Chemotherapy patients often develop anticipatory nausea, a learned response produced by an environmental cue triggering nausea in the absence of the emetic stimulus. This can be modelled in rats by pairing the administration of an emetic treatment with exposure to a distinct context. Rats are a non-emetic species, but they are still capable of experiencing nausea, which is observable through the presence of the gaping response. The rat model of anticipatory nausea mainly utilizes lithium chloride (LiCl) to evoke the gaping response, yet various other putative emetic toxins and agents have remained unexplored. The current study determined if emetine, found in ipecac, and scopolamine methyl nitrate (SMN), a derivative of scopolamine, can evoke the conditioned gaping response. Adult male Long Evans rats (n = 40) were administered emetine (5.0 mg/kg, intraperitoneal [i.p.]), SMN (0.5 or 1.0 mg/kg, i.p.), LiCl (127 mg/kg, i.p.), or sodium chloride (NaCl, 0.9 %, i.p., control) before exposure to a distinct context for 30 min, over four conditioning trials, followed by four extinction (drug-free) trials. During the extinction trials, no treatments were administered, and rats were placed directly into the context. Rat behaviour on all of the trials was videotaped and scored for the frequency of the conditioned gaping response. Findings from this study suggest that, in comparison to LiCl, emetine is an effective conditioning stimulus, whereas SMN is not.

Parasites and infections are one of the major costs associated with group living and high host density. Although infection threat can influence the behavior of both uninfected and infected individuals, investigations have focused on the responses of uninfected individuals. Here we describe the effects on, and response to, terrestrial snails, Cepaea nemoralis, treated with either a bacterial or viral pathogenic stimulus. Brief exposure of untreated (uninfected) snails to the mucus associated chemical cues of snails acutely treated with either the bacterial cell wall component, lipopolysaccharide (LPS), or the viral mimetic, polyinosinic:polycytidylic acid (Poly I:C), elicited active behavioral avoidance and antinociceptive responses (decreased sensitivity to noxious stimuli). Treated (infected) snails also avoided and displayed antinociceptive responses to the chemical cues of snails with either a simulated bacterial or viral infection; however, each according to their own treatment (infection) status. LPS (bacterial) treated snails avoided the cues of Poly I:C (viral), but not LPS, treated conspecifics, whereas Poly I:C treated snails primarily avoided the mucus associated cues of LPS, but not Poly I:C, treated individuals. These findings show that chemical mediated behavioral avoidance of bacterial and viral threat is affected by both the nature of the infection threat and the infection status of the individual.

Anticipatory nausea is a classically conditioned response to cues that have been associated with a nauseating stimulus. In rodents, anticipatory nausea can be modelled by pairing the novel cue of a distinct context with the toxic effects of lithium chloride (LiCl), which leads to anticipatory nausea responses (e.g. gaping) when exposed to the context alone. Previous work has shown that lipopolysaccharide (LPS) attenuates LiCl-induced anticipatory nausea. However, these studies use short inter-trial intervals (ITIs), which limits our understanding of how LPS attenuates LiCl-induced anticipatory nausea (e.g., through associative or non-associative mechanisms). We developed a long interval (7-day ITI) rodent model to enhance the translational relevance of anticipatory nausea research and to begin understanding the mechanisms underlying LPS effects. Adult male Long Evans rats were administered LiCl (127 mg/kg) or vehicle control (NaCl) intraperitoneally (i.p.) paired with a 30 min exposure to a distinct context for 4 conditioning trials at 7-day intervals. Rats were administered either LPS or NaCl (200 μg/kg, i.p.) immediately after the conditioning trials (post-conditioning) or LPS 90 mins prior to the conditioning trials (pre-conditioning). These trials were followed by 4 drug-free test/extinction trials. LiCl induced significant conditioned gaping responses with long ITIs. Pre-conditioning LPS robustly attenuated conditioned gaping. For post-conditioning LPS, we did not detect an attenuation using the long interval model. The use of long ITIs enabled the assessment of the temporally dependent effects of LPS on anticipatory nausea. These findings advance current models of anticipatory nausea and highlight new directions for investigating the immune modulation of nausea-related behaviours.

In humans, women are known to have a greater prevalence of eating-related disorders and stronger experience of food cravings than men. Similarly, in rodents, females display a greater preference and motivation for the highly palatable sweet food, sucrose, than do males. Pre-exposure to sucrose has been shown to enhance locomotor sensitization induced by dopaminergic agonists, however, evidence of sex differences in this effect is limited. Female (n = 16) and male (n = 16) Long-Evans rats received 30 min daily access to sucrose (0.3 M) or water for nine consecutive days followed by daily administration of the D2/D3 agonist, quinpirole (0.5 mg/kg), for nine consecutive days. Automated locomotor activity assessment occurred on the first, fifth, and ninth days of the sucrose and quinpirole phases. In the sucrose phase, sex × fluid interactions were broadly observed in activity measures across and within testing days with females but not males showing an effect of sucrose-induced locomotor sensitization. In the quinpirole phase, a sex × fluid interaction was only observed in a single activity measure across days, suggesting that sucrose pre-exposure does not robustly alter quinpirole sensitization by sex. A sex difference was identified in the effect of locomotor sensitization induced by sucrose, but not for sucrose pre-exposure on quinpirole sensitization. These results suggest that differences exist between sexes in sucrose-induced sensitization in rodents, perhaps underlying sex differences in food cravings and eating-related disorder prevalence in humans.

Research suggests that certain gut and dietary factors may worsen behavioral features of autism spectrum disorder (ASD). Treatment with propionic acid (PPA) has been found to create both brain and behavioral responses in rats that are characteristic of ASD in humans. A consistent male bias in human ASD prevalence has been observed, and several sex-differential genetic and hormonal factors have been suggested to contribute to this bias. The majority of PPA studies in relation to ASD focus on male subjects; research examining the effects of PPA in females is scarce. The present study includes two experiments. Experiment 1 explored sex differences in the effects of systemic administration of PPA (500 mg/kg, ip) on adult rodent social behavior and anxiety (light-dark test). Experiment 2 investigated differential effects of systemic administration of PPA (500 mg/kg) on social behavior and anxiety in relation to fluctuating estrogen and progesterone levels during the adult rodent estrous cycle. PPA treatment impaired social behavior and increased anxiety in females to the same degree in comparison to PPA-treated males. As well, females treated with PPA in their diestrus phase did not differ significantly in comparison to females administered PPA in their proestrus phase, in terms of reduced social behavior and increased anxiety.

Disgust is considered to be a fundamental affective state associated with triggering the behavioral avoidance of infection and parasite/pathogen threat. In humans, and other vertebrates, disgust affects how individuals interact with, and respond to, parasites, pathogens and potentially infected conspecifics and their sensory cues. Here we show that the land snail, Cepaea nemoralis, displays a similar "disgust-like" state eliciting behavioral avoidance responses to the mucus associated cues of infected and potentially infected snails. Brief exposure to the mucus of snails treated with the Gram-negative bacterial endotoxin, lipopolysaccharide (LPS), elicited dose-related behavioral avoidance, including acute antinociceptive responses, similar to those expressed by mammals. In addition, exposure to the mucus cues of LPS treated snails led to a subsequent avoidance of unfamiliar individuals, paralleling the recognition of and avoidance responses exhibited by vertebrates exposed to potential pathogen risk. Further, the avoidance of, and antinociceptive responses to, the mucus of LPS treated snails were attenuated in a dose-related manner by the oxytocin (OT) receptor antagonist, L-368,899. This supports the involvement of OT and OT receptor homologs in the expression of infection avoidance, and consistent with the roles of OT in the modulation of responses to salient social and infection threats by rodents and other vertebrates. These findings with land snails are indicative of evolutionarily conserved disgust-like states associated with OT/OT receptor homolog modulated behavioral avoidance responses to infection and pathogen threat.

A first-order association can be formed between toxin-induced nausea and a context, as well as nausea and a taste cue. However, comparatively little is understood about second-order associations. The present study examined if the bacterial endotoxin, LPS, could impair the first- and second-order conditioning of context aversion (anticipatory nausea paradigm) and subsequent conditioned taste avoidance (two-bottle task). Adult male Long Evans rats were treated with LiCl (127 mg/kg, intraperitoneal [i.p.]) or vehicle control (NaCl) and then exposed to a distinct context for 4 first-order conditioning trials. LPS (200 μg/kg, i.p.) or NaCl were administered 24 h after each trial. Seventy-two h after the final first-order conditioning trial, rats underwent 2 second-order conditioning trials where they were treated with 2% saccharin (i.p.) and then exposed to the same context. Twenty-four h after the final second-order conditioning trial, rats were tested in a two-bottle task (2 trials), where they were given a choice between water and a palatable 0.2% saccharin solution. LiCl-treated rats demonstrated a context aversion by the 3rd conditioning trial in the anticipatory nausea paradigm. Rats previously exposed to LiCl also displayed a conditioned taste avoidance of saccharin within the two-bottle task. LPS attenuated first-order context aversion but did not alter either second-order context aversion or conditioned taste avoidance in the two-bottle task. This study demonstrated that a secondary association formed within an aversive context could result in a conditioned taste avoidance. Further, LPS may be able to attenuate primary conditioning, but not secondary conditioning.

Here we review the effects of immune activation primarily via lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, on hippocampal and non-hippocampal-dependent learning and memory. Rodent studies have found that LPS alters both the acquisition and consolidation of aversive learning and memory, such as those evoking evolutionarily adaptive responses like fear and disgust. The inhibitory effects of LPS on the acquisition and consolidation of contextual fear memory are discussed. LPS-induced alterations in the acquisition of taste and place-related conditioned disgust memory within bottle preference tasks and taste reactivity tests (taste-related), in addition to conditioned context avoidance tasks and the anticipatory nausea paradigm (place-related), are highlighted. Further, conditioned disgust memory consolidation may also be influenced by LPS-induced effects. Growing evidence suggests a central role of immune activation, especially pro-inflammatory cytokine activity, in eliciting the effects described here. Understanding how infection-induced immune activation alters learning and memory is increasingly important as bacterial and viral infections are found to present a risk of learning and memory impairment.

Although the evolutionary causes and consequences of pathogen avoidance have been gaining increasing interest, there has been less attention paid to the proximate neurobiological mechanisms. Animals gauge the infection status of conspecifics and the threat they represent on the basis of various sensory and social cues. Here, we consider the neurobiology of pathogen detection and avoidance from a cognitive, motivational and affective state (disgust) perspective, focusing on the mechanisms associated with activating and directing parasite/pathogen avoidance. Drawing upon studies with laboratory rodents, we briefly discuss aspects of (i) olfactory-mediated recognition and avoidance of infected conspecifics; (ii) relationships between pathogen avoidance and various social factors (e.g. social vigilance, social distancing (approach/avoidance), social salience and social reward); (iii) the roles of various brain regions (in particular the amygdala and insular cortex) and neuromodulators (neurotransmitters, neuropeptides, steroidal hormones and immune components) in the regulation of pathogen avoidance. We propose that understanding the proximate neurobiological mechanisms can provide insights into the ecological and evolutionary consequences of the non-consumptive effects of pathogens and how, when and why females and males engage in pathogen avoidance.

Anticipatory nausea is a classically conditioned response to cues (e.g. contexts) that have been previously paired with a nauseating stimulus, such as chemotherapy in humans. In rodents, anticipatory nausea can be modeled by pairing a novel context with lithium chloride (LiCl), which leads to conditioned disgust behaviours (such as gaping) when exposed to the context alone. Growing evidence suggests that selective immune activation attenuates various forms of learning and memory. The present study investigated the effects of the endotoxin lipopolysaccharide (LPS) on LiCl-induced anticipatory nausea across critical stages of associative memory including acquisition, consolidation, and extinction. Adult male Long Evans rats were subject to intraperitoneal (i.p.) LiCl (127 mg/kg) or vehicle control (NaCl) paired with a 30 min conditioning trial in a distinct context for a total of 4 trials. To study acquisition, rats were administered either LPS or NaCl (200 μg/kg, i.p.) 90 mins before the conditioning trials. To study consolidation, different rats were administered either LPS or NaCl (200 μg/kg, i.p.) immediately after the conditioning trials. These trials were followed by 4 drug-free extinction trials within the same context. LPS significantly reduced conditioned gaping behaviours by the 4th conditioning trial and on the 1st drug-free extinction trial when administered 90 mins before or immediately after the conditioning trials. LPS had no significant effect on extinction. The present study provides strong evidence for the attenuating effects of LPS exposure on the acquisition and consolidation of LiCl-induced anticipatory nausea.

Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.

Although pathogen threat affects social and sexual responses across species, relatively little is known about the underlying neuroendocrine mechanisms. Progesterone has been speculated to be involved in the mediation of pathogen disgust in women, though with mixed experimental support. Here we considered the effects of acute progesterone on the disgust-like avoidance responses of female mice to pathogen threat. Estrous female mice discriminated and avoided the urinary and associated odors of males subclinically infected with the murine nematode parasite, Heligmosomoides polygyrus. These avoidance responses were not significantly affected by pretreatment with progesterone. Likewise, brief (1 min) exposure to the odors of infected males attenuated the subsequent responses of females to the odors of the normally preferred unfamiliar males and enhanced their preferences for familiar males. Neither progesterone nor allopregnanolone, a central neurosteroid metabolite of progesterone, had any significant effects on the avoidance of unfamiliar males elicited by pre-exposure to a parasitized male. Progesterone and allopregnanolone, did, however, significantly attenuate the typical preferences of estrous females for unfamiliar uninfected males, suggestive of effects on social recognition. These findings with mice indicate that progesterone may have minimal effects on the responses to specific parasite threat and the expression of pathogen disgust but may influence more general social recognition and preferences.

Individuals pay attention to the social and mate decisions of others and use these to determine their own choices, displaying mate choice copying. The present study with deer mice, Peromyscus maniculatus, showed that females copied the odor preferences and appetitive components of the mate choice of other females. It was found that an association between male and female odors, which is indicative of the apparent interest expressed by a female in a male, enhanced the preference of another female for the odors of that male. This socially learned odor preference lasted for at least 24 h and extended to a preference for the actual male that was the odor source. Neither kinship nor prior familiarity with the female whose odor was presented had a significant influence on the degree of odor-based mate choice copying displayed. These findings show that female deer mice can engage in mate choice copying using the odor-based social interest and mate choice of other females.

Lithium chloride (LiCl) is an emetic drug that has been used to create animal models of anticipatory nausea and conditioned place aversion. In this study we examined escape behaviours from a context in which rats experienced the aversive effects of LiCl treatments. The experiment had two phases: acquisition of context conditioning, which consisted of pairing a distinct context with the pharmacological effects of a moderate dose of the toxin LiCl, and extinction of context conditioning, which consisted of placement in the distinct context in a drug free state. During context conditioning, 16 adult male Long-Evans rats were injected intraperitoneally with 96 mg/kg lithium chloride (LiCl; n = 8) or 0.9% saline (NaCl; n = 8) and placed individually in an automated locomotor activity apparatus for 30 min every other day for 4 days. During the extinction phase, rats were placed in the apparatus for 30 min every other day without injections during a 4 day extinction phase. A significant Drug x Trial interaction was found for the time spent in vertical position in the open field apparatus during trials 1-3 of the extinction phase. The LiCl treated rats exhibited significantly increased rearing behavior, relative to the control rats, indicative of conditioned aversion. The results of this study suggest that escape behavior (vertical activity) occurs in rats experiencing the aversive conditioned effects of LiCl in a distinct context. In the context of current theoretical accounts, the LiCl-conditioned increase in apparent escape behaviors can be considered a reflection of anticipatory nausea.

All animals are under the constant threat of attack by parasites. The mere presence of parasite threat can alter behavior before infection takes place. These effects involve pathogen disgust, an evolutionarily conserved affective/emotional system that functions to detect cues associated with parasites and infection and facilitate avoidance behaviors. Animals gauge the infection status of conspecific and the salience of the threat they represent on the basis of various sensory cues. Odors in particular are a major source of social information about conspecifics and the infection threat they present. Here we briefly consider the origins, expression, and regulation of the fundamental features of odor mediated pathogen disgust in rodents. We briefly review aspects of: (1) the expression of affective states and emotions and in particular, disgust, in rodents; (2) olfactory mediated recognition and avoidance of potentially infected conspecifics and the impact of pathogen disgust and its' fundamental features on behavior; (3) pathogen disgust associated trade-offs; (4) the neurobiological mechanisms, and in particular the roles of the nonapeptide, oxytocin, and steroidal hormones, in the expression of pathogen disgust and the regulation of avoidance behaviors and concomitant trade-offs. Understanding the roles of pathogen disgust in rodents can provide insights into the regulation and expression of responses to pathogens and infection in humans.

Risk-taking behaviors are a primary contributor to elevated adolescent injury and mortality. Locomotor and anxiety-like behaviors in rodents have been used to examine risk-taking. Here, we examined risk-taking behavior (i.e., changes in locomotor and anxiety-like behaviors) from early to late adolescence and adulthood in male and female rats in the open-field (OF) apparatus and the light-dark (LD) test. We also examined whether these behaviors are affected by an early adolescent immune stressor, lipopolysaccharide (LPS). Long-Evans male and female rats were injected with LPS (200 μg/kg) or vehicle control in early adolescence (postnatal day [PND] 30 and 32). Anxiety-like behavior and locomotor activity were measured in early (PND 38-40), late adolescence (PND 50), and adulthood (PND 88 and 98) in the OF and in early adolescence (PND 42) and adulthood (PND 90) in the LD test. Early and late adolescent rats displayed significantly greater locomotor and anxiety-like behaviors than adult rats in the OF and LD test. Sex differences were also found, with adolescent and adult females displaying greater locomotor and anxiety-like behaviors than male rats in the OF and LD tests. LPS administered two times in early adolescence did not have a significant impact on either locomotor or anxiety-like behaviors suggesting minimal impact of the immune stressor.

Pathogen threat affects social preferences and responses across species. Here we examined the effects of social context and the infection status of conspecific females and males on the social and mate responses of female mice. The responses of female mice to males were rapidly affected by the presence of infected female con specifics and infected males. In mice odor cues drive appetitive and aversive social and mate responses. Brief (1 min) exposure to the fresh urinary odors of females infected with the murine nematode parasite, Heligmosomoides polygyrus, attenuated the responses of other uninfected females to the odors of naturally preferred unfamiliar males and enhanced their preferences for familiar males. Likewise exposure to the odors of a male either infected with H. polygyrus or treated with the bacterial endotoxin, lipopolysaccharide, reduced the responses of females to the odors of unfamiliar males. In addition, females displayed an avoidance of, and discrimination against, male mice whose odors had been associated with that of an infected female ("guilt by association") and a preference for the odors associated with an uninfected female ("mate copying"). These shifts in preferences for female associated male odors were attenuated in a dose-related manner by pre-treatment with the oxytocin receptor antagonist, L-368,899. These findings show that social information associated with the infection status of conspecifics can rapidly bias the mate preferences of female mice in an oxytocin receptor dependent manner.

Propionic acid (PPA) is a dietary short chain fatty acid and an enteric bacterial metabolite. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes similar to those seen in autism spectrum disorders (ASD), including perseveration. The effects of ICV infusions of PPA on spatial cognition were examined by giving rats infusions of either PPA (0.26 M, pH 7.4, 4 μl/infusion) or phosphate-buffered saline (PBS, 0.1 M) twice a day for 7 days. The rats were then tested in the Morris water maze (MWM) for acquisition of spatial learning. After a recovery period of 1 week of no treatment, the rats were then tested for reversal of spatial learning in the MWM. PPA-treated rats showed impaired spatial learning in the maze, relative to controls, as demonstrated by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. After a recovery period of 1 week of no treatment, these animals exhibited normal spatial reversal learning indicating that the behavioral cognitive deficits caused by PPA seem to be reversible.