Growth restriction alters adult spatial memory and sensorimotor gating in a sex-specific manner

Abstract

In Western society, impaired uteroplacental blood flow is the major cause of human intrauterine growth restriction. Infants born small and who experience late childhood accelerated growth have an increased risk of developing adult diseases. Recent studies also suggest a link between birth weight and altered adult behavior, particularly relating to motor function, learning and memory, depression and schizophrenia. The aim of this study was to determine the relative influence of prenatal and postnatal growth restriction on adult behavioral outcomes in male and female rats. Uteroplacental insufficiency was induced in Wistar Kyoto rats by bilateral uterine vessel ligation on day 18 of gestation producing growth-restricted offspring (Restricted group). The Control group had sham surgery. Another group underwent sham surgery, with a reduction in litter size to five at birth equivalent to the Restricted litter size (Reduced Litter group). At 6 months of age, a series of behavioral tests were conducted in male and female offspring. Growth restriction did not impair motor function. In fact, Restricted and Reduced Litter males showed enhanced motor performance compared with Controls (P < 0.05). Spatial memory was greater in Restricted females only (P < 0.05). The Porsolts test was unremarkable, however, males exhibited more depressive-like behavior than females (P < 0.05). A reduction in sensorimotor gating function was identified in Reduced Litter males and females (P < 0.05). We have demonstrated that growth restriction and/or a poor lactational environment can affect adult rat behavior, particularly balance and coordination, memory and learning, and sensorimotor gating function, in a sex-specific manner.

Models of Intrauterine growth restriction and fetal programming in rabbits

“…Moreover, rabbits exposed to uteroplacental insufficiency displayed neurobehavioral alterations such as reduced exploratory activities/increased anxiety‐related behavior as adults (Batalle et al, ; Illa et al, ). The findings of impaired neurocognitive development and function in rabbit kits were in line with those of rat offspring that showed altered spatial memory, motor function, and sensorimotor gating function as a result of uteroplacental insufficiency during development (Lauritz, Siebel, Guille, Jefferies, & Wlodek, ).…”

“…The findings of impaired neurocognitive development and function in rabbit kits were in line with those of rat offspring that showed altered spatial memory, motor function, and sensorimotor gating function as a result of uteroplacental insufficiency during development (Lauritz, Siebel, Guille, Jefferies, & Wlodek, 2012).…”

Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum

“…By P35, all granule cells had migrated out of the EGL in both control and IUGR rats, so, while migration may be delayed, it is not completely inhibited by IUGR. Regardless, a delay in granule cell migration at any time during postnatal cerebellar development could lead to altered connectivity of the cerebellar circuitry, which is supported by the adverse neurobehavioral outcomes that we have previously observed in this model of IUGR [30] .…”

“…In combination with damage to the migratory scaffold, Trop2 and Astn1 levels were altered in the IUGR cerebellum; these cellular and molecular factors may underlie the deficits in postnatal cerebellar development following IUGR. Given the importance of the cerebellum for regulating motor coordination as well as higher-order functions such as cognition and learning, abnormal development of the cerebellum in IUGR offspring is likely to contribute to the increased risk of motor, cognitive, and learning deficits in humans born after IUGR [30] . ( c , d ) cerebella from control ( a , c ) and IUGR ( b , d ) pups are labeled with TROP2 (green) and NeuN (red).…”

“…As previously demonstrated, fetal loss can occur in this model of IUGR, with the offspring closest to the ligation site the most at risk of not surviving [29] . We have previously published a reduction in IUGR litter size of about 25-45%, compared to controls, due to fetal loss [30,31] . There was no maternal loss following surgery.…”