Prenatal Nicotine Exposure Evokes Alterations of Cell Structure in Hippocampus and Somatosensory Cortex

Abstract

Offspring of women who smoke during pregnancy show behavioral abnormalities, including increased incidence of attentional deficit, learning disabilities, and cognitive dysfunction. Animal models indicate that nicotine elicits changes in neural cell replication and differentiation, leading to deficits in synaptic neurochemistry and behavioral performance, many of which first emerge at adolescence. We evaluated cellular morphology and regional architecture in the juvenile and adolescent hippocampus and the somatosensory cortex in rats exposed to nicotine prenatally. Pregnant rats were given nicotine throughout gestation via minipump infusion of 2 mg/kg/day, a regimen that elicits nicotine plasma levels comparable with those found in smokers. On postnatal days 21 and 30, brains were perfusionfixed, coronal slices were taken between the anterior commissure and median eminence, and the morphology of the dorsal hippocampus and somatosensory cortex was characterized. In the hippocampal CA3 region and dentate gyrus, we found a substantial decrease in cell size, with corresponding decrements in cell layer thickness, and increments in cell packing density. Smaller, transient changes were seen in CA1. In layer 5 of the somatosensory cortex, although there was no significant decrement in the average cell size, there was a reduction in the proportion of medium-sized pyramidal neurons, and an increase in the proportion of smaller, nonpyramidal cells. All regions showed elevated numbers of glia. Taken together with previous work on neurochemical and functional defects, these data demonstrate that prenatal nicotine exposure compromises neuronal maturation, leading to long-lasting alterations in the structure of key brain regions involved in cognition, learning, and memory.

Does Prenatal Nicotine Exposure Sensitize the Brain to Nicotine-Induced Neurotoxicity in Adolescence?

“…Indeed, previous morphological studies also revealed a higher neuron packing density in specific hippocampal layers in the adolescent brain after prenatal nicotine exposure (Roy et al, 2002). These results seem puzzling in light of the fact that hippocampal progenitor cells are especially susceptible to nicotine-induced apoptosis (Berger et al, 1998).…”

“…Prenatal exposure elicits alterations in parameters of cell number, cell size, and membrane surface area that persist into adolescence, thus representing the final outcome of earlier perturbations in patterns of cell acquisition and synaptogenesis during the period of rapid brain development (Levin and Slotkin, 1998;Roy et al, , 2002Sabherwal, 1994, 1998;Slotkin, 1992Slotkin, , 1998Slotkin, , 1999. Furthermore, the findings for adolescent treatment by itself, consonant with earlier conclusions (Abreu-Villaça et al, 2003a-c;Slotkin, 2002;Slotkin et al, 2002;Trauth et al, 2000aTrauth et al, -c, 2001Xu et al, 2001Xu et al, , 2002Xu et al, , 2003, indicate that the vulnerability of the brain to nicotine-induced neurotoxicity can be elicited when nicotine is given in adolescence, albeit to a lesser extent than in the fetus.…”

“…Morphological studies show that prenatal nicotine treatment elicits extensive apoptosis in the brain of the offspring during the exposure period (Berger et al, 1998; and, despite subsequent recovery and repair, structural anomalies are still present in adolescence (Roy and Sabherwal, 1994;Roy et al, 2002). At the biochemical level, initial deficits in cell number tend to recover or to rise above control levels during the later period associated with gliogenesis, suggesting reactive gliosis in response to neuronal damage , and indeed, elevated numbers of glial cells remain morphologically detectable in the hippocampus and somatosensory cortex at the adolescent stage (Roy et al, 2002).…”

“…At the biochemical level, initial deficits in cell number tend to recover or to rise above control levels during the later period associated with gliogenesis, suggesting reactive gliosis in response to neuronal damage , and indeed, elevated numbers of glial cells remain morphologically detectable in the hippocampus and somatosensory cortex at the adolescent stage (Roy et al, 2002). In the present study, we found small but significant DNA decreases in the midbrain after prenatal nicotine exposure, in association with an increase in cell surface-to-volume ratio (elevated membrane/total Figure 5 Effects of adolescent nicotine administration on the ratio of membrane to total protein, presented as the percent change from control values (see Table 1).…”

“…Clearly, one contributory factor to susceptibility is parental smoking (Bauman et al, 1990;Chassin et al, 2002;Niaura et al, 2001) and specifically maternal smoking during pregnancy (Cornelius et al, 2000;Kandel et al, 1994;Niaura et al, 2001). In animal models, prenatal nicotine exposure by itself evokes neuroteratogenic changes that result in cognitive and behavioral deficits (Levin and Slotkin, 1998;Roy et al, , 2002Sabherwal, 1994, 1998;Slotkin, 1992Slotkin, , 1998Slotkin, , 1999 and the vulnerability of specific brain regions and neural pathways to nicotine-induced damage also extends into adolescence (Abreu-Villaça et al, 2003a-c;Slotkin, 2002;Slotkin et al, 2002;Trauth et al, 2000aTrauth et al, -c, 2001Xu et al, 2001Xu et al, , 2002Xu et al, , 2003. Accordingly, one possibility is that prenatal nicotine exposure might predispose the brain to neural damage elicited by nicotine later in life, during adolescence, thus eliciting lasting neurobehavioral changes.…”