Gestational poly(I:C) attenuates, not exacerbates, the behavioral, cytokine and mTOR changes caused by isolation rearing in a rat ‘dual-hit’ model for neurodevelopmental disorders

Abstract

Many psychiatric illnesses have a multifactorial etiology involving genetic and environmental risk factors that trigger persistent neurodevelopmental impairments. Several risk factors have been individually replicated in rodents, to understand disease mechanisms and evaluate novel treatments, particularly for poorly-managed negative and cognitive symptoms. However, the complex interplay between various factors remains unclear.Rodent dual-hit neurodevelopmental models offer vital opportunities to examine this and explore new strategies for early therapeutic intervention. This study combined gestational administration of polyinosinic:polycytidylic acid (poly(I:C); PIC, to mimic viral infection during pregnancy) with post-weaning isolation of resulting offspring (to mirror adolescent social adversity).After in vitro and in vivo studies required for laboratory-specific PIC characterization and optimization, we administered 10 mg/kg i.p. PIC potassium salt to time-mated Lister hooded dams on gestational day 15. This induced transient hypothermia, sickness behavior and weight loss in the dams, and led to locomotor hyperactivity, elevated striatal cytokine levels, and increased frontal cortical JNK phosphorylation in the offspring at adulthood.Remarkably, instead of exacerbating the well-characterized isolation syndrome, gestational PIC exposure actually protected against a spectrum of isolation-induced behavioral and brain regional changes. Thus isolation reared rats exhibited locomotor hyperactivity, impaired associative memory and reversal learning, elevated hippocampal and frontal cortical cytokine levels, and increased mammalian target of rapamycin (mTOR) activation in the frontal cortex -which were not evident in isolates previously exposed to gestational PIC. Brains from adolescent littermates suggest little contribution of cytokines, mTOR or JNK to early development of the isolation syndrome, or resilience conferred by PIC. But notably hippocampal oxytocin, which can protect against stress, was higher in adolescent PICexposed isolates so might contribute to a more favorable outcome. These findings have implications for identifying individuals at risk for disorders like schizophrenia who may benefit from early therapeutic intervention, and justify preclinical assessment of whether adolescent oxytocin manipulations can modulate disease onset or progression.

Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways

“…Different behavioral and morphofunctional brain abnormalities in offspring of poly (I:C)-treated dams have been observed after puberty ( Zuckerman et al, 2003 ; Ozawa et al, 2006 ; Meyer and Feldon, 2012 ; Meyer, 2014 ; Luchicchi et al, 2016 ). In concordance with findings in brain of subjects with schizophrenia, previous works confirmed that this MIA model promotes the accumulation of pro-inflammatory mediators such as different cytokines, as well as intracellular inflammatory and oxido/nitrosative mediators such as the transcription factor NFkB or the inducible nitric oxide synthase (iNOS) ( Song et al, 2011 ; Volk et al, 2015 ; MacDowell et al, 2017 ; Goh et al, 2020 ). All these abnormalities suggest that MIA induced by poly (I:C) promotes in offspring a face-valid schizophrenia-like model.…”

“…Likewise, a decrease in the rat brain cortical 5-HT content was observed in the offspring born from bacterial toxin lipopolysaccharide-immune-challenged mothers ( Swanepoel et al, 2018 ). However, there are also studies reporting unaltered tissue 5-HT concentrations in the FC of MIA animal models ( Winter et al, 2009 ; Abazyan et al, 2010 ; Hadar et al, 2015 ; Goh et al, 2020 ). The discrepancies highlight the importance of the intensity of MIA, as evidenced by the dose of immunogenic substance used, as well as the impact on the neurodevelopmental trajectory in relation to gestation time for the MIA.…”

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

“…Although the consensus is that schizophrenia begins with hypofunction of NMDA receptors on GABAergic interneurons leading to disinhibition of pyramidal cells and excitotoxic damage to CA1 [75], MRS generally shows little hippocampal change in early schizophrenia [76]. Our NOD studies began at the accepted onset of adulthood, which is approximately 3 weeks after typical emergence of isolation-induced dopaminergic changes and hyperlocomotion [77]. Since our microsensor studies continued for almost 3 months after this first emergence it can be argued that current findings more closely mirror chronic disease where MRS can reveal decreased glutamate in patients [19], potentially due to reduced synaptic density [20] and VGLUT1 expression [21,22].…”

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

“…Specifically, single housing following prolonged EE exposure was associated with increased weight gain, elevated helplessness and passive coping behaviors, and blunted hypothalamic-pituitary-adrenocortical activity (Morano et al, 2019; Smith et al, 2017). In contrast, isolation rearing following MIA in SD-housed animals was protective against negative impacts on behavior and neurophysiology (Goh et al, 2020).…”

“…Specifically, a mid-gestational injection of polyinosinic:polycytidylic acid (poly (I:C)), a viral mimetic toll-like receptor 3 agonist, can induce an extensive collection of innate immune responses (Mueller et al, 2019) and lead to a wide array of abnormalities in neurophysiology, behavior and cognitive abilities (see (Haddad et al, 2020) for review). Whereas the vast majority of previous studies have addressed the adverse effects of MIA, prior research has also revealed that MIA-treated offspring can exhibit improvements in cognitive functioning (Makinson et al, 2019; Nakamura et al, 2021), blunted responses to a second immune challenge in adolescence (Clark et al, 2019), and a higher level of resilience to the disruptive effects of isolation rearing on behavior and neurophysiology (Goh et al, 2020). Recently, it has been shown that poly (I:C)-induced MIA at a specific window of parvalbumin interneuron development can lead to improvements in spatial working memory (Nakamura et al, 2021).…”