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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 (e.g. 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 (127mg/kg) or vehicle control (NaCl) paired with a 30min conditioning trial in a distinct context for a total of 4 trials. To study acquisition, rats were administered either LPS or NaCl (200μg/kg, i.p.) 90mins before the conditioning trials. To study consolidation, different rats were administered either LPS or NaCl (200μg/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 4

Highlights • Pathogen disgust is an evolutionarily conserved affective system for the recognition and avoidance of infection threat. • Pathogen disgust entails a number of fundamental features (valence, scalability, flexibility, persistence). • Pathogen disgust in rodents in rodents is odor mediated. • Pathogen disgust involves trade-offs between the acquisition of social information/social interaction and infection. • Pathogen disgust involves a number of neuromodulatory systems., 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.

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.

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.

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 conspecifics 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.

Early life immune challenges are risk factors for neurodevelopmental disorders. In adolescence, they elicit behavioral symptoms that resemble clinical disorders. Stressors during this time may alter signaling from the gut microbiome, which increases the risk for psychiatric disorders. It was hypothesized that adolescent immune challenges may interact with a gut bacterial product, the short-chain fatty acid, propionic acid (PPA), to potentiate symptoms of anxiety and sensory abnormality. The present study investigated the effects of repeated lipopolysaccharide (LPS) exposure during early adolescence, on the behavioral effects of PPA in late adolescence and adulthood. Male adolescent rats were injected with LPS (0.2 mg/kg i.p.) or the vehicle on postnatal days (P) 28, P30, P32, and P34. They were later administered either PPA (500 mg/kg i.p.) or the vehicle during late adolescence on P40 and P43, and were subsequently tested on the light-dark anxiety test and acoustic startle response, respectively. In adulthood, the rats were again injected with PPA or the vehicle and tested on the light-dark and acoustic startle tasks on P74 and P77. The results of this study showed that LPS and PPA both decreased locomotor activity. PPA reduced vertical activity, percent prepulse inhibition, and acoustic startle response magnitude. LPS increased anxiogenic behaviors and induced a delayed increase in acoustic startle response magnitude in adulthood. Although no LPS and PPA interactions were found, the results of this study suggest that early adolescent immune activation can induce long-term behavioral changes that resemble the complex phenotypes of clinical disorders.

It is becoming evident than the adolescent period is a sensitive period in stress response programming. Stressors during this time may alter signaling from the gut microbiome, which has been shown to increase the risk for psychiatric disorders. It was hypothesized that adolescent stressors may potentiate the symptoms of anxiety and sensory abnormalities induced by a gut bacterial product, the short-chain fatty acid, propionic acid (PPA). The present study investigated the effects of repeated predator odor exposure during early adolescence on male rats administered PPA in late adolescence and adulthood on a behavioral test battery. Male adolescent Long-Evans rats were repeatedly exposed to a worn or unworn cat collar stimulus in early adolescence on postnatal days (P) 28, P30, P32, and P34. They were administered either PPA (500 mg/kg i.p.), or its vehicle in late adolescence on P40 and P43, and were subsequently tested on the light-dark anxiety task and acoustic startle task, respectively. In adulthood, the rats were again injected with PPA or its vehicle on P74 and P77, and subsequently tested on the light-dark apparatus and acoustic startle task, respectively. The repeated predator odor exposure was aversive and produced long-term anxiogenic effects as measured by the light-dark apparatus. PPA decreased activity and percent prepulse inhibition of the acoustic startle response, with its effects on vertical activity, a putative measure of escape behavior, being potentiated by prior predator stress. PPA's effects in adulthood were diminished in comparison to adolescence. These results suggest the importance of evaluating the effects of early adolescent stress on subsequent environmental insults on the development of behavioral abnormalities.

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.

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.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by cognitive and sensorimotor deficits, among others. Hypo-sensitivity and hyper-sensitivity to different stimuli within the same sensory modality, a prominent symptom of ASD, can be assessed by acoustic startle response (ASR) and prepulse inhibition (PPI). Propionic acid (PPA) is a short-chain fatty acid and a by-product of the human gut microbiome. Rodents treated with PPA has been found to produce ASD-related behavioral abnormalities, gastrointestinal discomfort, and conditioned aversions. The present study examined ASR and PPI in adult male rats treated systemically (intraperitoneal injections) with two different doses of PPA. A single injection of PPA produced significant dose-dependent reductions in startle response magnitude relative to control rats. However, PPA-treated rats did not show significant sensorimotor gating abnormalities relative to controls, based on the PPI measures. These findings add to the growing body of evidence supporting the validity of the PPA rodent model of ASD.

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.

This study examined sex differences in the establishment of lithium chloride (LiCl)-induced conditioned disgust behavior (anticipatory nausea) to a distinct context in adult male and female rats. Also examined were potential sex differences in response to treatment with the bacterial endotoxin, lipopolysaccharide (LPS), and its effect on learning and memory. Twenty-nine male and 31 female naive Long-Evans rats were injected (intraperitoneally; i.p.) with either 200 μg/kg LPS or 0.9% (NaCl), 90 min prior to i.p. injections of either 128 mg/kg LiCl or 0.9% NaCl, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each subject was re-exposed to the context on a drug-free test day where orofacial and somatic behaviors were recorded. Results showed that LiCl-treated females conditioned stronger disgust reactions, relative to LiCl-treated males, as evidenced by significantly higher frequencies of conditioned “gaping” behavior (p

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 pre-treatment 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.

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by abnormal social interactions, impaired language, and stereotypic and repetitive behaviours. Among genetically susceptible subpopulations, gut and dietary influences may play a role in etiology. Propionic acid (PPA), produced by enteric gut bacteria, crosses both the gut-blood and the blood-brain barrier. Previous research has demonstrated that repeated intracerebroventricular (ICV) infusions of PPA in adult rats produce behavioural and neuropathological changes similar to those seen in ASD patients, including hyperactivity, stereotypy, and repetitive movements. The current study examined dose and time related changes of exploratory and repetitive behaviours with the use of the hole-board task. Adult male Long-Evans rats received ICV infusions twice a day, 4 h apart, of either buffered PPA (low dose 0.052 M or high dose 0.26 M, pH 7.5, 4 μL/infusion) or phosphate buffered saline (PBS, 0.1 M) for 7 consecutive days. Locomotor activity and hole-poke behaviour were recorded daily in an automated open field apparatus (Versamax), equipped with 16 open wells, for 30 min immediately after the second infusion. In a dose dependent manner PPA infused rats displayed significantly more locomotor activity, stereotypic behaviour and nose-pokes than PBS infused rats. Low-dose PPA animals showed locomotor activity levels similar to those of PBS animals at the start of the infusion schedule, but gradually increased to levels comparable to those of high-dose PPA animals by the end of the infusion schedule, demonstrating a dose and time dependent effect of the PPA treatments.

The role of the gut microbiome and its enteric metabolites, such as short-chain fatty acids (SCFAs), in the etiology of autism spectrum disorders (ASDs) has recently received increased attention. Of particular interest has been the SCFA, propionic acid (PPA). Several different rodent models have been developed using PPA treatment to examine behaviors of relevance to ASD. The effects of systemic (intraperitoneal, i.p.) administration of PPA on social behavior, anxiety-related behavior, and locomotor activity in juvenile male rats (age 35 days) were examined in this study. Rats received seven i.p. injections of buffered PPA (500 mg/kg) or phosphate-buffered saline. Behavior was video-recorded during social interaction in a large open field (first four injections) or assessed in an automated activity system (individual animals, last three injections). PPA treatment significantly reduced social interaction, increased anxiety-related behavior, and produced hypoactivity and increased abnormal motor movements. These findings suggest that PPA alters behaviors of relevance to ASD in juvenile rats. These results contribute to the behavioral validity of the rodent model of ASD with systemic PPA treatment.

The role of sex and estrous phase in the conditioning of toxin-induced disgust reactions (anticipatory nausea) to a novel context were examined in adult rats. Conditioned oral gaping responses have been shown to be a reliable index of nausea in rats. In Experiment 1 male and female rats were injected with LiCl (0, 64, 96, or 128 mg/kg) on each of 4 conditioning trials (72 h apart) and then placed in a novel context for 30 min. 72 h following the last conditioning trial each animal was re-exposed to this context in a toxin-free state for 10 min and disgust responses (gapes, forelimb flails, chin rubs, and paw treads) were scored from video records. A significant toxin dose-related monotonic increase in conditioned gaping showed a significantly greater increase in females, relative to males. In Experiment 2 female rats were conditioned, using the same paradigm, on either diestrus or proestrus days (trials 96 h apart) with LiCl (96 mg/kg) or saline control injections. Disgust responses were recorded on each of the 4 conditioning trials and a toxin-free test trial. Significant increases in conditioned disgust were obtained on proestrus relative to diestrus days on the toxin-free test trial. However no significant estrous cycle differences in disgust responding were obtained on the acquisition trials. The sex difference in conditioned gaping and the increased conditioned disgust responses in proestrus suggest that increased levels of estradiol likely enhance the strength of the association of the toxin-induced nausea with the novel context in rats.

Although lipopolysaccharide (LPS) is widely used to examine immune behavior relationships there has been little consideration of the effects of low doses and the roles of sensitization and, or tolerance. Here low doses of LPS (1.0, 5.0 and 25.0 μg/kg) were peripherally administered to male mice on Days 1, 4, 28 and 32 after a baseline recording of anxiety-like behaviors in an automated light–dark apparatus (total time in the light chamber, number of light–dark transitions, nose pokes into the light chamber). LPS at 1.0 μg/kg, while having no significant effects on anxiety-like behaviors in the light–dark test on Days 1 and 4, displayed sensitization with the mice exhibiting significantly enhanced anxiety-like responses on Days 28 and 32. LPS at 5.0 μg/kg had no consistent significant effects on anxiety-like behavior on Days 1 and 4, with sensitization and enhanced anxiety-like behaviors on Day 28 followed by tolerance on Day 32. LPS at 25 μg/kg significantly enhanced anxiety-like behaviors on Day 1, followed by tolerance on Day 4, which was not evident by Day 28 and re-emerged on Day 32. There was a similar overall pattern of sensitization and tolerance for LPS-induced decreases in locomotor activity in the safe dark chamber, without, however, any significant effects on activity in the riskier light chamber. This shows that low doses of LPS induce anxiety-like behavior and these effects are subject to sensitization and tolerance in a dose, context, and time related manner.

Potential environmental risk factors for autism spectrum disorders (ASD) include viral/bacterial infection and an altered microbiome composition. The present study investigated whether administration of immune and gastrointestinal factors during gestation and early life altered startle response and prepulse inhibition in adolescent offspring using lipopolysaccharide (LPS), a bacterial mimetic, and propionic acid (PPA), a short chain fatty acid and metabolic product of antibiotic resistant enteric bacteria. Pregnant Long-Evans rats were injected once a day with PPA (500 mg/kg SC) on G12-16, LPS (50 μg/kg SC) on G15 and G16, or vehicle control on G12-16 or G15-16. Male and female offspring were injected with PPA (500 mg/kg SC) or vehicle twice a day, every second day from postnatal days 10-18. Acoustic startle and prepulse inhibition was measured on postnatal days 45, 47, 49, and 51. Prenatal and postnatal treatments altered startle behavior in a sex-specific manner. Prenatal LPS treatment produced hyper-sensitivity to acoustic startle in males, but not females and did not alter prepulse inhibition. Subtle alterations in startle responses that disappeared with repeated trials occurred with prenatal PPA and postnatal PPA treatment in both male and female offspring. Prenatal PPA treatment decreased prepulse inhibition in females, but not males. Lastly, females receiving a double hit of PPA, prenatal and postnatal, showed sensitization to acoustic startle, providing evidence for the double hit hypothesis. The current study supports the hypotheses that immune activation and metabolic products of enteric bacteria may alter development and behavior in ways that resemble sensory abnormalities observed in ASD.

There is mounting evidence that pathogen threat affects social preferences and responses. In humans, the presence of strangers also elicits heightened sensitivity to pathogen threat, promoting ‘in-group’ bias and ‘out-group’ avoidance. Whether or not a similar effect of social context on responses to pathogen threat occurs in nonhuman animals is unclear. Here we show that the responses of female laboratory mice, Mus muculus, to males are also rapidly affected by the presence of unfamiliar or infected males. In female mice, where odour cues drive appetitive and aversive social responses, brief (1 min) exposure to the urinary odours of an unfamiliar male led to females subsequently discriminating more strongly against the odours of males subclinically infected with the murine nematode parasite, Heligmosomoides polygyrus. Likewise, brief exposure to the odours of infected males attenuated the responses of females to the odours of the normally preferred unfamiliar males and enhanced their preferences for familiar males. These findings are consistent with the concept of ‘assortative’ sociality, whereby the presence of pathogen threat and unfamiliar individuals biases female preferences for uninfected and familiar individuals (‘in-group’ preference and, in human terms, ‘ethnocentrism’) and leads to the avoidance of unfamiliar individuals (‘out-group’ avoidance and ‘xenophobia’). Hence, as in humans, social information associated with infection can rapidly bias the social preferences of female mice. These rapid shifts in social preferences can have implications for our understanding of the evolution of social interactions and group composition.

Emerging evidence suggests that the gut microbiome plays an important role in immune functioning, behavioral regulation and neurodevelopment. Altered microbiome composition, including altered short chain fatty acids, and/or immune system dysfunction, may contribute to neurodevelopmental disorders such as autism spectrum disorders (ASD), with some children with ASD exhibiting both abnormal gut bacterial metabolite composition and immune system dysfunction. This study describes the effects of prenatal propionic acid (PPA), a short chain fatty acid and metabolic product of many antibiotic resistant enteric bacteria, and of prenatal lipopolysaccharide (LPS), a bacterial mimetic and microbiome component, on social behavior in male and female neonatal, adolescent and adult rats. Pregnant Long-Evans rats were injected once a day with either a low level of PPA (500 mg/kg SC) on gestation days G12-16, LPS (50 μg/kg SC) on G12, or vehicle control on G12 or G12-16. Sex- and age-specific, subtle effects on behavior were observed. Both male and female PPA treated pups were impaired in a test of their nest seeking response, suggesting impairment in olfactory-mediated neonatal social recognition. As well, adolescent males, born to PPA treated dams, approached a novel object more than control animals and showed increased levels of locomotor activity compared to prenatal PPA females. Prenatal LPS produced subtle impairments in social behavior in adult male and female rats. These findings raise the possibility that brief prenatal exposure to elevated levels of microbiome products, such as PPA or LPS, can subtly influence neonatal, adolescent and adult social behavior.

Disgust has been proposed to have evolved as a means to rid the body and mouth of noxious substances and toxins, as well as to motivate and facilitate avoidance of contact with disease-causing organisms and infectious materials. Nonemetic species, such as the rat, show distinctive facial expressions, including the gaping reaction, indicative of nausea-based disgust. These conditioned disgust responses can be used to model anticipatory nausea in humans, which is a learned response observed following chemotherapy treatment. As social factors play a role in the modulation and expression of conditioned disgust responses in rats, and the nonapeptide, oxytocin (OT), is involved in the modulation of social behavior, the present study examined the effects of an OT antagonist, L-368 899, on the development and expression of socially mediated conditioned disgust in male rats. When administered 10 min before testing in a distinct context (different from the original conditioning context), L-368 899 (5 mg/kg) significantly decreased gaping behavior in rats that were conditioned with a social partner. LiCl-treated rats administered L-368 899 before testing also showed decreased social initiations toward their social partner. These findings suggest that OT may play a role in the modulation and expression of socially mediated conditioned disgust in rats.

Neonatal administration of the bacterial cell wall component, lipopolysaccharide (LPS) has been shown to alter a variety of behavioural and physiological processes in the adult rat, including altering adult anxiety-like behaviour. Research conducted to date, however, has produced conflicting findings with some results demonstrating increases in adult anxiety-like behaviour while others report decreases or no changes in anxiety-like behaviour. Thus, the current study conducted additional evaluation of the effects of neonatal LPS exposure on adult anxiety-like behaviours by comparing the behavioural outcomes in the more traditional light–dark test, together with the less common hyponeophagia to sucrose solution paradigm. Male and female Long–Evans rats were treated systemically with either LPS (50 μg/kg) or saline (0.9%) on postnatal days 3 and 5. Animals were then tested in the light–dark apparatus on postnatal day 90 for 30 min. Next, following 5 days of habituation to distilled water delivery in Lickometer drinking boxes, animal were tested for neophagia to a 10% sucrose solution (0.3 M) for 30 min daily on postnatal days 96 and 97. In the light–dark test, neonatal LPS treatment decreased adult anxiety-like behaviour in females, but not males. In contrast, neonatal exposure to LPS did not influence adult anxiety-like behaviour as measured by hyponeophagia, but altered the licking patterns of drinking displayed towards a novel, palatable sucrose solution in adult males and females, in a manner that may reflect a decrease in situational anxiety. The current study supports the idea that neonatal LPS treatment results in highly specific alterations of adult anxiety-like behaviour, the nature of which seems to depend not only on the measure of anxiety behaviour used, but also possibly, on the degree of anxiety experienced during the behavioural test.

This study examined the effects of the bacterial endotoxin, lipopolysaccharide (LPS), on the establishment of anticipatory nausea and conditioned taste avoidance in a simultaneous conditioning paradigm using an intravascular/intraperitoneal saccharin taste. 83 naive adult male Long-Evans rats were injected (intraperitoneal) with either 200 μg/kg LPS or 0.9% saline (NaCl), 90 min prior to ip treatment with either 64 mg/kg LiCl, 64 mg/kg LiCl + 2.0% saccharin, 0.9% NaCl, or 0.9% NaCl + 2.0% saccharin, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day where orofacial responding was recorded. The next day, animals received a 24 h 2-bottle preference test with a choice between water and a palatable 0.2% saccharin solution. Results showed that LPS exposure, prior to LiCl or LiCl + Saccharin treatment, inhibited the establishment of anticipatory nausea, as evidenced by significantly lower conditioned gaping frequencies relative to animals pre-treated with NaCl followed by LiCl or LiCl + Saccharin. LPS pre-treatment also inhibited the formation of LiCl-induced taste avoidance, as evidence by significantly higher saccharin preferences in Group LPS–LiCl + Saccharin relative to Group NaCl–LiCl + Saccharin. The results of the current study provide additional evidence for the deleterious effects of LPS on learning and memory in aversive conditioning.

The effects of the bacterial endotoxins, lipopolysaccharide (LPS) and muramyl dipeptide (MDP; Experiment 1), and the viral mimetic, polyinosinic: polycytidylic acid (poly I:C; Experiment 2), on the acquisition of “conditioned gaping” behavior in the rodent model of LiCl-induced anticipatory nausea were examined. Experimentally naive adult male Long–Evans rats were injected (intraperitoneal, ip) with either 200 μg/kg LPS, 1.6 mg/kg MDP, or 0.9% saline (Experiment 1), or 4.0 mg/kg poly I:C or 0.9% saline (Experiment 2), 90 min prior to treatment with 127 mg/kg LiCl or saline control and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). On a drug-free test day (72 h following conditioning day 4), each animal was re-exposed to the context for 10 min, and orofacial and aversive behavioral responses were video recorded and analyzed. The results showed that pre-treatment with LPS, MDP (Experiment 1), or poly I:C (Experiment 2) prior to LiCl + context conditioning significantly impaired the establishment of conditioned gaping behavior, thus blocking the acquisition of anticipatory nausea. Results varied in regards to peripheral acute-phase response sickness behaviors, with significantly reduced weight loss in LPS-treated animals, less robust weight loss in poly I:C-treated animals, and no significant reductions in body weight in MDP-treated animals. The learning impairments observed in the current study suggest that endotoxin treatment with bacterial and viral endotoxin may have stronger central effects on learning and memory behavior, relative to peripheral effects on body weight and other sickness-related responses.

This study examined whether rats can simultaneously learn to associate lithium chloride (LiCl)-induced nausea with both contextual and intravascular taste cues. During the conditioning phase (4 days, 72h apart), 32 male Long Evans rats were injected intraperitoneally with either isotonic saline (NaCl), lithium chloride (LiCl, 127mg/kg), saline plus 2% saccharin (NaCl+Saccharin), or lithium chloride plus 2% saccharin (LiCl+Saccharin) immediately prior to a 30min exposure to a novel context. 72h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day. The next day, animals received a 24h 2-bottle preference test with a choice between water and a palatable saccharin solution. Results showed that animals treated with LiCl during conditioning, with or without saccharin, displayed significantly higher levels of conditioned gaping responses, indicative of nausea, upon re-exposure to the context, relative to NaCl and NaCl+Saccharin controls. Animals administered LiCl+Saccharin during conditioning also displayed significant conditioned taste avoidance to the saccharin solution during the two bottle choice test. These results indicate that systemic administration (intraperitoneal) of a LiCl+Saccharin solution is effective in simultaneously conditioning toxin elicited nausea to both internal (taste) and external (context) cues.

Acute administration of corticosterone has been shown to facilitate learning in a number of associative paradigms, including LiCl-induced conditioned taste aversion learning. The present study examined the effects of acute corticosterone on LiCl-induced conditioned anticipatory nausea in male rats. Anticipatory nausea is produced by pairing a novel distinctive context with the nausea-inducing effects of a toxin, such as LiCl. Following a number of pairings of the context with the effects of the toxin, rats will display a distinctive conditioned "gaping" response when placed into the context in a drug free state. Adult male Long-Evans rats were injected (intraperitoneal, ip) with a LiCl solution (32, 64, or 128 mg/kg, 0.15M) or saline (NaCl, 0.15 M) followed 10 min later by either corticosterone (5 mg/kg) or β-cyclodextrin vehicle (45%) prior to placement in a distinctive context on four conditioning days (72 h apart) for 30 min. On the conditioning test day rats were placed in the distinctive context in a drug-free state and orofacial and somatic responses were video-recorded for 10 min. Gaping responses increased with increasing doses of LiCl in a linear fashion (P0.01) but were not significantly influenced by the corticosterone treatment. In contrast, significant increases in the frequency of conditioned spontaneous orofacial behaviors on the drug free test day were produced by the corticosterone treatment during the acquisition phase, whereas LiCl treatment during acquisition had no significant effect on these behaviors. Thus, acute corticosterone did not alter the strength of conditioning of anticipatory nausea in rats.

The vestibular system has been suggested to participate in spatial navigation, a function ascribed to the hippocampus. Vestibular stimulation during spatial navigation activates a hippocampal theta rhythm (4–10 Hz), which may enhance spatial processing and motor response. We hypothesize that a cholinergic, atropine-sensitive theta is generated during passive whole-body rotation in freely behaving rats. Hippocampal EEGs were recorded by implanted electrodes in CA1 while rats were rotated on a vertical axis, for a minute or longer, at different angular velocities. Rotation induced a continuous hippocampal theta rhythm while the rat was immobile, in both light and dark conditions. Theta peak frequency showed a significant increase during high (50–70 rpm) as compared with a lower (20–49 rpm) rotational velocity. Rotation-induced theta was abolished by muscarinic receptor antagonist atropine sulfate (50 mg/kg i.p.) but not by atropine methyl nitrate (50 mg/kg i.p.), which did not pass the blood-brain barrier. Theta was attenuated in rats in which cholinergic neurons in the medial septum (MS) were lesioned with 192 IgG-saporin (0.14 μg in 0.4 μl), as confirmed by depletion of MS cells immunoreactive to choline acetyltransferase and an absence of acetylcholinesterase staining in the hippocampus. Bilateral lesion of the vestibular receptors by sodium arsanilate (30 mg in 0.1 ml, intratympanically) also attenuated the rotation-induced theta rhythm. In intact rats, field excitatory postsynaptic potentials (fEPSPs) in CA1 evoked by commissural stimulation were smaller during walking or rotation as compared with during immobility. Modulation of fEPSP was absent following atropine sulfate in intact rats and in 192 IgG-saporin lesion rats. In summary, this is the first report of a continuous atropine-sensitive hippocampal theta in the rat induced by vestibular stimulation during rotation, and accompanied by cholinergic modulation of hippocampal synaptic transmission. Vestibular-activated septohippocampal cholinergic activity could be an important component in sensorimotor processing and spatial memory. © 2011 Wiley Periodicals, Inc.

Recent evidence suggests that a variety of environmental factors, including dietary and gastrointestinal agents, may contribute to autism spectrum disorders (ASD). Here we administered propionic acid (PPA), a short chain fatty acid that is used as a food preservative and also is a metabolic end-product of enteric bacteria in the gut, to adolescent (41 ± 4 days) male rats in a study of restricted/repetitive behavior, social behavior, and cognition. The goal was to further evaluate the effects of PPA in young rodents. PPA (4 μl of 0.26 M solution) was administered intracerebroventricularly prior to each behavioral test. Rats treated with PPA displayed restricted behavioral interest to a specific object among a group of objects, impaired social behavior, and impaired reversal in a T-maze task compared to controls given phosphate buffered saline. Immunohistochemical analysis of brain tissue from PPA rats revealed reactive astrogliosis and activated microglia, indicating an innate neuroinflammatory response. These findings are consistent with our earlier findings of ASD-relevant behavioral and brain events in adult rats given PPA, and support further study of effects of PPA in young rodents by establishing similar effects in adolescent animals.

Disgust can be thought of as an affective system that has evolved to detect signs of pathogens, parasite and toxins as well as to stimulate behaviors that reduce the risk of their acquisition. Disgust incorporates social cognitive mechanisms to regulate exposure to and, or anticipate and avoid exposure to pathogens and toxins. Social cognition entails the acquisition of social information about others (ie, social recognition) and from others (ie, social learning). This involves recognizing and assessing other individuals and the pathogen/parasite/contamination/toxin threat they pose and deciding about when and how to interact with and, or avoid them. Social cognition provides a frame-work for examining the expression of disgust and the associated neurobiological mechanisms. Here, we briefly consider the relations between social cognition and pathogen/parasite/toxin avoidance behaviors. We briefly discuss aspects of: (1) the odor mediated social recognition of actual and potentially infected individuals and the impact of parasite/pathogen threat on disgust mate and social partner choice; (2) the roles of "out-groups" (strangers, unfamiliar individuals) and "in-groups" (familiar individuals) in the expression of disgust and pathogen avoidance behaviors; (3) individual and social learning of disgust and empathy for disgust; (4) toxin elicited disgust and anticipatory disgust; (5) the neurobiological mechanisms, and in particular the roles of the nonapeptide, oxytocin and estrogenic mechanism associated with social cognition and the expression of disgust. These findings on the social neuroscience of disgust have a direct bearing on our understanding of the roles of disgust in shaping human and nonhuman social behavior.

BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists/inverse agonists, potentiate toxin-induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB1 receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist. EXPERIMENTAL APPROACH The conditioned gaping model of nausea in rats was used to compare the CB1 receptor antagonist/inverse agonist, AM251, and the CB1 receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl-induced gaping in this model was also evaluated. KEY RESULTS At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg·kg−1) potentiated LiCl-induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg·kg−1 of AM6545 and AM6527 neither potentiated LiCl-induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 µg) or the 4th ventricle (2.5, 12.5 and 125 µg) did not potentiate LiCl-induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test. CONCLUSIONS AND IMPLICATIONS Inverse agonism, but not neutral antagonism, of CB1 receptors potentiated toxin-induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB1 receptors, located distal to the cerebral ventricles.

Estrogen receptor activation has been shown to reduce body weight and produce a conditioned reduction in food intake in male rats that is putatively mediated by estradiol's suggested aversive effects. Evidence has shown that the selective estrogen receptor modulator tamoxifen used in the prevention and treatment of breast cancer may also produce a change in food intake and body weight, which are known to impact cancer development and survival. The purpose of the present study was to examine whether tamoxifen produces a conditioned reduction in intake similar to estradiol by producing a conditioned aversion. A one bottle lickometer test was used to examine conditioned changes in sucrose drinking, while the taste reactivity test was used to measure rejections reactions, which serve to index aversion in rats. A backward conditioning procedure that consisted of 3 conditioning days and one vehicle test day was used to examine for conditioned changes in 0.3 M sucrose intake and taste reactivity. Our results show that tamoxifen produced a conditioned reduction in sucrose drinking in a one bottle fluid intake test that was similar to the effects produced by estradiol (positive control); however, no active rejections reactions were produced by either tamoxifen (1 and 10 mg/kg) or estradiol. The present results suggest that tamoxifen, at the doses used in the present study, acts as an estrogen receptor agonist to regulate food intake and that the conditioned reduction in intake produced by tamoxifen and estradiol reflects conditioned taste avoidance rather than conditioned taste aversion.

Propionic acid (PPA) is a dietary short chain fatty acid and a metabolic end-product of enteric bacteria. Intracerebroventricular (ICV) injections of PPA can result in brain and behavioral abnormalities in rats similar to those seen in humans suffering from autism. To evaluate cognition and sensorimotor ability in the PPA model, male Long-Evans hooded rats received ICV injection of PPA or control compounds prior to behavioral testing in water maze and beam tasks. Compared to controls, PPA-treated rats were impaired in the water maze task as indicated by an unusual pattern of mild or no impairment during spatial acquisition training, but marked impairment during spatial reversal training. PPA-treated rats were also impaired on the beam task. Neuropathological analysis from PPA-treated rats revealed an innate neuroinflammatory response. These findings add to evidence that PPA can change the brain and behavior in the laboratory rat consistent with symptoms of human autism.

Aims Estrogen receptor activation has been shown to reduce body weight and produce conditioned taste avoidance (CTA) when estradiol administration is paired with a novel tastant. This study determined if the selective estrogen receptor modulators tamoxifen and raloxifene, which effectively prevent and treat breast cancer, can induce a CTA and alter body weight in ovariectomized (OVX)-female rats. Main methods During conditioning, OVX-female rats were injected with tamoxifen, raloxifene, 17β-estradiol or vehicle, or were uninjected, prior to drinking 0.3 M sucrose in a lickometer. Immediately following sucrose access, alterations in locomotor activity and thigmotaxis (anxiety) were assessed in an open field apparatus. Conditioned drug effects on drinking, locomotor activity and anxiety were examined on a separate test day. Key findings Our results suggest that both tamoxifen and raloxifene produce CTA that is similar to that produced by estradiol. Both the number and size of bursts of licking were significantly reduced, as well as body weight gain, in OVX-female rats treated with tamoxifen or raloxifene. Significance The results of the present study suggest that tamoxifen and raloxifene may have the potential to produce CTA in breast cancer patients receiving chemoprevention care.

Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.

Innate neuroinflammatory changes, increased oxidative stress and disorders of glutathione metabolism may be involved in the pathophysiology of autism spectrum disorders (ASD). Propionic acid (PPA) is a dietary and gut bacterial short chain fatty acid which can produce brain and behavioral changes reminiscent of ASD following intraventricular infusion in rats. Adult Long-Evans rats were given intraventricular infusions of either PPA (.26M, 4µl animal -1 ) or phosphate buffered saline (PBS) vehicle, twice daily for 7 days. Immediately following the second daily infusion, the locomotor activity of each rat was assessed in an automated open field (Versamax) for 30 min. PPA-treated rats showed significant increases in locomotor activity compared to PBS vehicle controls. Following the last treatment day, specific brain regions were assessed for neuroinflammatory or oxidative stress markers. Immunohistochemical analyses revealed reactive astrogliosis (GFAP), activated microglia (CD68, Iba1) without apoptotic cell loss (Caspase 3' and NeuN) in hippocampus and white matter (external capsule) of PPA treated rats. Biomarkers of protein and lipid peroxidation, total glutathione (GSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) were examined in brain homogenates. Some brain regions of PPA treated animals (neocortex, hippocampus, thalamus, striatum) showed increased lipid and protein oxidation accompanied by decreased total GSH in neocortex. Catalase activity was decreased in most brain regions of PPA treated animals suggestive of reduced antioxidant enzymatic activity. GPx and GR activity was relatively unaffected by PPA treatment while GST was increased, perhaps indicating involvement of GSH in the removal of PPA or related catabolites. Impairments in GSH and catalase levels may render CNS cells more susceptible to oxidative stress from a variety of toxic insults. Overall, these findings are consistent with those found in ASD patients and further support intraventricular PPA administration as an animal model of ASD.

Research has shown that acute immune activation during the early postnatal period with the Gram-negative endotoxin, lipopolysaccharide (LPS), alters a variety of physiological and behavioural processes in the adult animal. For example, neonatal LPS exposure affects disease susceptibility later in life, though these effects appear to be modulated by time of exposure, sex, and immune stimulus. The current study examined sex differences in the effect of neonatal LPS treatment on the locomotor activity response to adult LPS administration. Male and female Long-Evans rats were treated systemically with either LPS (50 microg/kg) or saline (0.9%) on postnatal days 3 and 5. Later in adulthood (postnatal day 92), all animals were subjected to an adult LPS challenge and were injected (i.p.) with 200 microg/kg LPS. Two hours after injection, animals were placed in a non-novel open-field and locomotor activity was assessed for 30 min. Body weights were determined both at the time of injection and 24h later to examine LPS-induced weight loss. Adult males treated neonatally with LPS exhibited significantly less horizontal and vertical activity in response to the LPS challenge relative to males treated neonatally with saline. This effect was not observed in females. Thus, the current study provides important evidence of sexual dimorphism in the long-term effects of neonatal LPS exposure on the responses to an adult homotypic immune challenge in rats. These findings have potential clinical significance given that neonatal exposure to pathogens is a fairly common occurrence and Gram-negative bacteria are a common cause of neonatal bacterial infections.

Administration of the bacterial cell wall component, lipopolysaccharide (LPS), stimulates the immune and endocrine systems inducing an acute phase of sickness and stress responses in adult and neonatal rats. Neonatal LPS exposure has been shown to alter a variety of behavioural and physiological processes in the adult animal. Early developmental stress, such as maternal separation, causes similar acute as well as long-term behavioural changes in adults, including altered sensitivity to drugs of abuse. Moreover, results of studies have shown evidence of a direct link between immune activation and sensitivity to dopamine-based drugs of abuse. The current study examined the effects of neonatal LPS treatment on subsequent locomotor sensitization to the dopamine (D2/D3) agonist, quinpirole, in adult rats as an index of drug sensitivity. Male and female Long-Evans rats were treated systemically with either LPS (50 μg/kg) or saline (0.9%) on postnatal days 3 and 5. Locomotor sensitization was then examined in the adult rats (postnatal day 70). Animals were injected with quinpirole (0.5 mg/kg, s.c.) or saline every other day for a total of 10 injections and locomotor activity was assessed for 60 min immediately following injections 1, 2, 4, 6, and 10. Animals also received a ‘challenge’ injection of 0.5 mg/kg quinpirole 28 days after injection 10, to assess persistence of behavioural sensitization. Locomotor activity progressively increased with repeated administration of quinpirole, indicating locomotor sensitization in all of the drug-treated groups. There was an overall sex difference, with females showing significantly greater sensitization than males. Moreover, neonatal LPS treatment potentiated both the level and the rate of development of locomotor sensitization to quinpirole administration in females, but not in males. Thus, the current study revealed that neonatal exposure to bacterial infection increases dopamine (D2/D3) agonist sensitivity in a sex-specific manner. These findings have important implications for the sexually dimorphic development of addictions to both natural and artificial rewards.

Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3 � immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.

Acute administration of corticosterone (CORT) facilitates learning in a number of associative paradigms including lithium chloride (LiCl)-induced conditioned taste aversion learning. The present study examined the effects of acute CORT on LiCl-induced conditioned place aversions in male rats. Automated open-fields were partitioned into two chambers distinct in tactile and visual cues. Animals received either LiCl (64 mg/kg, 0.15 M) or saline (NaCl, 0.15 M) followed 10 min later by either CORT (5 mg/kg) or beta-cyclodextrin vehicle (45%) prior to placement in one of the chambers. Control rats received NaCl-Vehicle paired with both chambers. Three experimental groups received either NaCl-CORT, LiCl-Vehicle or LiCl-CORT paired with the preferred chamber and NaCl-Vehicle (control) paired with the non-preferred chamber. During extinction trials, animals were allowed to choose between the two chambers. Locomotor activity and its distribution within the chambers were assessed during both conditioning and extinction trials. CORT administration produced significant increases in a variety of measures of locomotor activity during conditioning trials. During extinction trials both LiCl groups displayed a conditioned place aversion while the NaCl-CORT group did not. In addition, significant increases in vertical activity were recorded in both LiCl groups in the LiCl-paired chamber. Moreover, CORT administration had no effect on LiCl-induced conditioned place aversion as time spent in the LiCl-paired chamber did not significantly differ between LiCl-Vehicle and LiCl-CORT groups. Significant increases in a number of measures of horizontal activity were also observed in both CORT groups. The present study shows that acute CORT administration does not significantly influence LiCl-induced conditioned place aversions and suggests that the facilitatory effects of acute CORT administration on learning are highly context-dependent.

The neurosteroid allopregnanolone may increase feeding by altering food palatability; however, it may also increase feeding by reducing anxiety (neophobia). Moreover, it is unclear whether this induced hyperphagia is selective to safe, palatable foods only. Male rats were injected with allopregnanolone 20 min prior to behavioral testing. The taste reactivity test was used to examine possible shifts in the palatability of a 0.3 M sucrose solution. A lickometer was used to monitor intake and licking of either a sucrose or sucrose-quinine solution. Sucrose palatability was not enhanced; however, allopregnanolone significantly increased sucrose intake and licking on Test Day 1 when the solution was novel, but not on Test Day 2 when the solution was familiar. Sucrose-quinine intake was not enhanced. Allopregnanolone-induced hyperphagia is not a result of altered sucrose palatability, but rather reflects a reduction in the neophobia elicited by a novel solution; an effect that further seems to be selective to safe, palatable foods.

Summary The relations between the estrous cycle, inflammatory responses and the development of tolerance to endotoxin were examined. Female Long-Evans rats were injected intraperitoneally with lipopolysaccharide (LPS; 200 μg/kg) or saline vehicle at 08:00 h on either diestrus (D) or proestrus (P). Ninety‐five minutes after injection locomotor activity was assessed in an automated non-novel open-field for 20 min. To assess tolerance development to LPS, rats were re-injected at the next identical stage (i.e. 4 days later; groups: DD, PP) or at the alternate stage (i.e. 6 days later; groups: DP, PD) of the estrous cycle and locomotor activity was again assessed. On Test Day 1 all groups injected with LPS exhibited similar significant activity decrements, regardless of the stage of the estrous cycle. However, on Test Day 2 rats which received both injections of LPS during proestrus (PP) showed no signs of tolerance development, whereas rats in all other groups were tolerant to LPS. In a follow up study, the time between injections was extended to 8 days. Still the animals injected both times at proestrus showed no signs of tolerance to LPS after the second injection. Thus, the stages of the estrous cycle both at the time of initial exposure and of re-exposure appear critical in the formation of behavioral tolerance to LPS in rats.

Activation of the immune system with lipopolysaccharide (LPS) has been shown to result in decreased consumption of normally preferred substances while at the same time not affecting palatability. The present study examined the effects LPS administration on both intake and palatability of a relatively unpalatable bitter-sweet taste. Bitter is thought to signal a danger cue to an animal representing a potential toxin-containing food. Using a one-bottle consumption test, voluntary intake of a sucrose-quinine (0.15 M sucrose + 0.00015 M quinine; S-Q) solution was assessed in rats on two conditioning days (days 1 and 4) after a systemic injection with LPS, LiCl, or NaCl. On the test day (day 7), rats were given 1h access to the same solution in the absence of any injection. In a separate experiment, rats fitted with intraoral cannulae received similar testing schedules, however, the solution was delivered intraorally, activating only the consummatory responses of the animal. During conditioning, rats received 5 brief (1 min) intraoral infusions of the taste across a 1h period following injections of LPS, LiCl or NaCl. Individual taste reactivity responses were recorded and analyzed. Both LPS and LiCl resulted in decreased consumption of the unpalatable taste relative to controls on the test day, suggesting typical conditioned taste avoidance. When the consummatory responses were examined, LPS-treatment produced an increase in active oral rejection relative to NaCl- and LiCl-treated groups on both conditioning days. The present study demonstrates that although both LPS- and LiCl-treatment result in similar conditioned avoidance using an intake measure, they do not elicit similar patterns of taste reactivity responding to intraoral infusions of the bitter-sweet taste. Furthermore, the present results suggest that immune activation with LPS-treatment results in increased rejection of a mildly aversive stimulus and supports the hypothesis that reorganization of behavioral priorities occurs during bacteria-induced sickness.

This study examined the influence of photoperiod on affective behavior (anxiety) of adult male and female meadow voles (Microtus pennsylvanicus), maintained in either a long or short day photoperiod, when tested in an automated (VersaMax) light-dark test. The light-dark test is based on an innate aversion of rodents to novel, brightly illuminated spaces and has been used with laboratory raised species, such as mice, to assess anxiety and/or fear related behaviors. Male and female meadow voles, housed either in a long day (LD: 16 h light) or short day (SD: 8 h light) photoperiod, were tested in the light-dark apparatus for 30 min on 3 consecutive days. All animals spent significantly (p0.001) less time in the brightly lit chamber (900 lux) than in the dark chamber. LD voles, especially females, spent significantly less time in the brightly lit area than did SD voles. Both horizontal and vertical movements occurred less frequently per unit time in the dark area relative to the light, but only in the LD voles. LD female voles were the least active group in the dark area on the first test day but the most active group in the light area, despite spending the least amount of time in this area on the second and third test days. The present results show that LD voles exhibit more anxiety related behaviors in this test situation than do SD voles. LD females avoided the brightly lit area the most, particularly when the apparatus was novel. Thus, both photoperiod and sex influence situation-based anxiety in this species. These findings suggest that meadow voles are an excellent animal model in which to examine the role of gonadal hormones, and their modulation of defence related neural systems, in the induction of anxiety.

The present study examined the multi-variable locomotor activity effects of lithium chloride (LiCl) treatment in male rats. Of interest was a determination of which variables might show a dose-response relationship in LiCl-induced conditioned place aversions. Automated open-fields were partitioned into two chambers distinct in tactile and visual cues. A control group [n=8] received saline (NaCl; 0.15 M) paired with both chambers while three LiCl groups (0.15 M; 32 mg/kg [n=7], 95 mg/kg [n=7], 127 mg/kg [n=7]) received LiCl paired with the normally preferred chamber and saline paired with the non-preferred chamber. During extinction trials, rats were allowed to choose between the two chambers to provide an index of conditioned place aversions. Locomotor activity and its distribution within the chambers were also assessed during both conditioning and extinction trials. Dose-dependent decreases occurred in all measures of locomotor activity following LiCl administration during conditioning. During extinction trials, place aversions developed in animals conditioned with LiCl. LiCl-treated rats spent significantly less time in the LiCl-paired chamber relative to controls but not in a dose-dependent manner. Animals that had been conditioned with 95 or 127 but not 32 mg/kg LiCl, displayed significantly more vertical activity in the LiCl-paired chamber than controls during extinction trials. These findings indicate that, in addition to producing dose-dependent unconditioned effects on locomotor activity, LiCl also produces dose-dependent conditioned effects on vertical activity. These conditioned rearing response effects provide a valid measure of the conditioned avoidance response that provides evidence for dose-dependent LiCl-induced conditioned place aversions.