publications
An up-to-date list is available on my Google Scholars.
2025
- Sex and Region-Specific Differences in Microglial Morphology and Function Across DevelopmentIndra R Bishnoi, and Evan A BordtNeuroglia, 2025
Microglia are exceptionally dynamic resident innate immune cells within the central nervous system, existing on a continuum of morphologies and functions throughout their lifespan. They play vital roles in response to injuries and infections, clearing cellular debris, and maintaining neural homeostasis throughout development. Emerging research suggests that microglia are strongly influenced by biological factors, including sex, developmental stage, and their local environment. This review synthesizes findings on sex differences in microglial morphology and function in key brain regions, including the frontal cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum, across the lifespan. Where available, we examine how gonadal hormones influence these microglial characteristics. Additionally, we highlight the limitations of relying solely on morphology to infer function and underscore the need for comprehensive, multimodal approaches to guide future research. Ultimately, this review aims to advance the dialogue on these spatiotemporally heterogeneous cells and their implications for sex differences in brain function and vulnerability to neurological and psychiatric disorders.
2024
- Sex differences in sucrose-induced locomotor sensitization and cross-sensitization with the D2/D3 agonist quinpirole in ratsVangel Matic, Matthew Huynh, Indra R Bishnoi, and 2 more authorsResearch Square Preprint, 2024
Background: Female-biased sex differences are known to exist in the prevalence of eating-related disorders and the experience of food cravings. Similarly, in rodents, females display a greater preference and motivation for the highly palatable sweet food, sucrose, than do males. Locomotor sensitization, the increase in locomotor activity that occurs with repeated administrations of drugs of abuse, is thought to occur through drug-induced sensitization of the mesolimbic dopamine pathway and reflect enhancements in drug craving. Pre-exposure to sucrose has been shown to enhance locomotor sensitization induced by dopaminergic agonists, however, it is unknown if sex differences exist in this effect. Methods: 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. On the first, fifth, and ninth day of the sucrose and quinpirole phases, rats were placed in automated activity monitors for 30 min after fluid access and drug administration, respectively, to assess locomotor activity. Mixed model analyses of variance were used to evaluate differences in locomotor activity between Female + Sucrose, Female + Water, Male + Sucrose, and Male + Water treated rats. Results: Female + Sucrose rats showed significantly greater weight-adjusted fluid consumption of sucrose than did Male + Sucrose rats. Female + Sucrose rats exhibited a significant increase in locomotor activity across the sucrose phase and significantly greater locomotor activity relative to other groups. In the quinpirole phase, both groups pre-exposed to sucrose (Female + Sucrose, Male + Sucrose) showed greater activity than their same-sex control pre-exposed to water (Female + Water, Male + Water). Further, both female groups generally displayed greater activity than both male groups in the quinpirole phase. Conclusions: A female-biased sex difference was identified in the effect of locomotor sensitization induced by sucrose (0.3 M), but not for sucrose pre-exposure on quinpirole sensitization (0.5 mg/kg). These results suggest that differences may exist between sexes in the mesolimbic response to sucrose, perhaps underlying sex differences in food cravings and eating-related disorder prevalence.
- The missing half: Paternal immune activation’s role in transgenerational sex differences.Indra R Bishnoi, and Evan A BordtBrain, Behavior, and Immunity, 2024
- Lipopolysaccharide (LPS) attenuates the primary conditioning of lithium chloride (LiCl)-induced context aversion but not the secondary conditioning of context aversion or taste avoidanceIndra R Bishnoi, Martin Kavaliers, and Klaus-Peter OssenkoppBehavioural Brain Research, 2024
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.
2023
- Disgusted snails, oxytocin, and the avoidance of infection threatMartin Kavaliers, Deanne TO Wah, Indra R Bishnoi, and 2 more authorsHormones and Behavior, 2023
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.
- Immune activation attenuates memory acquisition and consolidation of conditioned disgust (anticipatory nausea) in ratsIndra R Bishnoi, Martin Kavaliers, and Klaus-Peter OssenkoppBehavioural Brain Research, 2023
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.
2022
- Infection, learning, and memory: Focus on immune activation and aversive conditioningIndra R Bishnoi, Caylen J Cloutier, Cashmeira-Dove Tyson, and 3 more authorsNeuroscience & Biobehavioral Reviews, 2022
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.
- Odor-based mate choice copying in deer mice is not affected by familiarity or kinshipMartin Kavaliers, Indra R Bishnoi, Klaus-Peter Ossenkopp, and 1 more authorAnimal Cognition, 2022
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.
- Social factors and the neurobiology of pathogen avoidanceMartin Kavaliers, Klaus-Peter Ossenkopp, Cashmeira-Dove Tyson, and 2 more authorsBiology letters, 2022
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.
- Disliking: from adaptive disgust to uglinessChristoph Klebl, Michael Donner, and Indra R BishnoiIn The Routledge International Handbook of Neuroaesthetics, 2022
Humans and other animals have evolved the emotion disgust as an early line of defence against pathogen threat. Disgust neutralizes the possibility of pathogen transmission by motivating avoidance responses. It has been argued that disgust may serve a range of functions beyond pathogen avoidance, including sexual partner selection (i.e., sexual disgust) and the regulation of social norm violators (i.e., moral disgust). These disgust systems have implications for a range of social psychological phenomena. One emerging area of work suggests that disgust is implicated in aesthetic judgments. Specifically, ugliness judgments may function to alert us to cues of pathogen presence and evoke disgust. The signal detection process in each disgust system is hypersensitive, as failing to detect a threat may lead to high costs. This can lead to stigmatization of people who are wrongly perceived to pose pathogen risk, such as ethnic outgroups or people with facial and bodily disfigurement. Neuroanatomically, primitive disgust is associated with activation in the anterior insular cortex and the area postrema, whereas more complex disgust is processed in brain regions within the social decision-making network (SDMN). The ventromedial prefrontal cortex (vmPFC)—an area within the SDMN—may be specifically linked to social disgust.
- Progesterone and disgust: A response to" progesterone does raise disgust"Martin Kavaliers, Indra R Bishnoi, Klaus-Peter Ossenkopp, and 1 more authorHormones and behavior, 2022
2021
- Sex and age differences in locomotor and anxiety-like behaviors in rats: From adolescence to adulthoodIndra R Bishnoi, Klaus-Peter Ossenkopp, and Martin KavaliersDevelopmental psychobiology, 2021
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.
- Differential effects of progesterone on social recognition and the avoidance of pathogen threat by female miceMartin Kavaliers, Indra R Bishnoi, Klaus-Peter Ossenkopp, and 1 more authorHormones and behavior, 2021
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.
2019
- Conspecific infection threat rapidly biases the social responses of female mice: involvement of oxytocinMartin Kavaliers, Douglas D Colwell, Deanne TO Wah, and 3 more authorsHormones and Behavior, 2019
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.
- Lipopolysaccharide (LPS) induced sickness in early adolescence alters the behavioral effects of the short-chain fatty acid, propionic acid, in late adolescence and adulthood: examining anxiety and startle reactivityDeanne Tak On Wah, Martin Kavaliers, Indra R Bishnoi, and 1 more authorBehavioural Brain Research, 2019
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.
- Predator odor exposure in early adolescence influences the effects of the bacterial product, propionic acid, on anxiety, sensorimotor gating, and acoustic startle response in male rats in later adolescence and adulthoodDeanne Tak On Wah, Klaus-Peter Ossenkopp, Indra Bishnoi, and 1 more authorPhysiology & behavior, 2019
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.
- Systemic treatment with the enteric bacterial fermentation product, propionic acid, reduces acoustic startle response magnitude in rats in a dose-dependent fashion: contribution to a rodent model of ASDCorey L Kamen, Danna L Zevy, Jordan M Ward, and 3 more authorsNeurotoxicity Research, 2019
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.