1. Introduction
Intrauterine life is thought to be a very important developing period that is sensitive to both external and internal environmental changes. Maternal hormonal and nutritional status effects, which are the consequences of both internal and external (environmental) factors on a pregnant mother’s brain stress system function, are among the main factors which can affect the growth and programming of the fetus. In this regard, studies have shown that stress can induce adverse effects on normal fetus brain development, especially the (hypothalamic-pituitary-adrenal) HPA axis, both in the human and animal models (Glover, O’connor, & O’Donnell, 2010). Among the most important parts of the brain which is affected by prenatal stress is the hippocampus (Weinstock, 2001). The resulting alteration in offspring brain morphology induced by prenatal stress is the change in the offspring’s behavior (Weinstock, 2017), including learning deficit. It is well known that glucocorticoid hormones which are released during stressful events from the mothers’ adrenal glands, and also different inflammatory mediators are produced during and or after stress (Hantsoo, Kornfield, Anguera, & Epperson, 2019; McEwen, Nasca, & Gray, 2016) can easily reach the fetus via blood placenta barrier and cause abnormal growth and development in the fetus (Bronson & Bale, 2016; McEwen, 2019).
Moreover, it is established that maternal malnutrition due to the experience of stressful events can also cause retardation in the fetus (Maghami et al., 2018; Nätt et al., 2017). Data also indicate that prenatal stress adversely affects the offspring’s glutamate N-methyl-D-aspartate (NMDA) receptor dysfunction in the hippocampus (Fang et al., 2018). In their experiments, Fang et al. indicated that offspring from dams that experienced chronic restrain stress from gestational day 8 (GD8) to GD20show lower expression of glutamate NMDA receptor NR1subunit in the hippocampal dentate gyrus, CA1, and CA3 regions (Fang et al., 2018) which was abundant in the male offspring. In another study, it is indicated that prenatal mild chronic stress from GD7 to GD20 in the pregnant female Wistar rats reduced the expression of glutamate NMDA NR2B subunit in the offspring hippocampus in a sex-specific manner (Wang et al., 2016). Interestingly, the offspring in these studies show spatial memory deficiency as they could not find the target page in Morris Water Maze (MWM) task (Fang et al., 2018; Wang et al., 2016), which also was sex-specific. In addition to alteration in glutamate NMDA receptor expression in the hippocampus, studies revealed that the expression of the metabotropic glutamate receptors type 2/3 was also reduced in males but not in female offspring hippocampus with prenatal stress history (Wang et al., 2015).
In addition to the rodents, experiments on primates also revealed that prenatal stress can affect the offspring’s hippocampus development. In this regard, Coe et al. indicated that babies of pregnant Rhesus monkeys which experienced dark room staying stress combined with noise shocks showed an increased basal serum cortisol levels and reduced hippocampal dentate gyrus neurogenesis, and decreased hippocampal volume (Coe et al., 2003). Considering the role of hippocampus neurogenesis in spatial learning and memory and also the pivotal role of the NMDA glutamate receptors within the hippocampus in this regard, it is not surprising that prenatal stress, which can affect both of these two factors, can impair the spatial learning and memory in the offspring (Kim & Diamond, 2002).
On the other hand, increasing research has indicated a role of hippocampal insulin resistance in hippocampal malfunction (Biessels & Reagan, 2015a). Hippocampal insulin resistance is indicated by the lower insulin level and insulin receptor in the hippocampus (Biessels & Reagan, 2015a). Interestingly, prenatal stress is associated with glucose intolerance and insulin resistance (Entringer et al., 2008; Karbaschi, Sadeghimahalli, & Zardooz, 2016; Karbaschi et al., 2017; Rostamkhani, Zardooz, Parivar, & Roodbari, 2013), and deficit in working memory performance. (Entringer et al., 2009). 
However, less attention is paid to the effects of prenatal stress on hippocampal insulin resistance and spatial learning and memory. In the present study, attempts were made for further evaluation of the effects of prenatal stress on spatial learning and memory in offspring and its relation to hippocampal insulin resistance.

2. Materials and Methods
Study animals
Female NMRI mice (n=20; average weight: 25 g), purchased from Pasture Institute, Tehran, Iran, were mated overnight with male (F/M ratio: 2/1), and GD0 was determined by sperm observation in their vaginal smear. After mating, the male mice were removed. The pregnant females were divided into stress and control groups (n=10/group). Animals were kept in cages (2/cage) until delivery at a controlled temperature (22°C±2°C). Standard mouse chow (Pars Animal Food Co, Tehran, Iran) and tab water were available ad lib except during the experiments. Experiments were carried out according to the animal care guidelines, Baqiyatallah University of Medical Sciences Animal Ethics Committee (BMSU/AEC#256).

Experimental procedure
Figure 1 shows the experimental timeline.

Briefly, animals in the stress group experienced electric foot shock stress during GD1 to GD10, remaining undisturbed until delivery. The control group did not experience any stress during pregnancy until delivery. Offspring of all animals were taken care of by their mothers until postnatal day 30 (PND30). On this day, the offspring were separated and randomly assigned to male control, female control, male stress, and female stress groups (n=8/group). On PND31-PND35, Barnes Maze (BM) test was performed. On PND35, the animals were deeply anesthetized, and their brains were removed for hippocampus extraction. At the same time, animals’ blood was collected from their trunk. 

Electric foot shock stress procedure 
Induction of electric foot shock was applied to the pregnant mice between 9 AM and 12noon from GD1 to GD10. For this purpose, each pregnant female mouse was placed in a communication box (Borj-e-Sanat Co., Tehran, Iran) chamber (15×10×50 cm; L×A×H) 30 min before the shock. Then a brief electric shock (0.04 mA) was applied to the animal’s foot (10 Hz) for 6 seconds. The animals were kept in the chambers for an additional 30 min, and after this time, the animals were removed to their home cages. This procedure was repeated in the coming days until GD10.  

Spatial learning and memory testing
The spatial learning and memory tests were performed using a Barnes maze (BM) according to Maghami et al. (2018) with minor modifications. The maze platform was made of opaque blue circular Plexiglas (D: 100 cm) with 18 holes (D: 10 cm) placed at the platform’s edge with equal spacing. The platform was on a base (H: 120 cm) from the ground. An escape box made of black Plexiglas (20×20×20 cm) was attached under one of the holes, which considered as target hole. The target hole had the same position for each animal throughout the test. For spatial cues, black strips with different shapes were attached to the walls of the experimental room, and the experimenter was hidden behind a curtain during the experiments. Animals’activity in the maze was monitored and recorded by a CCTV camera located 90 cm above the maze platform. This device recorded all animal activity and software manufactured by Borj-e-Sanat Co., Tehran, Iran, and could analyze the animals’ movement in the maze. The software offered all factors mentioned in this study, including time and distance traveled by the animal. Each animal experienced four trials per day. For this purpose, each animal was brought to the test room 60 min before the learning trial. The animal was put in the maze’s center under a black bucket while the lights were off. Then the lights were on, the bucket was removed, and the animal was allowed for 90 s (cut-off time) to find the target hole. If the animal did not find the target hole after this time, it was guided by the experimenter to the target hole. To familiarize the animals with the maze environment, one day before starting the learning trials, the animals were put in the escape box for 2 min, then placed directly in the target hole and allowed to enter and stay in the escape box, beneath the hole, for another 2 min. When the animal entered the target hole, it was allowed to stay there for 2 min and then removed to its cage for 15 min. After each trial session, the maze and the target hole were cleaned using 70% ethanol. This procedure was repeated for four consecutive days. For spatial memory testing, on the fifth day, each animal was placed in the maze while the target hole was covered by a dark plate, and each animal was allowed to move in the maze for 90 s freely. The time the animals spent on the plate was recorded as an indicator of the spatial memory index.

Hippocampus extraction
The animals were deeply anesthetized, and their brain was fixed by cold saline transcardiac infusion. The animals’ brains (8 mice/group) were removed surgically and placed on ice for hippocampal removal. After hippocampal removing, it placed in a tube containing the lysis buffer solution (sodium deoxycholate 0.25%=0.025 g, NaCl=0.08 g, SDS=0.01 g, EDTA=0.003 g, protease inhibitor cocktail=1 tablet, Triton X-100 (0.01%)=10 λ) at a rate of 4 times of hippocampus volumes. After homogenization, the suspension was removed and centrifuged at 3500 g for 10 min at 4˚C. Then the supernatant was separated for insulin and insulin receptor assessment. 

Blood and hippocampal insulin and hippocampal insulin receptor content assessment
An ultra-sensitive mouse insulin ELISA kit (minimum detection: 0.02 μg/L; Mercodia, Sweden) and a mouse (Murine) Insulin Receptor ELISA Kit (Cloud-Clone Corp., TX, USA) were used to measure the blood and hippocampus insulin, and hippocampal insulin receptor content, respectively. The measurements were performed in one run, and the intra-assay coefficients of variation were 9.2% and 7.1%. 

Statistical analysis
Data are presented as Mean±SEM (standard error of the mean). To better understand differences, the Area Under The Curve (AUC) was calculated for ‘time and distance spent for reaching target hole’ variables. One-way ANOVA followed by Tukey post hoc test was used. Moreover, The Pearson correlation test was performed to assess the relationship between the variables. In all cases, P<0.05 was considered statistically significant.

3. Results
Effects of prenatal stress on time elapsing to reach the target hole by offspring 
The time elapsed by the offspring from the stress and control groups is presented in Figure 2A.

The data analysis indicated that the male stress and female stress groups needed more time to reach the target hole than the male control and female control groups. (one-way ANOVA; F3, 24=2.415, P < 0.01; Figure 2A). Further post hoc analysis indicated that the male stress group needed more time than the female stress group. 

Effects of prenatal stress on distance traveling to reach the target hole by offspring
Simultaneous distance recording of the animals’ activity also revealed that the male stress and female stress groups traveled longer to reach the target hole than the control groups (one-way ANOVA: F3, 24=12.83, P<0.0001; Figure 2B). Again, post hoc analysis indicated that the male stress group traveled more distances than the female stress group. 

Effects of prenatal stress on offspring blood and hippocampal insulin levels 
The offspring’s plasma insulin level is shown in Figure 3A. Clearly, the male stress and female stress groups had a lower plasma insulin concentration than the control groups (one-way ANOVA; F3, 24=3.68, P<0.01; Figure 3A). The hippocampal insulin level of the male stress and female stress groups also was lower than the control groups (one-way ANOVA; F 3,24=4.9, P<0.01; Figure 3B).

Effects of prenatal stress on offspring hippocampal insulin receptor level
The results of the offspring hippocampal insulin receptor levels are shown in Figure 3C. One-way ANOVA indicates that the offspring belonging to the stressed mothers have fewer insulin receptors in their hippocampus than the offspring belonging to the control (non-stressed) mothers (one-way ANOVA; F3, 24=2.24, P<0.1; Figure 3C).

Relationship between offspring blood and hippocampal insulin level and hippocampal insulin receptor content and their spatial learning 
The Pearson correlation analysis indicates a positive correlation between the stress offspring’s spatial learning deficit and their blood and hippocampal insulin level and their hippocampal insulin receptor content as well (Table 1).

However, this relationship is not seen in the control groups. 

4. Discussion
Prenatal stress-induced spatial learning and memory deficit in offspring and hippocampal insulin resistance were more abundant in the male offspring than in female ones. These findings suggest the importance of prenatal stress on the hippocampus development and function in the offspring. In addition, these findings may indicate the sex difference in response to prenatal stress as the male offspring were more sensitive than the female offspring. 
Results of the present study indicate that the male and female offspring from the stressed dams spend more time and travel more distance to reach the target hole than their counterparts in the control groups. These findings are in agreement with other findings that indicate that prenatal stress can induce spatial learning and memory in rats and mice, which is accompanied by atrophy in the hippocampal neurons and a decrease in neurogenesis in the hippocampus as well (Benoit, Rakic, & Frick, 2015; Bock, Wainstock, Braun, & Segal, 2015; Hosseini-Sharifabad & Hadinedoushan, 2007; Lemaire, Koehl, Le Moal, & Abrous, 2000). For example, Benito et al. ( 2015) have shown that prenatally stressed C57BL/6 mice (dams received chronic unpredictable stress during gestational days) perfume less spatial learning and memory than non-stressed ones in the Morris water maze task. The prenatally stressed animals swam slower and needed a longer time to reach the platform in the task. These researchers also showed several epigenetic changes in the hippocampal neurons, which they proposed to be involved in the spatial learning and memory deficit. In addition, it is shown that prenatal restraint stress from day 15 until delivery (3 times, 45 min) also induced spatial learning deficit in Sprague-Dawley rats. This deficit was accompanied by inhibiting neurogenesis in the hippocampus (Lemaire et al., 2000). It is also shown that prenatal restraint stress (1 h/day from day 15 of pregnancy until delivery) can induce spatial learning deficit and decrease CA3 cell dendritic tree size in Wistar rats’ offspring (Hosseini-Sharifabad & Hadinedoushan, 2007). Interestingly, sex differences are also shown in the previous studies in relation to prenatal stress. In this regard, it is shown that prenatal restraint stress on the female pregnant Sprague-Dawley rats from day 17 of pregnancy until delivery (1 h/day) can inhibit the spatial learning and memory in T and Y maze and also affect passive avoidance test in the offspring (Gué et al., 2004). The male offspring were more vulnerable to deficit than females in this experiment. These findings which are in agreement with our findings, indicated that prenatal stress could affect the hippocampus function in spatial learning and memory. Even though we did not investigate the morphological and epigenetic changes in the hippocampus, similar changes may happen in the animals in our study as well. 
A significant part of our findings was prenatal stress-induced insulin resistance in the hippocampus, which was in relation to spatial learning and memory deficit in the male and female offspring. Our data indicated that prenatal stress decreased plasma insulin levels in male and female offspring. This finding agrees with previous studies in this regard (Lesage et al., 2004). Previous studies indicate that prenatal stress can induce glucose intolerance and reduced basal plasma insulin levels in the offspring (D’mello & Liu, 2006; Lesage et al., 2004; Tamashiro, Terrillion, Hyun, Koenig, & Moran, 2009). Our data also indicated hippocampal insulin content was reduced in male and female stressed offspring. Insulin can cross the blood-brain barrier via an active process, and any decrease in plasma insulin level could be reflected in the brain as well (Banks, 2004; Banks, Owen, & Erickson, 2012; Baura et al., 1993). Prenatal stress-induced plasma insulin level decrement in the offspring might be responsible for our observation.
In addition to hippocampal insulin content decline, a decrease in the hippocampal insulin receptors was also observed in our study. According to previous studies, hippocampal insulin resistance is characterized by hippocampal insulin content and hippocampal insulin receptor content decrement (Biessels & Reagan, 2015b). Our data indicate that prenatal stress can induce hippocampal insulin resistance in male and female offspring. Since hippocampal insulin resistance is considered the main cause of spatial learning and memory deficit (Craft, 2007), it is not surprising that the male and female offspring belonging to the stressed dams showed a decrease in learning and memory in the Barnes Maze task. Interestingly, the spatial learning and memory deficit and hippocampal insulin receptor and insulin content show a significant correlation. This correlation indicates that hippocampal insulin resistance must be considered one of the possible mechanisms involved in the effect of prenatal stress on spatial learning and memory deficit in the offspring. However, the relationship between hippocampal insulin resistance and spatial learning and memory deficit also was sex-specific and the male offspring were more affected than the females. This finding has a potential interest to be the object of future studies in this regard.

Ethical Considerations
Compliance with ethical guidelines
All the experiments were conducted according to the animal care guidelines of Animal Ethics Committee of Baqiyatallah University of Medical Sciences.

Funding
The current work was granted from the Neuroscience Research Center, Baqiyatallah University of Medical Sciences.

Authors' contributions
Investigation: Masoomeh Mohammadi; Conceptualization: Ali Haeri-Rohani; Data curation and methodology: Parichehr Yaghmaei; Writing, review and editing, visualization, supervision, project administration, and funding acquisition: Hedayat Saharei.

Conflict of interest
The authors declared no conflict of interest

Acknowledgments
The authors would like to thank Miss Zahra Bourbour for her kind corporation for data acquisition in this research. 


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