Characterization of the cognitive impairments induced by prenatal exposure to stress in the rat

Abstract

We have previously shown that male rats exposed to gestational stress exhibit phenotypes resembling what is observed in schizophrenia, including hypersensitivity to amphetamine, blunted sensory gating, disrupted social behavior, impaired stress axis regulation, and aberrant prefrontal expression of genes involved in synaptic plasticity. Maternal psychological stress during pregnancy has been associated with adverse cognitive outcomes among children, as well as an increased risk for developing schizophrenia, which is characterized by significant cognitive deficits. We sought to characterize the long-term cognitive outcome of prenatal stress using a preclinical paradigm, which is readily amenable to the development of novel therapeutic strategies. Rats exposed to repeated variable prenatal stress during the third week of gestation were evaluated using a battery of cognitive tests, including the novel object recognition task, cued and contextual fear conditioning, the Morris water maze, and iterative versions of a paradigm in which working and reference memory for both objects and spatial locations can be assessed (the "Can Test"). Prenatally stressed males were impaired relative to controls on each of these tasks, confirming the face validity of this preclinical paradigm and extending the cognitive implications of prenatal stress exposure beyond the hippocampus. Interestingly, in experiments where both sexes were included, the performance of females was found to be less affected by prenatal stress compared to that of males. This could be related to the finding that women are less vulnerable than men to schizophrenia, and merits further investigation.

Keywords: adolescence; animal models; cognition; gestational stress; schizophrenia; sex differences.

Figure 1

Locomotor activity during open field habituation for the novel object recognition task. (A) Distance traveled decreased with multiple exposures to the open field/testing apparatus (p < 0.01 × 10⁻¹⁶), and prenatally stressed (PS) animals were more active than controls (**p < 0.01). (B) Adolescents engaged in more mobile episodes than adults (***p < 0.00001), but (C) spent less time mobile overall (*p < 0.02), especially on the first exposure (age × exposure interaction, p < 0.01; adolescents <  adults on exposure 1, (p < 0.0001) indicating shorter but more frequent bouts of activity for younger animals. Males and females did not differ on any measure of locomotor activity. Lines above graphs indicate significant group differences. Values are group mean ± SEMs.

Figure 2

Novel object recognition. (A) During the introduction phase, adolescents initiated fewer investigatory bouts with the objects compared to adults (p < 0.0001) and females engaged in fewer investigatory bouts than males (*p < 0.04). (B) Females also spent less time overall investigating the objects during the introduction than males (*p < 0.02). (C) Object recognition memory matured over the periadolescent time frame; adolescents were not competent on this task whereas adult control males (**p < 0.01) and control females (+p < 0.066) performed above chance. Prenatally stressed (PS) males failed to gain competence on this task (p > 0.7), whereas PS females were unaffected (**p < 0.01). Lines above graphs indicate significant group differences. Values are group mean ± SEMs.

Figure 3

Morris water maze. (A) Prenatally stressed (PS) male rats took significantly longer to locate a hidden platform over 3 days of training (*p < 0.04). (B) On a memory retention test 4 days following training, control rats maintained their level of performance, whereas PS rats did not (retention > day 3 training latency, *p = 0.05). Values are group mean ± SEMs.

Figure 4

Fear conditioning. Freezing in response to the tone during conditioning and cue extinction trials conducted 24 and 96 h later in male (A) and (B) female rats. Prenatal stress impaired the development of conditioned responses to the tone (treatment effect, p < 0.05), and females tended to respond more than males (sex effect, p < 0.054). Additionally, sex and treatment interacted (p < 0.03) to influence behavior on the 96 h cue extinction test (C); the ability to extinguish conditioned responses to the tone was impaired in prenatally stressed males (+p < 0.09) but not females, and prenatal stress eliminated the sex difference observed in control animals (***p < 0.0001). Context-dependent freezing was not influenced by either sex or treatment, during either the 24 h (D) or 96 h (E) trials.

Figure 5

Spatial/visual discrimination. (A) Prenatally stressed (PS) male rats made more working memory errors during training on this task (*p < 0.03), particularly on the first day of training (**p < 0.01) and (B) tended to make more working memory errors on a memory retention test 2 weeks following training (+p < 0.066), compared to control animals. (C) Among prenatally stressed (PS) animals, a significant negative correlation was found between the number of working memory errors made on the first day of training and the number of correct trials during the retention test 2 weeks following training (**p < 0.01). (D) Animals trained during their active phase made fewer correct trials (*p < 0.05) and (E) more reference memory errors (**p < 0.01) than those trained during their inactive phase. Values are group mean ± SEMs.

Figure 6

Spatial discrimination. (A) Animals trained during their active phase made more reference memory errors on this task, especially on the first day of training, than animals trained during their inactive phase (phase × training interaction p < 0.03; *p < 0.02). (B) On a memory retention 2 weeks following training, animals traine tested during their active phase committed fewer working memory errors compared to animals trained and tested during their inactive phase (*p < 0.02). Values are group mean ± SEMs.

Figure 7

Visual discrimination: (A) Prenatally stressed (PS) male rats committed more working memory errors than controls (*p < 0.04) on a memory retention test conducted 2 weeks following training. (B) Prenatally stressed male rats also had fewer correct trials (*p < 0.02), (C) more reference memory errors (*p < 0.02), and (D) more working memory errors than controls (*p = 0.05) on a retention test conducted two months following training. (E) On the 2-month retention test, animals trained during their inactive phase made fewer correct trials (**p < 0.01), (F) more reference memory errors (*p < 0.02), and (G) tended to make more working memory errors (+p < 0.071) than rats trained and tested during their inactive period. Values are group mean ± SEMs.