Attention and working memory deficits in a perinatal nicotine exposure mouse model

Abstract

Background: Cigarette smoking by pregnant women is associated with a significant increase in the risk for cognitive disorders in their children. Preclinical models confirm this risk by showing that exposure of the developing brain to nicotine produces adverse behavioral outcomes. Here we describe behavioral phenotypes resulting from perinatal nicotine exposure in a mouse model, and discuss our findings in the context of findings from previously published studies using preclinical models of developmental nicotine exposure.

Methodology/principal findings: Female C57Bl/6 mice received drinking water containing nicotine (100μg/ml) + saccharin (2%) starting 3 weeks prior to breeding and continuing throughout pregnancy, and until 3 weeks postpartum. Over the same period, female mice in two control groups received drinking water containing saccharin (2%) or plain drinking water. Offspring from each group were weaned at 3-weeks of age and subjected to behavioral analyses at 3 months of age. We examined spontaneous locomotor activity, anxiety-like behavior, spatial working memory, object based attention, recognition memory and impulsive-like behavior. We found significant deficits in attention and working memory only in male mice, and no significant changes in the other behavioral phenotypes in male or female mice. Exposure to saccharin alone did not produce significant changes in either sex.

Conclusion/significance: The perinatal nicotine exposure produced significant deficits in attention and working memory in a sex-dependent manner in that the male but not female offspring displayed these behaviors. These behavioral phenotypes are associated with attention deficit hyperactivity disorder (ADHD) and have been reported in other studies that used pre- or perinatal nicotine exposure. Therefore, we suggest that preclinical models of developmental nicotine exposure could be useful tools for modeling ADHD and related disorders.

Fig 1. Perinatal nicotine exposure and spontaneous locomotor activity.

Cumulative spontaneous locomotor activity was analyzed during the lights-off period (19:00–07:00 h) in male and female mice from the nicotine+saccharin (N + S), saccharin alone (S) and plain drinking water (W) groups. There was no significant difference in this measurement among the three experimental groups. [Mean ± SEM: Male; W = 9148 ± 1722; S = 9009 ± 1862; N + S = 9410 ± 1862; Female: W = 9172 ± 2048; S = 11284 ± 1783; N + S = 12394 ± 1983].

Fig 2. Perinatal nicotine exposure and anxiety-like phenotype in elevated plus maze (EPM).

The percentage of time spent in the open versus closed arms (A) and the number of entries into open arms (B) of the EPM were analyzed. Neither measure showed significant difference in male or female mice from the nicotine+saccharin (N + S), saccharin alone (S) and plain drinking water (W) groups. [Mean ± SEM % time spent in open arms: Male: W = 26.44 ± 4.34; S = 23.89 ± 2.88; N + S = 23.56 ± 2.56; Female: W = 17.65 ± 3.88; S = 19.05 ± 23.84; N + S = 21.53 ± 3.64. Mean ± SEM number of entries into open arms: Male: W = 9.67 ± 1.21; S = 9.33 ± 1.17; N + S = 9.5 ± 1.16; Female: W = 8.40 ± 1.32; S = 8.20 ± 1.33; N + S = 8.00 ± 1.20].

Fig 3. Perinatal nicotine exposure produces a significant decrease in spontaneous alternation in the Y-maze in male but not female offspring.

Spontaneous alternation in the Y-maze was analyzed in male and female mice from the nicotine+saccharin (N + S), saccharin alone (S) and plain drinking water (W) groups. There was a significant decreases in this measurement in male mice from the N+S group. ***p<0.001. [Mean ± SEM: Male: W: 71.31 ± 1.20; S: 71.11 ± 4.33; N + S: 52.37 ± 4.63; Female: W: 65.57 ± 4.43; S: 66.63 ± 4.42; N + S: 67.19 ± 3.56].

Fig 4. Perinatal nicotine exposure produces attention deficits in male offspring in the object based attention (OBA) test.

Recognition index was analyzed in male and female mice from the nicotine+saccharin (N + S), saccharin alone (S) and plain drinking water (W) groups. There was a significant decrease in this measurement in male mice from the N+S group. *p<0.05. [Mean ± SEM: Male: W: 73.95 ±4.65; S: 74.93 ± 4.85; N + S: 50.04 ± 4.65; Female: W: 56.01 ± 4.60; S: 62.61 ± 4.80; N + S: 59.46 ± 7.85].

Fig 5. Perinatal nicotine exposure and Novel-object recognition test (NOR).

Data combined from the nicotine+saccharin (N + S), saccharin alone (S) and plain drinking water (W) groups are shown There was no significant difference in the time spent exploring novel versus familiar object (discrimination index) in male and female mice from the N + S, S and W groups. [Mean ± SEM: Male: W = 69.92 ± 5.26; S = 58.8 ± 1.11; N + S = 58.57 ± 2.11.

Fig 6. Perinatal nicotine exposure and cliff avoidance reflex (CAR).

The latency to first fall over the 60 min interval were analyzed. There was no significant difference in the latency to first fall [Mean ± SEM (min): Male: W = 50.41 ± 3.83; S = 48.67 ± 5.56; N + S = 44.84 ± 7.78; Female: W = 53.83 ± 2.91; S = 55.92 ± 3.01; N + S = 58.83 ± 2.08] in male or female mice from the nicotine+saccharin (N + S), saccharin alone (S) and plain drinking water (W) groups.