Perinatal IL-1β-induced inflammation suppresses Tbr2+ intermediate progenitor cell proliferation in the developing hippocampus accompanied by long-term behavioral deficits

Abstract

Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes, and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. As systemically administering interleukin-1 β (IL-1β) to neonatal mice recapitulates many of the brain abnormalities seen in premature babies including developmental delays, the goal of this study was to determine whether IL-1-mediated neuroinflammation would affect hippocampal growth during development to produce cognitive and behavioral abnormalities. For these studies, 10 ​ng/g IL-1β was administered twice daily to Swiss Webster mice during the first 5 days of life, which increased hippocampal levels of IL-1α and acutely reduced the proliferation of Tbr2 + neural progenitors in the DG. In vitro , both IL-1α and IL-1β produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transit amplifying progenitor cell cohort. By contrast, IL-1β treatment increased neural stem cell frequency. Upon terminating IL-1β treatment, the progenitor cell pool regained its proliferative capacity. An earlier study that used this in vivo model of perinatal inflammation showed that mice that received IL-1β as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered, mice were tested in tasks designed to assess exploratory and anxiety behavior as well as working and spatial memory. Interestingly, mice that received IL-1β as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. Additionally, these mice did not display working memory deficits in adulthood, but they did display deficits in long-term spatial memory. Altogether, these data support the view that perinatal inflammation negatively affects the developing hippocampus by producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely-born sick infants.

Environmental enrichment improves declined cognition induced by prenatal inflammatory exposure in aged CD-1 mice: Role of NGPF2 and PSD-95

“…Current evidence demonstrates that exposure to maternal immune activation (MIA) in utero in rodents causes cognitive abnormalities, such as spatial learning and memory impairments, in adult offspring ( Batinić et al, 2016 ; Simões et al, 2018 ). These abnormalities are similar to those reported in human studies ( Ross-Munro et al, 2020 ; Veerasammy et al, 2020 ). Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, activates the immune system ( Domínguez-Rivas et al, 2021 ).…”

Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries

“…Perinatal exposition to IL-1β induced a significant decrease in spontaneous locomotor activity evaluated by the total traveled distance over 20 min. In accordance with previous data (Veerasammy et al 2020 ), IL-1β-exposed animals spent significantly less time in the center stage of the arena, suggesting anxiety-like behavior. LP-211 co-treatment significantly prevented both locomotor deficits and anxiety-like behavior (Fig.…”

“…Analysis of the behavior of IL-1β-exposed animals at P39 in the elevated plus-maze and open field previously showed an increase in anxiety-like behavior, indicated by significantly less time spent exploring the center zone (Veerasammy et al 2020). LP-211 has been reported to be a treatment that alleviates behavioral deficits associated with NDDs in a rat model, including anxiety (Khodaverdi et al 2021).…”

Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods

“…Regulation of TAPs’ by AP2γ seems to be also relevant for the preservation of cognitive performance, as shown by its impact on hippocampal-dependent emotional and memory tasks. These observations are in agreement with previous publications where suppression of the TAP’s regulator Tbr2 exerted both an anxiety-like phenotype during the juvenile period and induced cognitive deficits during early adulthood ( Veerasammy et al, 2020 ). Moreover, Ngn2, another regulator of TAP cells, is also reported as important for the modulation of cognitive behavior, namely in the rescue of cognitive function in the T-Maze task ( Zhao et al, 2018 ).…”