid compound molecule corticoste-
rone plays an important role in fear and anxiety, although it is thought
that whether, and how, behaviour is affected is dependent on the tim-
ing of its release. Furthermore, evidence suggests that corticosterone
does not directly influence behaviour, but instead alters neural path-
ways making certain behavioural outcomes more likely in certain con-
texts (Korte, 2001). The activity of the noradrenergic system has also
been observed to be increased during stress and anxiety in several ani-
tide hormone released from the endocrine system in response to a
number of physical and psychological stresses. It is thought to have an
anxiolytic effect, as central oxytocin administration reduces stress-
induced corticosterone release and subsequent anxiety behaviour in
rats (Windle et al., 1997). This effect is thought to be mediated by the
oxytocin receptor (Bale et al., 2001).
Hormonal and neuromodulatory mechanisms involved in feline aversion
Fear and anxiety specifically related to predation are controlled by
endocrine and neuromodulatory mechanisms. These effects are
dependent on several factors such as the intensity of predator
odour, and the species of predator (Takahashi et al., 2005). In rats,
exposure to feline odour has been observed to, for example, initiate
greater c-Fos expression in the medial amygdala (Dielenberg et al.,
2001). c-Fos is a transcription factor that is used as a functional
marker of activated neurons, and can be used to monitor transcrip-
tional activity in the stress-related circuitry of the CNS (Kovacs,
1998). Exposure to feline odour has also been demonstrated to raise
corticosterone levels in the rat (File et al., 1993a, 1993b, 1993c).
Male rats exposed daily for 60 minutes over 20 days to a cat displayed
higher basal plasma corticosterone levels, higher adrenal weights and
lower thymus weights in comparison with unexposed controls
(Blanchard et al., 1998). Conversely these rats then displayed a low
corticosterone response to an acute restraint stressor, suggesting
that chronic exposure to feline stimulus alters subsequent patterns
of endocrine response (Blanchard et al., 1998). This chronic exposure
to a cat was not shown to alter levels of testosterone, nor spleen or
testes weights, suggesting that the stress response induced by feline
stimulus is different from, for example, the stress induced by social
subordination in male rats (Blanchard et al., 1998) where such asso-
ciated reductions in fitness are observed.
Exposure to feline odour has also been shown to increase the re-
lease and decrease the uptake of the neurotransmitter GABA in both
the cortex and the hippocampus (File et al., 1993a, 1993b, 1993c). Con-
versely levels of the neurotransmitter 5-HT and 5-Hydroxyindoleacetic
acid (5-HIAA), a metabolite of 5-HT, have been shown to decrease in
the hippocampus, but increase in the cortex following feline odour
exposure (Andrews et al., 1993). As described above, the GABA and
5-HT systems act within these brain regions to modulate animal
behavioural traits related to aversive environmental event responses
(Miczek et al., 1995). In rats that show high avoidance of feline
odour, cortical noradrenaline levels were observed to be higher after
exposure to feline odour, suggesting that the cortical noradrenergic
system may play a role in phobic avoidance (Andrews et al., 1993). It
has been suggested that feline odour also activates the wolframin
gene in the amygdaloid area (Koks et al., 2002), suggestive of multiple
potential mechanisms involved in feline aversion in rodents. Activation
of the wolframin gene occurs in parallel with the activation of carboxy-
peptidase E, indicating that wolframin may be involved in neuropep-
tide synthesis (Koks et al., 2002). The function of the wolframin
protein is not fully understood, however, although it appears to be a
multi-spanning membrane glycoprotein of the endoplasmic reticulum
(Hofmann et al., 2003).
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
Some protozoal and helminthic parasites that influence anxiety-related behaviours in rodents.
Host species Effect on anxiety-related
Potential mechanisms involvedGeneral or specific effect
ProtozoaNeurotropicIndirect Non-human mammals
Vector: Tsetse fly
↓ Locomotor activity; ↓
Onset of meningo-encephalitis;
altered cytokine levels and
GABA receptor mechanisms;
General pathology(Darsaud et al., 2003; Saric et al.,
↓ fear of feline odour Reduction in generalised
(Kavaliers and Colwell, 1995;
Kavaliers et al., 1997a, 1997b,
(Kavaliers et al., 1997a, 1997b,
(Cox and Holland, 1998, 2001a,
2001b; Good et al., 2001;
Holland and Cox, 2001)
Helminth EntericDirect Mice
↓ fear of predator
↓ fear of feline odour; ↑ time
in illuminated and open spaces;
↓ exploratory behaviour;
↓ investigation of novel
objects; ↓ and ↑ activity levels
↓ fear of feline odour; ↑ activity;
↑ spontaneous running activity;
NMDA receptor mechanisms Reduction in generalised
General pathology and/or
Reduction in generalized
HelminthNeurotropicIndirect Definitive host: Dogs
Intermediate host: Rodents
and small mammals
Paratenic hosts: Humans,
Definitive host: Cats
Intermediate host: Rodents
and small mammals
Secondary hosts: Humans,
Number and positioning of larvae in
brain; neurochemical alterations
Protozoa Neurotropic Indirect
Production of dopamine by parasite
cysts; location of cysts in brain; host
Specific reduction in feline
(definitive host) aversion;
possible reduction in
(Berdoy et al., 1995, 2000;
Lamberton et al., 2008;
Prandovszky et al., 2011; Webster,
1994a, 1994b, 2001, 2007;
Webster and McConkey, 2010;
Webster et al., 1994, 2006)
(Day and Edman, 1983; Grau
et al., 1987)
P. berghei, P. yoelii)
↓ activity; ↓ anti-mosquito
Accumulation and activation of
macrophages leading to lesions;
production of tumour necrosis factor
Increased cytokine levels; metabolic
changes in plasma and urine;
neuroinflammation; induction of brain
granulomas; altered brain nerve growth
HelminthEnteric IndirectDefinitive hosts: Humans,
non-human primates, rodents
Intermediate host: Molluscs.
↓ nociception; ↓ exploratory
behaviour; ↓ cognitive abilities
General pathology(Aloe and Fiore, 1998; Aloe et al.,
1996; Fiore et al., 1998, 2002;
Saric et al., 2010a, 2010b)
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
In mice, data on neurotransmitters has revealed that overall brain
levels of noradrenaline, dopamine, and 5-HT may not be significantly
different in feline-odour-exposed mice from those of non feline-odour-
exposed individuals. However, the turnover rates of noradrenaline and
pamine increased in the hypothalamus and striatum, after feline odour
exposure (Belzung et al., 2001). Exposure to feline odour is also thought
Δ, and Μ opioid receptors are the three main types of opioid receptors
found in the CNS and its periphery (Mansour et al., 1994). Endogenous
opioid peptides can stimulate noradrenergic, serotonergic and enkepha-
Κ and Μ receptors has been shown to be involved in the modulation of
the mesolimbic dopaminergic pathway (Spanagel et al., 1992).
Evidence suggests that rats respond differently to feline odour as
opposed to fox odour (active component 2,3,5-Trimethyl-3-thiazoline-
TMT) (McGregor et al., 2002). The anxiolytic benzodiazepine drug mid-
azolam, for example, was shown to have opposing modulatory effects on
the rat's response to cat and fox odour, suggesting that the two predator
odours may be quite distinct in their anxiogenic effects within the CNS.
Exposure to TMT on its own can increase dopamine metabolism in the
prefrontal cortex (Morrow et al., 2000), an effect that has not been ob-
served with exposure to feline odour. It has been suggested, however,
that this effect could be due, at least in part, to the intense acrid smell of
TMT, rather than it being a specific anti-predator response (McGregor et
There is therefore evidence to suggest that the neuromodulatory
response of rats and mice to feline odour is different from any general-
ised anxiety responses or indeed that of responses to other predator
odours. There are also differences in response to feline odour between
individual rats. It has been demonstrated that rats exposed to feline
odour can be divided into two categories, ‘responders’ and ‘non-
responders’ (Hogg and File, 1994). Responders show a clear innate
behavioural response to feline odour, whilst non-responders show no
response. However, these two groups do not differ in other tests of
anxiety or social interaction. This result further supports the distinction
between phobic anxieties, generated by cat odour, and generalised
anxiety states. This theory is supported by the different patterns of
release of 5-HT and GABA observed after exposure to cat odour (File
et al., 1993a, 1993b, 1993c) and after exposure to other stressors and
behavioural tests (File et al., 1993a, 1993b, 1993c). The difference in
behavioural and neurochemical responses to phobic anxiety and
generalised anxiety is likely to be due, at least in part, to their different
evolutionary paths. Generalised anxiety, measured in classic approach-
avoidance tests, measures anxiety that does not vary within time, and
is an enduring feature of the animal (Belzung and Griebel, 2001).
Anxiety elicited by a stimulus such as predator odour is a sudden
fear, accompanied by autonomic system arousal (Sullivan et al.,
1999). Generalised anxiety, such as neophobia and a fear of entering
unfamiliar, aversive (e.g. open/ illuminated) places, reduces the
animal's risk of predation in general, whereas the phobic anxiety
elicited by predator odour allows the rat to respondto a suddenchange
in its environment (Belzung and Griebel, 2001). The partly conditioned
aspect of phobic anxiety to feline odour (Adamec, 2001; Adamec and
Shallow, 1993; Zangrossi and File, 1992) may plausibly allow the rat's
fear response to be more adaptable, as some rats may be in environ-
ments where they are far more likely to encounter a predator than
Manipulation by parasites and pathogens on hormonal and
neuromodulatory levels in anxiety-related behaviours in rodent hosts
As discussed above, there are many neurological and hormonal
pathways involved in generalised anxiety and predation-related fear
in rodents. There are a variety of mechanisms by which parasites
may alter these pathways to achieve manipulation of anxiety-
related behaviours in their host. Parasites that influence predation
risk related behaviour, through modified anxiety of their hosts, are
likely to do this either by altering the host's perception of the risk
and/or by altering their fear response to this risk (Poulin, 1998).
Anxiety levels in mice infected with the neurotropic canine
nematode Toxocara canis have been shown to be reduced, both in
general anxiety tests and in relation to feline (non-definitive predator
host) odour (Holland and Cox, 2001). As there are no obvious
selective advantages to the parasite for enhancing predation by a
dead-end feline host here, such behavioural alterations may be sus-
pected to be indicative only of general infection-induced pathology/
by-product rather than specific manipulation. Nevertheless, infected
mice spend increased time in proximity to feline odour, and increased
time in illuminated and open spaces in general anxiety tests in compar-
ison with uninfected mice (Holland and Cox, 2001). Infected mice have
also been observed to display decreased exploratory behaviour and
decreased investigation of novel objects (Cox and Holland, 2001a,
2001b). Activity levels of mice have, however, been shown to either
increase or decrease depending on the strain of the mouse (Cox and
Holland, 2001a, 2001b). Altered behaviours were also observed to be
dependent on intensity of infection, i.e. the number of parasite larvae
within the brain (Cox and Holland, 1998). The mechanisms by which
these parasites are altering host behaviour remain unclear, although
it has been shown that the administration of lead in conjunction with
T. canis infection can ameliorate the behavioural alterations caused by
T. canis alone (Dolinsky et al., 1981), suggesting that one mechanism
is, at least in part, due to neurochemical alterations rather than simply
due to the physical positioning of larvae in the brain (Holland and Cox,
2001). Lead was selected for this investigation as it is a common envi-
ronmental contaminant, although how it attenuates the behavioural
effects of T. canis are unknown, particularly as it does not appear to
alter viability or distribution of larvae within the CNS (Dolinsky et al.,
Neurotropic positioning of parasites and pathogens need not, as
mentioned above, be essential to alter neuromodulator levels and
anxiety behaviours. Mice infected with the enteric protozoan Eimeria
vermiformis, for instance, have been observed to spend a significantly
greater amount of time in proximity to feline odour in comparison
with their uninfected controls (Kavaliers and Colwell, 1995). However,
whilst E. vermifomis-infected mice do not display malaise or illness,
suggesting that reductions in predator response are not due to general
pathological changes, the feline-attraction response in E. vermifomis-
infected mice may also plausibly be suspected to be a by-product of a
reduction in generalised anxiety rather than a specific manipulation
towards ‘feline attraction’, particularly as felines are again not part of
this parasite's life cycle, and thereby predation would result in the
death of the parasite as well as the mouse host. Likewise, the observed
behavioural changes do not appear to be due to any augmented opioid
activity or decreased pain sensitivity, as opiate antagonists have little
effect on infected mice's avoidance of cat odour (Kavaliers et al.,
1997a, 1997b). Furthermore, evidence indicates that E. vermiformis
neither non-selectively decreases olfactory sensitivity nor locomotor
activity, as infection has also been shown to cause male mice to display
an increased preference for the odours of oestrus females (Kavaliers et
al., 1997a, 1997b). E. vermiformis is, however, thought to influence the
behaviour of its host through neurochemical systems associated with
anxiety, involving, at least in part, GABAA receptor mechanisms
(Kavaliers and Colwell, 1995). Indeed, GABA antagonists have been
shown to significantly decrease the anxiety-reducing effects of the
parasite infection, increasing the avoidance of predator odour by the
infected mice (Kavaliers and Colwell, 1995). As stated above, exposure
to feline odour has been shown to decrease GABA uptake and increase
its release in the rat (File et al., 1993a, 1993b, 1993c), so there is the
possibility that E. vermiformis is causing altered GABA activity that
influence fear and anxiety in the host. As the GABA antagonists do
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
not completely block the effects of parasite infection, it is likely that
other neurochemical mechanisms are also involved, in particular the
serotonergic mechanisms that have been implicated in the mediation
of predator-controlled anxiety and analgesia (Andrews et al., 1994;
File et al., 1993a, 1993b, 1993c).
The enteric murine nematode Heligmosomoides polygyrus has also
been shown to reduce the fear response of mice to predator odour
(Kavaliers et al., 1997a, 1997b), although this again is likely to be
explicable as a generalised anxiety alteration response, since
predation of an infected rodent by a cat would result in death of both
host and parasite. Infection appears to remove the non-opioid
analgesia displayed by uninfected mice in response to predator
odour, significantly lowering levels of opioid analgesia (Kavaliers et
al., 1997a, 1997b). It has been suggested that N-methyl-D-aspartate
(NMDA) receptor mechanisms are involved in the expression of
predator-exposure induced analgesia, and the evidence indicates that
H. polygyrus alters this mechanism to cause the observed behavioural
changes (Kavaliers et al., 1997a, 1997b).
Seoul virus, a hantavirus, has been shown to increase aggressive
behaviours and wounding in male rats. This is another example of
how a general alteration in aggressive behaviour can facilitate trans-
mission of a pathogen, in this case potentially via contact of wounds
and virus present in saliva or excrement. Here, whilst there appears
to be no viral antigen present in the brain, it is present in the gonadal
and adrenal glands, suggesting that levels of hormones such as testos-
terone or corticosterone may be altered by the virus with a subsequent
impact on host behaviour (Hinson et al., 2004; Klein et al., 2004).
Finally, a recent study has demonstrated that the colonisation of gut
microbiota impacts mammalian brain development and subsequent
adult host behaviour (Heijtz et al., 2011). When germ free (GF) mice
were compared with specific pathogen free (SPF) mice with a normal
gut microbiota, it was observed that the GF mice displayed increased
motor activity, reduced anxiety, elevated turnover of noradrenaline,
dopamine and serotonin in the striatum, and altered expression of
synaptic plasticity-related genes (Heijtz et al., 2011). Another study
indicated that the commensal bacteria Bifidiobacteria infantis could
modulate tryptophan metabolism in rats, and thereby influence the
precursor pool for 5-HT (Desbonnet et al., 2008). Campylobacter jejuni
is another bacterial microbe that inhabits the intestines of humans.
This has been shown to activate visceral sensory nuclei in the brain-
stem, in the absence of any measurable systemic immune responses
in mice (Gaykema et al., 2004). C. jejuni can alter anxiety behaviours
in mice (Lyte et al., 1998), demonstrating further that parasites and
other micro-organisms have the capability of altering neural pathways
and impacting the CNS even without any direct positioning or even
cytokine response from the host. The gut–brain communication that
these organisms are utilising may be via signals through the vagal
nerve, via modulation of stress hormones, or via modulation of trans-
mitters within the gut itself, although mechanisms are yet to be fully
elucidated (Heijtz et al., 2011).
Parasitic impact on the human CNS and behaviour
Parasites and pathogens well known for affecting the human CNS
include viruses of the genus Lyssavirus, the causative agents of rabies,
an acute encephalitis. Rabies causes severe symptoms in humans,
ending in an acute neurological phase, which can present either as
encephalitis or as paralysis and is almost invariably fatal if post-
exposure prophylaxis is not administered before the onset of severe
symptoms (Hemachudha et al., 2002). Changes in behaviour observed
in infected individuals include hyperactivity, phobic spasms and severe
agitation. There are a few mechanisms by which these changes in
behaviour could be induced. Infection of the CNS by the rabies virus
leads to the production of cytokines and nitric oxide. These can modify
limbic system functions, the HPA-axis, and serotonin metabolism. The
cytokines may also activate the p55 TNFα receptor, resulting in the
recruitment of T and B cells, which can then provoke another amplifi-
cation of the cytokine cascade, exaggerating the disturbance of the
limbic and sympathetic nervous systems (Hemachudha et al., 2002).
Humans are not natural hosts of Lyssavirus spp., and therefore these
behavioural changes are likely to be by-products of the virus’ mecha-
nisms in the brain, that in the wild/appropriate hosts (dogs, bats etc.)
would increase its chance of transmission. Dogs with furious rabies
show higher levels of aggression and biting (Kaplan, 1986), increasing
the chance of transmission via infected saliva to the susceptible hosts
blood and/or body tissues (Rupprecht et al., 2002).
The bacterial spirochete Treponema pallidum is well known histori-
cally for its role in neurosyphilis, one of the later stages of the sexually
transmitted infection. Neurosyphilis has various manifestations,
potentially due to the pathology caused by the bacteria in the CNS. T.
pallidum invades the CNS early in infection and reaches the meninges,
most commonly, during the secondary stage of the disease (O'Donnell
and Emery, 2005). Early pathological findings in patients with chronic
syphilitic meningitis consist of collections of lymphocytes, plasmacytes
and occasional polymorphonuclear leukocytes in meningeal spaces
(Hotson, 1981). The behavioural symptoms of neurosyphilis, however,
become apparent during the tertiary stages of the disease. General
paresis, which occurs 10–20 years after infection, includes deteriora-
tion of cognitive function and concentration, irritability and dementia.
This is thought to be attributed to a progressive neuronal loss in the
cerebral cortex, with most cortical atrophy occurring in the frontal
and temporal lobes (O'Donnell and Emery, 2005). As such behavioural
changes caused by T. pallidum occur long after the period of highest
infectivity, and hence are unlikely to be under strong selective pres-
sures at this stage, it appears that these behavioural alternations are
likely to be non-adaptive, and hence due to general pathology caused
by infection rather than any specific form of parasite manipulation.
Trypanosoma brucei gamiense and T. b. rhodesiense, brucei are
protozoans that can cause sleeping sickness in humans (and T. b.
brucei causes nagana disease in livestock, as well as additional
behavioural changes in various animal species) (Darsaud et al.,
2003). Trypanosomes penetrate the CNS and can be found in the
cerebrospinal fluid. Infection impairs locomotor activity and explor-
atory behaviour in laboratory rats, potentially due to the onset of
meningo-encephalitis (Darsaud et al., 2003). Although a general
pathological effect, it could be perhaps argued that this is indicative
of parasite manipulation aimed to increase the chance of transmission
from the vertebrate host to the tsetse fly vector. A decrease in host
energy and activity increases the likelihood of being bitten by an
insect vector (in contrast to the benefits of increased activity in
predation-transmitted parasites) via an increase in host landing rate
and a reduction in fly swatting behaviours (Ewald, 1994; Holmstad
et al., 2006).
In contrast to the severe pathological changes seen in humans with
rabies, neurosyphilis or sleeping-sickness, latent T. gondii infection may
cause much more subtle behavioural changes in humans, and indeed
until recently was thought to be asymptomatic in immunocompetent
adults. Rodents, as well as other small homeothermic animals predated
upon by felines, are the natural intermediate hosts of the parasite, and
here we discuss, in detail, how this parasite may alter behaviour in
both its natural intermediate hosts (potentially indicative of specific
manipulation) and in secondary, dead end human hosts (potentially
indicative of a by-product of infection).
Case study: Toxoplasma gondii and altered mammalian host behaviour
T. gondii is an indirectly transmitted parasite. The sexual stage of the
parasite's life cycle occurs in the feline intestine, from which oocysts
are excreted with the faeces. Natural intermediate hosts of the parasite
include rodents and birds, which can then ingest these oocysts when
foraging. Intermediate hosts may also acquire the parasite via ingesting
infected meat, via congenital transmission, and even potentially via
sexual transmission (Dass et al., 2011; Dubey, 2010). In the intermediate
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
or secondary host the parasite forms a fast-replicating tachyzoite stage,
and subsequently a slow-replicating bradyzoite (cyst) stage. These cysts
are able to persist in the CNS, placing the parasite in a prime position to
host is then predated upon by the definitive feline host to complete the
life cycle. Altering an infected intermediate host's behaviour to increase
the chance of predation and successful transmission to the definitive fe-
line host could have strong evolutionary benefits for such a parasite, par-
ticularly as sexual recombination can only occur within the feline host.
Specificity of behavioural manipulation by T. gondii
A potentially important factor of parasite manipulation is the
specificity of the behavioural change it causes. An alteration that
specifically increases the contact rate of the infected host with the
subsequent predatory host strongly supports the likelihood that the
behavioural change has been selected for this adaptive advantage.
Whilst many parasites can cause gross pathological changes that
reduce activity levels or social interaction in their host simply
through a general reduction in the host's fitness, in the case of T.
gondii, behavioural changes in the infected rat host have been
shown to be highly specific to increase the chance of predation by
the definitive feline host (Hay et al., 1983a, 1983b, 1984; Hutchison
et al., 1969, 1980a, 1980b; Jackson et al., 1986; Webster, 2001;
Webster and McConkey, 2010). Infected rats have been observed to
approach feline odour more readily (Berdoy et al., 2000; Vyas et al.,
2007), demonstrate increased activity (Webster, 1994a, 1994b),
increased ‘trappability’, and decreased neophobia (Webster et al.,
1994) and predator vigilance activities (Webster et al., 2006) relative
to their uninfected counterparts. Furthermore, infected rats been
observed to spend more time specifically within proximity to feline
odours and not other non-predatory mammal (rabbit) odours
(Berdoy et al., 2000; Webster et al., 2006), or even alternative predato-
ry mammals such as mink (Lamberton et al., 2008) or dog (Kannan,
2010). Moreover, it has been suggested that the loss of fear amongst
T. gondii-infected rodents is restricted to feline odour and that infection
does not affect other learned fears, olfaction and non-aversive learning
(Vyas et al., 2007). Previous studies have, however, conflicting indica-
tions on the effect of T. gondii infection in rodents in general anxiety
tests (Gonzalez et al., 2001, 2007; Piekarski, 1981; Vyas et al., 2007).
There is some evidence that infection may reduce fear of open spaces
in the elevated plus maze (Gonzalez et al., 2007), whilst other studies
have indicated no effect in the open field test (designed to test the
same type of response of a fear of open spaces) (Vyas et al., 2007),
and there has been evidence both for and against food-related neopho-
bia (Vyas et al., 2007; Webster et al., 1994). The conflicting results from
these studies may be due to the different strains, dosage and stages
of the parasite used, the species, strain, or sex of the rodent host and/
or, in particular, the test and experimental (laboratory versus ‘semi-
naturalistic’) set-up used. For instance, it has been suggested that infec-
tion may reduce neophobia in naturally neophobic rats, but reduce
neophilia in naturally neophilic mice (Hodkova et al., 2007).
Potential mechanisms of action of T. gondii
The route/s by which T. gondii uses to influence host behaviour
remain to be fully elucidated, although recent discoveries have indi-
cated a few clues towards potential mechanisms of action (Webster
and McConkey, 2010; Webster et al., 2012). There is, for instance, a
possibility that T. gondii may in part alter host behaviour via the pref-
erential localisation of cysts within the brain (McConkey et al., 2012).
Various studies have suggested different regions of the brain as pre-
dominant cyst locations, such as the olfactory bulbs, amygdala, nucle-
us accumbens, cerebral cortex, cerebellum, medulla oblongata, basal
ganglia, and hippocampal regions (McConkey et al., 2012). However,
although it appears that cysts are able to locate in most regions of the
brain, and are found in a non-random manner, this may plausibly be
due to the relative accessibility of particular brain structures, rather
than to any targeted tropism (Berenreiterova et al., 2011; McConkey
et al., 2012). Therefore it is unlikely that this is the sole mechanism by
which the parasite causes specific behavioural alterations (Webster
and McConkey, 2010).
There is, however, stronger evidence that T. gondii may achieve
such manipulation through, at least in part, altering neuromodulator
levels in the brain (Webster and McConkey, 2010). Chronic T. gondii
infection in mice has been associated with elevated dopamine levels
of 14% (Stibbs, 1985), and acute infections were associated with
elevated levels of homovanillic acid and reduced levels of noradrena-
line (Stibbs, 1985). The T. gondii genome also, rather uniquely amongst
such Apicomplexan parasites (with the notable exception, amongst
those parasites examined to date, also of the indirectly-transmitted
related species Neospora caninum) contains two genes that encode for
the enzyme tyrosine hydroxylase (Gaskell et al., 2009). This enzyme
is involved in the synthesis of L-DOPA, a precursor of dopamine. A
recent study showed that T. gondii infection increases dopamine
metabolism in the mammalian host (Prandovszky et al., 2011). In
dopaminergic cells, the parasite increases the K+-induced release of
dopamine more than three-fold. High levels of dopamine were also
found within T. gondii cysts in brain tissue. Furthermore, the enzyme
tyrosine hydroxylase detected within intracellular T. gondii cysts was
demonstrated to be encoded for by the parasite itself, rather than by
the mammalian host (Prandovszky et al., 2011).
The T. gondii parasites may also be altering anxiety-like behaviours
indirectly, via the host's immune response. Cytokine production plays
an important role in sustaining the latent T. gondii infection of the
cysts (Carruthers and Suzuki, 2007). Cytokines are produced by
microglia, astrocytes and neurons, which promote or suppress
inflammatory responses. Interferon-γ (IFN-γ) is one of the most
important cytokines involved in the cell-mediated immune response
to T. gondii, and is produced in response to the proliferation of
tachyzoites, leading to the development of the chronic latent cyst
stages in the brain (Carruthers and Suzuki, 2007). Cytokines involved
in the rodent inflammation process have been shown to directly
influence the level and turnover of many neuromodulator levels,
including dopamine (Novotna et al., 2005). Interleukin 2, for example,
has been shown to potentiate dopaminerelease and toalter behaviours
known to be mediated by forebrain dopamine pathways (Petitto et al.,
1997). IFN-γ is involved in the expression of indoleamine 2,3-
dioxygenase (IDO), which results in strong toxoplasmostatic effects
(inhibition of parasite replication) through the depletion of intracellu-
lar pools of tryptophan (Carruthers and Suzuki, 2007). Elevated IFN-γ
and IDO have both been associated with altered behaviour in mice
(Moreau et al., 2008; O'Connor et al., 2009). IDO degrades tryptophan
along the kynurenine pathway, which generates compounds such as
kynurenic acid, and an increase in kynurenic acid has been shown to
alter dopaminergic activity in the rat brain (Erhardt and Engberg,
2002; Miranda et al., 1997; Rassoulpour et al., 2005). In this way, the
host immune response to the proliferation of tachyzoites in the brain
may further, albeit indirectly, result in alterations of dopamine and
other neuromodulator levels and hence subsequently host behaviour.
Such indirect effects of the host immune response may be predicted
to interact with the direct route of the parasite increasing dopimaner-
gic activity via production of tyrosine hydroxylase (Prandovszky et
al., 2011), and future research should aim to disentangle the relative,
and/or potential facilitatory, influence of the two routes on dopamine
levels and manipulation of host behaviour.
Finally, it should also be perhaps acknowledged that the potential
effects of enteric parasites and pathogens on host behaviour may also
apply to T. gondii, as this parasite has an intestinal stage both within
the feline definitive host and when first ingested by the intermediate
or secondary host. This initial enteric infection may be likely to
initiate a cascade of changes that lead to further alterations in the
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
CNS, as described above, although, to the authors' knowledge, this has
yet to be investigated.
Implications of latent toxoplasmosis in humans
Whilst T. gondii appears to specifically manipulate the behaviour
of its rodent intermediate hosts to enhance predation to the feline
definitive host, similar behavioural alterations, from subtle to severe,
have also been reported in other host species. Within the definitive
host itself, for instance, whilst CNS toxoplasmosis is uncommon,
some neurological signs have been reported, such as circling, headbob-
bing, atypical crying, and increased affectionate behaviour (Bowman,
2002; Dubey and Carpenter, 1993). In terms of alternative potential
secondary (though not intermediate) animal host species, California
sea otters with moderate to severe toxoplasmic encephalitis have
been observed to be 3.7 times more likely to be attacked by sharks
than otters without encephalitis (Miller et al., 2004), suggesting that
they may exhibit aberrant behaviour, similar to findings in infected
rodents. Likewise, behavioural alterations observed in T. gondii-
infected humans may reflect a non-specific by-product of the adaptive
changes seen in the rodent intermediate host. It seems unlikely that
that the effects of T. gondii infection on humans are specifically
manipulative, as humans are not a natural intermediate host of the
parasite's life cycle, and therefore the parasite is unlikely to have
come under a strong selective pressure to cause specific manipulations
in humans. Furthermore, the effects of the parasite on behaviour are
likely retained in humans, and other secondary mammalian hosts,
due to the phylogenetically primitive structures of mammalian brains
and neurochemical systems (Klein, 2003). Therefore, as latent human
toxoplasmosis is highly prevalent around the world, the implications
for knowledge on the effect of this parasite in the brain are highly
relevant, particularly with recent advances in neuroscience and mental
Studies carried out in human populations have indicated that
there is a link between T. gondii infection and observed personality
differences in humans. For example, T. gondii infected men were
found to have lower superego strength (be more likely to disregard
rules) and higher protension (related to suspiciousness and jealousy).
Infected women score higher in other personality factors, e.g.
affectothymia (warm-hearted and outgoing traits) and alaxia (trusting
and tolerant traits) (Flegr et al., 1996, 2000, 2003). A recent finding has
even suggested that the feline fatal attraction phenomenon seen in rats
(Berdoy et al., 2000) may also be observed in humans, where T. gondii-
infected humans showed altered questionnaire responses to the
odours of the domestic cat (and of the brown hyena) (Flegr et al.,
2011).Researchbythe samegroupalso reportedthat T.gondiiinfection
increases testosterone levels in men, and decreases testosterone levels
in women (Flegr et al., 2008), and that latent toxoplasmosis may cause
differential immunomodulatory effects in men and women (Flegr and
Striz, 2011). Indeed a range of human behavioural studies have indicat-
ed that gender interacts strongly with T. gondiiinfection in determining
different outcomes (Flegr, 2007). The importance of gender and how it
may be specifically interactingwith infection remains little understood,
and highlights the importance of testing both sexes when looking at
both humans and animal models of infection. There is also evidence
to suggest that the Rhesus D (RhD) protein molecule, found
in individuals with a Rh positive blood group phenotype, may confer
a protective effect on latent toxoplasmosis in humans, negating the
effects of infection on reaction times (Novotna et al., 2008) and person-
ality changes (Flegr et al., 2010). Future T. gondii studies in human
cohorts would therefore benefit from knowledge on the Rh phenotype.
An epidemiological link has also been established between T. gondii
infection and the increased risk of development of schizophrenia
(Torrey and Yolken, 2007; Torrey et al., 2007), suggesting that T. gondii
may be an environmental risk factor for this disease, alongside other
environmental, genetic and social risk factors (Allen et al., 2008;
Howes and Kapur, 2009; McDonald and Murray, 2000). The association
between toxoplasmosis and schizophrenia appears to be strong, having
a higher odds ratio than for any one human gene in a genome-wide
linkage analysis (Purcell et al., 2009). It has also been shown that
schizophrenia patients with T. gondii infection are more likely to be
women than men (Dickerson et al., 2007a). The suggestion of elevated
dopamine levels in the brain caused by infection with T. gondii provide
further understandingof this link, supportingthe dopaminehypothesis
of schizophrenia (Howes and Kapur, 2009; Snyder, 1976). It has also
been suggested that T. gondii may impact brain morphology in schizo-
phrenia patients, with a reduction in gray matter volume observed in T.
gondii-positive patients compared with T. gondii-negative patients
(Horacek et al., 2011).
Several studies performed on military personnel and blood donors
implicated dopamine as a link between T. gondii infection and schizo-
phrenia, and were based on evidence suggesting that the level of T.
gondii antibodies was inversely correlated with novelty seeking in
men (Flegr et al., 2003, 2010; Novotna et al., 2005; Skallova et al.,
2005). Novelty seeking is thought to negatively correlate with dopa-
mine concentration in the ventral midbrain, and to be associated with
certain alleles of dopamine transporter and receptors. Therefore the
personality change observed in men has been proposed to imply an in-
crease in dopimanergic activity in infected individuals (Flegr et al.,
2003; Novotna et al., 2005).
Another study directly looking at schizophrenia patients suggested
that infection with T. gondii may recurrently induce a response from
proinflammatory T-helper lymphocyte (TH1) cells (Hinze-Selch et al.,
2007). This in turn may modulate the dopimanergic and serotonergic
systems. High T. gondii titres were associated with increased
C-reactive protein (CRP) and leukocyte values (Hinze-Selch et al.,
2007). Alterations in T-helper cell responses and CRP levels are
known to be found in schizophrenia patients (Dickerson et al., 2007b;
Fan et al., 2007; Schwarz et al., 2001), and therefore it may be that T.
gondii is involved in inducing a proinflammatory response that leads
to dysregulated dopimanergic and serotonergic neurotransmitter
systems, which in turn may lead to psychiatric symptoms and the pre-
cipitation of schizophrenia in vulnerable human subjects (Hinze-Selch
et al., 2007).
There are a few other human neurological disorders that latent
toxoplasmosis has been implicated in. These include obsessive-
compulsive disorder (OCD) (Miman et al., 2010b), Parkinson's disease
(Miman et al., 2010a), Alzheimer's disease (Kusbeci et al., 2011), au-
tism (Prandota, 2010a, 2010b), and a history of suicide attempts
(Arling et al., 2009; Ling et al., 2011; Yagmur et al., 2010). It is possi-
ble that T. gondii infection is also linked with bipolar disorder, as it has
been shown that drugs used in the treatment of bipolar disorder in-
hibit replication of T. gondii in vitro (Jones-Brando et al., 2003). Fur-
thermore, as dopamine has been also shown to play a role in OCD,
bipolar disorder, suicide attempts, and other such mood disorders
(Berk et al., 2007; Denys et al., 2004; Diehl and Gershon, 1992; Roy
et al., 1992), these findings may suggest that related dopimanergic
mechanisms are at work, if these relationships are indeed causal.
Overall conclusions and implications
Parasite-induced alterations in host behaviour have been reported
in a wide range of protozoan, metazoan, bacterial and viral agents,
most of which have complex life-cycles. Some of these behavioural
alterations may be non-adaptive and non-specific, and are simply by-
products of gross pathology caused by the parasite. Some behavioural
changes may be a by-product of another behavioural phenotype that
increases the parasite's chance of transmission in a different host, or
even a consequence of simple infection-induced malaise. Other
behavioural changes may, however, have specific adaptive advantages
for the parasite. There are likely to be many, often interacting, mecha-
nisms by which parasites may manipulate host behaviour. These
M. Kaushik et al. / Hormones and Behavior 62 (2012) 191–201
include behavioural changes after infection that are mediated by the
host immune response, and manipulations caused by the parasite itself
infecting neurons, causing CNS inflammation, and altering hormonal
and neuromodulator communication. Behavioural alterations caused
by parasite manipulation to specifically facilitate transmission may
even be, in certain cases, caused by the parasite infecting specific cells
or regions of the brain, or by altering specific neuromodulatory or
hormonal pathways.Theroleof the hostimmuneresponseinmediating
behavioural changes following infection has in the past mainly been
studied with regards to general sickness pathologies, and more research
needs to be conducted as to whether parasites can specifically exploit
host immunological pathways. Behavioural outcomes of infection are
also likely to be affected by several host factors, including age, gender
mone and neurotransmitter levels and beyond within the mammalian
host is, nevertheless, vital to elucidate the mechanisms behind parasite
manipulation of host behaviour, the evolutionary implications of these
and the subsequent impact upon health, including implications for the
complex fields of mental health and psychology.
The authors' current research into parasite-altered behaviour is
support by funding from the Stanley Medical Research Institute
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