scholarly journals Poly (I:C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment

2021 ◽  
Author(s):  
Xin Zhao ◽  
Ruqayah Mohammed ◽  
Hieu Tran ◽  
Mary Erickson ◽  
Amanda C. Kentner
Keyword(s):  
Animal Models ◽  
Dentate Gyrus ◽  
Immune Activation ◽  
Maternal Care ◽  
Environmental Enrichment ◽  
Poly I:C ◽  
Receptor Protein ◽  
List Type ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid

AbstractEnvironmental enrichment (EE) has been successfully implemented in human rehabilitation settings, including demonstrated benefits for children with autism. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built nests of poorer quality, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers (e.g., corticotropin releasing hormone (Crh) and Crh receptor 1, glucocorticoid receptor, oxytocin receptor, protein kinase C and Camk2a mRNA). Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus, including the suprammamillary nucleus (an important region for social novelty) was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. Gestational poly (I:C) and EE also altered gene expression of stress and synaptic plasticity markers in the prefrontal cortex and hypothalamus. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA dysregulation.Highlights- Environmental enrichment (EE) protocols are used clinically to promote rehabilitation- Use of EE in animal models may identify mechanisms underlying clinical successes- Maternal immune activation (MIA) decreased social engagement; this effect was blocked by EE- MIA reduced c-Fos activation in the dentate gyrus, while EE reduced activation in the hypothalamus, in response to social stimuli- EE inhibited MIA-induced HPA dysregulation in ventral hippocampus

scholarly journals Hidden Talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.

2021 ◽  
Author(s):  
Xin Zhao ◽  
Hieu Tran ◽  
Holly DeRose ◽  
Ryland C Roderick ◽  
Amanda C Kentner
Keyword(s):  
Reversal Learning ◽  
Immune Activation ◽  
Visual Discrimination ◽  
Early Life ◽  
Discrimination Performance ◽  
Poly I:C ◽  
Dependent Manner ◽  
Negative Consequences ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on the developing brain, very little attention is directed towards potential advantages of early life challenges. In this study we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual discrimination (VD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA improved the latency for males to make a correct choice in the VD task while females reached criterion sooner, made fewer errors and utilized fewer correction trials in RL compared to saline-treated controls. These surprising improvements were accompanied by the sex-specific upregulation of several neural markers critical to cognitive functioning (e.g., Gabrg2, Grin1, Grin2b, Htr2a, Chrm1, Prkca, and Camk2a mRNA in prefrontal cortex (PFC)), indicative of compensatory plasticity in response to the MIA challenge. In contrast, when exposed to a "two-hit" stress model (MIA combined with loss of the social component of environmental enrichment (EE)), mice showed no evidence of anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the PFC. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right "dose", early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

scholarly journals Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3503
Author(s):  
Todd M. Stollenwerk ◽  
Cecilia J. Hillard
Keyword(s):  
Immune Activation ◽  
Synergistic Effects ◽  
Acoustic Startle ◽  
Acoustic Startle Reflex ◽  
Behavioral Effects ◽  
Poly I:C ◽  
Adult Males ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid ◽  
Increased Risk

Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and ∆9-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg/kg/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.

scholarly journals Long-Lasting Impact of Maternal Immune Activation and Interaction With a Second Immune Challenge on Pig Behavior

2020 ◽  
Vol 7 ◽  
Author(s):  
Haley E. Rymut ◽  
Courtni R. Bolt ◽  
Megan P. Caputo ◽  
Alexandra K. Houser ◽  
Adrienne M. Antonson ◽  
...  
Keyword(s):  
Immune Activation ◽  
Social Behaviors ◽  
Combined Effect ◽  
Poly I:C ◽  
Immune Challenge ◽  
Mixed Effect ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid ◽  
Behavioral Disruptions ◽  
The Impact

The combined effects on pig behavior of maternal immune challenge during gestation followed by a second immune challenge later in life have not been studied. Porcine reproductive and respiratory syndrome virus (PRRSV) infection during gestation can elicit maternal immune activation (MIA) yet the interactions with the offspring response to a second immune challenge after birth remains unexplored. Knowledge on the response to viral challenges in rodents has been gained through the use of the viral mimetic polyinosinic-polycytidylic acid (Poly(I:C)), yet the effects of this immune stimulant on pig behavior have not been assessed. This study advances the understanding of the combined effect of MIA and a second immune challenge later in life on female and male pig behavior. Three complementary experiments enabled the development of an effective Poly(I:C) challenge in pigs, and testing the interaction between PRRSV-elicited MIA, Poly(I:C) challenge at 60 days of age, and sex on behaviors. Individual-level observations on sickness, locomotor, and social behaviors were measured 1–3 h after Poly(I:C) challenge. Vomiting, panting, lethargy, walking, laying, playing, and touching behaviors were analyzed using generalized linear mixed effect models. Results indicated that a Poly(I:C) dose of 1 mg/kg within 1 h after injection increased the incidence of laying and sickness behavior. The Poly(I:C) challenge decreased the incidence of locomotor behaviors and activity levels. Pigs exposed to MIA had lower rates of social behaviors such as playing. The combined effect of PRRSV-elicited MIA and Poly(I:C) immune challenge further sensitized the pigs to behavior disruption across sexes including changes in sternal and lateral laying, walking, lethargy, and touching incidence. Notably, the effects of Poly(I:C) immune challenge alone on behaviors tended to be more extreme in males, whereas the effects of Poly(I:C) following MIA tended to be more extreme in females. Our findings demonstrate that MIA and Poly(I:C) affected behaviors, and the viral mimetic effects shortly after injection can offer insights into the prolonged effect of postnatal viral infections on feeding, social interactions and health status. Management practices that reduce the likelihood of gestational diseases and accommodate for behavioral disruptions in the offspring can minimize the impact of MIA.

scholarly journals Got Milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats

2022 ◽  
Author(s):  
Holly DeRosa ◽  
Hieu Tran ◽  
Amanda C Kentner
Keyword(s):  
Animal Models ◽  
Immune Activation ◽  
Maternal Care ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Female Rats ◽  
Maternal Immune Activation ◽  
Adolescent Offspring ◽  
And Behavior

The neonatal environment requires a high level of maternal demand in terms of both breastfeeding and other forms of maternal care. Previous studies have underscored the importance of these maternal factors on offspring development and behavior. However, their contribution as dynamic variables in animal models of early life stress are often overlooked. In the present study, we show that lipopolysaccharide (LPS)-induced maternal immune activation (MIA) on postnatal day (P)10 immediately elevated milk corticosterone concentrations, which recovered by P11. In contrast, both milk triglyceride and percent creamatocrit values demonstrated a prolonged decrease following inflammatory challenge. Sustained inflammatory-induced changes to the nutritional quality of milk were also evidenced by its composition of microbial communities associated with inefficient energy and lipid metabolism. Nutritional deficits in early development have been associated with metabolic dysfunction later in life. Indeed, MIA-associated changes in the nutritional profile of milk were reflected by increased adolescent offspring bodyweights. While MIA did not decrease maternal care quality, there was a significant compensatory increase in maternal licking and grooming the day that followed the inflammatory challenge. However, this did not protect against disrupted neonatal huddling or later-life alterations in sensorimotor gating and mechanical allodynia in MIA offspring. Animal models of early life stress can impact both parents and their offspring. One mechanism that can mediate the effects of such stressors is changes to maternal lactation quality which our data show can confer multifaceted and compounding effects on offspring physiology and behavior.

Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

2021 ◽  
pp. 026988112110297
Author(s):  
Wayne Meighan ◽  
Thomas W Elston ◽  
David Bilkey ◽  
Ryan D Ward
Keyword(s):  
Animal Models ◽  
Drug Discrimination ◽  
Immune Activation ◽  
Internal State ◽  
Nmda Receptor Antagonist ◽  
Activation Model ◽  
Data Link ◽  
Maternal Immune Activation ◽  
Internal States ◽  
Reliable Methods

Background: Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Aims/methods: Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Results/outcomes: The MIA rats’ discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. Conclusion: These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

scholarly journals The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

2021 ◽  
Vol 11 (3) ◽  
pp. 344
Author(s):  
Kinga Gzielo ◽  
Agnieszka Potasiewicz ◽  
Ewa Litwa ◽  
Diana Piotrowska ◽  
Piotr Popik ◽  
...  
Keyword(s):  
Immune Activation ◽  
Social Play ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Rats ◽  
Poly I:C ◽  
Maternal Immune Activation ◽  
Increased Risk ◽  
Adolescent Rats ◽  
The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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