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Published in final edited form as: Behav Brain Res. 2021 Jan 27;403:113145. doi: 10.1016/j.bbr.2021.113145

Maternal immune activation and repeated maternal separation alter offspring conditioned avoidance response learning and antipsychotic response in male rats

Shinnyi Chou 1, Collin Davis 2, Ming Li 3,*
PMCID: PMC7902402  NIHMSID: NIHMS1667227  PMID: 33515643

Abstract

Previous work shows that repeated administration of several commonly used antipsychotic drugs, such as olanzapine (OLZ) over several days, induces an enhanced disruption of conditioned avoidance response (CAR) (termed antipsychotic sensitization) in normal adolescent and adult rats. However, it is unclear whether the same phenomenon can also be demonstrated in rat models of schizophrenia. The present study investigated OLZ sensitization in a combined maternal immune activation (MIA) and repeated maternal separation (RMS) model of schizophrenia. Sprague-Dawley male rats were first subjected to an early prenatal exposure to polyinosinic:polycytidylic acid (PolyI:C) on gestation days 13 (4 mg/kg, iv) and 15 (6 mg/kg, iv). They were then repeatedly separated from their mothers for 3 h daily during the first two weeks of postpartum. After they became adolescent (on postnatal day, PND 43), acute and OLZ sensitization effects in the CAR model was assessed. Adolescent MIA rats showed an impaired acquisition of conditioned avoidance response, but displayed a normal acute OLZ-induced avoidance suppression and OLZ sensitization effect. In adulthood (PND 81), MIA rats again showed an impairment in the acquisition of CAR. However, they showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days, indicating a disruption of the induction of OLZ sensitization. In the OLZ sensitization challenge test, both MIA and control rats exhibited a robust and similar sensitization effect. In both adolescence and adulthood, RMS alone had no effect on any of the behavioral outcomes, and combined MIA-RMS even abolished the MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. These results indicate that MIA disrupts associative learning and may reduce antipsychotic efficacy in the early stage of OLZ treatment. RMS does not appear to affect associative learning and behavioral responses to OLZ, and may possibly attenuate MIA-induced deficits. Our findings demonstrate that OLZ sensitization is a robust phenomenon but its magnitude can be altered by early MIA.

Keywords: Adolescent, Adult, Conditioned avoidance response, Maternal immune activation, Olanzapine, Repeated Maternal Separation

1. Introduction

Early life stress is known to produce persistent behavioral alterations. In particular, maternal immune activation (MIA), a preclinical model of neurodevelopmental disorder induced via cytokine upregulations, has demonstrated to be a valid procedure to induce behavioral abnormalities relevant to clinical symptoms of schizophrenia and autism. These include deficits in latent inhibition [1] sensorimotor gating [2], and working memory [3]. Similarly, repeated maternal separation (RMS), an ecologically driven model of early life stress that disrupts the offspring stress hyporesponsive state and prevents proper neurodevelopment, is shown to cause behavioral alterations in learning such as reduced discrimination index in the novel object recognition task [4], depression-like behavior such as decreased time spent swimming in the forced swim test [5], and anxiety regulation including reduced time spent in the open arms of the elevated plus maze [6].

Research examining rodent MIA models have identified the efficacy of antipsychotic drugs (APD) pretreatment in rescuing some pathological phenotypes, including hypersensitivity to amphetamine-induced hyperlocomotion and working memory deficits [7], [8]. However, there has been no study examining APD’s effect on both MIA and RMS using the conditioned avoidance response (CAR) task, especially the repeated APD treatment-induced sensitization effect [9]. The CAR model is a commonly used behavioral screening tool for antipsychotic drugs, as avoidance suppression is a common and distinct property of antipsychotic drugs but not that of other psychotropic drugs [10]. In recent years, we have shown that repeated treatment with haloperidol, olanzapine (OLZ) or risperidone daily for 5-7 days causes a progressively increased inhibition of avoidance responding (a sensitization effect), and this effect has been demonstrated in both adolescent and adult rats [11–16]. Clinically, APD sensitization plays an important role in treatment considerations, as increased physiological response to APD may influence neurodevelopment in childhood and induce long-term changes in adulthood [17].

The assessment of MIA and RMS, two temporally distinct stressors, allows for comparison of their APD responses both independently and in combination. Previous work has demonstrated synergistic effects of in utero and adolescent insults [18], while others suggest antagonistic outcomes [19]. Some researchers also believe that phenotypes induced by prenatal stress may be “adaptive” to the presumed hostile postnatal environment [20], while others postulate that early mild stress may promote resiliency by “priming” one for similar stressors in later life[21], [22].

In considering these findings, we investigated OLZ sensitization in a combined MIA and RMS model of schizophrenia. OLZ was chosen as a representative atypical antipsychotic drug, as it is one of most widely used drugs in the clinic [23]. Specifically, we examined whether OLZ-induced sensitization in the CAR model in normal rats manifested differently in rats that were subjected to early MIA and RMS. We hypothesized that MIA and RMS would independently disrupt an animal’s behavioral response to OLZ, leading to a reduction in OLZ-induced suppression of CAR and OLZ sensitization, and that this disruption would be augmented with combination MIA-RMS.

2. Material and methods

2.1. Animals

2.1.1. Parent generation

Procedural timeline for animal treatments is depicted in Figure 1. Sprague-Dawley dams (n = 18; parent generation) from Charles River (Portage, MI; gestation day [G] 6 on arrival) were single housed in 48.3 × 26.7 × 20.3 cm transparent polycarbonate cages lined with TEK-Fresh® cellulose that was changed weekly. The facility maintained a 12h light/dark condition (light on between 0630 and 1830 h), 22 ± 1°C and 45-60% humidity. Experiments were run during the light cycle. Food and water were available ad libitum. Beginning two days prior to expected parturition (G 21), dams were monitored twice daily. Parturition was considered postpartum day (PPD) 0. Shredded paper towels were provided as nesting material. On PPD 1, pups were culled to 5 males and 5 females wherever possible. All procedures were approved by the Institutional Animal Care and Use Committee at the University of Nebraska-Lincoln.

Figure 1.

Figure 1.

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Procedural timeline for animal treatments and behavioral testing.

2.1.2. Maternal immune activation (MIA)

Pregnant female rats received either 0.9% saline (n = 10; SAL) or polyinosinic:polycytidylic acid (n = 8; PolyI:C; Sigma-Aldrich, St. Louis, MO) dissolved in 0.9% saline on G 13 (4 mg/kg, iv) and G 15 (6 mg/kg, iv). They were anesthetized with 3% isoflurane and given a single tail vein injection. Weights of pregnant females were recorded both immediately prior to and one day post injection, and MIA was confirmed by PolyI:C induced decrease in total weight gain (data not shown).

2.1.3. Repeated maternal separation (RMS)

Half of all litters from each prenatal treatment (SAL v. MIA) condition underwent 3 h RMS on postnatal days (PND) 2, 3, 4, 6, 8, 10, 12, 13, and 14. This RMS procedure was adopted from our previous study in which we showed that repeated daily 3-h maternal separation from PND 3 to 10 increased the novelty-induced anxiety/fear in adolescent rats and disrupted normal PPI development in adult rats, behavioral abnormalities resembling those seen in schizophrenia [24]. Litters were removed from home cages and placed together in new, clean cages on approximately 37.8°C heating pads housed in a quiet testing room. Dams remained in home cages away from pups. Litters not subjected to RMS (controls [Ctrl]) remained in the colony room throughout.

2.1.4. Experimental groups

Pups were weaned on PND 21 and housed two per cage with same sex littermates in 182 × 50 × 188.1 cm transparent polysulfone individually ventilated cages. Offspring subject male rats (n = 69, female offspring were used in a separate study) were trained and then tested during either adolescence (starting on PND 43) or adulthood (starting on PND 81). They were randomly assigned into four groups according to their ages, MIA and RMS conditions: controls with no stress exposure (SAL-Ctrl; adolescent n = 10; adult n = 9); RMS-only (SAL-RMS; adolescent n = 10; adult n = 9); MIA-only (MIA-Ctrl; adolescent n = 10; adult n = 7); and those exposed to both (MIA-RMS; adolescent n = 7; adult n = 7).

2.2. Apparatus

2.2.1. Two-way avoidance conditioning apparatus

Eight identical two-way shuttle boxes (Med Associates, St. Albans, VT) were used. Each box (64 cm W x 24 cm D x 30 cm H from grid floor) was housed in a ventilated, sound-insulated isolation cubicle (96.52 cm W × 35.56 cm D × 63.5 cm H). Each box was divided into two equal-sized compartments by a partition with an arch style doorway (15 cm H × 9 cm D at base) and a barrier (4 cm H from grid floor) so that rats had to jump in order to cross from one compartment to the other. The grid floor consisted of 40 stainless-steel rods measuring 0.48 cm in diameter spaced 1.6 cm apart center to center, through which a scrambled footshock (unconditioned stimulus [US], 0.8mA, maximum duration: 5 s) was delivered by a constant current shock generator (Model ENV-410B) and scrambler (Model ENV-412). The rat location and crossings between compartments were monitored by a set of 16 photobeams (ENV-256-8P) affixed at the bottom of the box (3.5 cm above the grid floor). Illumination was provided by two houselights mounted at the top of each compartment. The conditioned stimulus (CS; i.e. 76 dB white noise) was produced by a speaker (ENV 224 AMX) mounted on the ceiling of the cubicle, centered above the shuttle box. Background noise (~74 dB) was provided by a ventilation fan affixed at the top corner of each isolation cubicle. All training and testing procedures were controlled by Med Associates programs running on a computer.

2.3. Procedures

2.3.1. Conditioned avoidance response (CAR) training

Subject rats were habituated to CAR boxes for 2 days (30 min/day) then trained for CAR for either 10 consecutive days/sessions (adolescents) or 5 days (adults). Each rat was either trained in adolescence or in adulthood, but not both. Adolescent training lasted for 10 days in order to ensure complete CAR acquisition due to impaired CAR acquisition observed in the MIA-Ctrl animals (see Results section). Each training session consisted of 30 trials. Each trial started with a 10 s white noise (conditioned stimulus, CS), followed by a continuous scrambled foot shock (unconditioned stimulus, US; 0.8 mA, maximum duration 5 s)on the grid floor. These stimuli had been used previously with successful demonstration of CAR acquisition in both adolescent and adult animals [9], [12]–[14], [25]–[30]. Avoidance was recorded if the subject crosses compartments during the CS presentation. Escape was recorded if the subject crosses during the US presentation. If no response was made through both CS and US, the trial was terminated and recorded as escape failure. Inter-trial intervals varied randomly between 30 and 60 s.

2.3.2. Olanzapine (OLZ) sensitization induction and expression (in a challenge test)

One day after the last training session, all rats were given a subcutaneous injection of OLZ 1.0 mg/kg and tested for CAR 1 h later for five consecutive days. This dose of OLZ is equivalent to the clinical dosage used in schizophrenia patients [31], [32]. OLZ (a gift from the NIMH drug supply program) was dissolved in distilled sterile water with 1.0% glacial acetic acid. Only CS (no shock, 30 trials/session) was used to eliminate possible relearning effects caused by the US. Following the five OLZ test days, rats were retrained drug-free for two days, first under the CS-only then under the CS-US, to bring their avoidance back to the pre-drug level before the OLZ challenge test. OLZ sensitization was assessed one day later in a challenge test during which all rats were injected with OLZ 0.5 mg/kg and tested with 30 CS-only trials 1 h later.

2.4. Statistical analysis

All data were expressed as mean ± standard error of mean. Repeated measures mix-factorial ANOVA (between-subjects: SAL/MIA, Ctrl/RMS; within-subjects: Day) was used for CAR training and repeated drug test days. CAR retraining and OLZ challenge were analyzed by multi-factorial ANOVA (between-subjects: SAL/MIA, Ctrl/RMS). All significant differences were followed by post hoc LSD. For all analyses, p < 0.05 was considered statistically significant.

3. Results

3.1. Adolescent conditioned avoidance response training

Throughout the ten days of CAR training, adolescent male rats gradually acquired avoidance response. There was a main effect of Day, F(9,25) = 24.353, p < 0.001, and a significant MIA × RMS interaction, F(1,33) = 8.141, p = 0.007 (Fig. 1). Post hoc LSD indicated that MIA-Ctrl rats made significantly fewer avoidances relative to both SAL-Ctrl and MIA-RMS across the training days (both p=0.009), suggesting that MIA alone impaired the acquisition of conditioned avoidance response in adolescence.

3.2. Adolescent repeated OLZ testing and challenge

Throughout the five OLZ sensitization induction sessions, there was a main effect of Day, F(4,29) = 17.838, p < 0.001 (Fig. 2a). All groups showed increased sensitivity to OLZ across days with gradually increased suppression of CAR. During the two drug-free retraining sessions, although all groups returned to a high level of avoidance response, significant differences were seen on the second drug-free retraining (CS-US) session (Fig. 2b). There was a main effect of MIA, F(1,33) = 8.086, p = 0.008, a main effect of RMS, F(1,33) = 9.639, p = 0.004, and a significant MIA × RMS interaction, F(1,33) = 6.012, p = 0.020. Post hoc LSD indicated that MIA-RMS rats made significantly fewer avoidances compared to all other groups (p < 0.001 relative to SAL-Ctrl, and p = 0.001 relative to both SAL-RMS and MIA-Ctrl), indicating that MIA-RMS rats might have a deficit in re-acquiring avoidance response. No significant group differences were seen in the final OLZ sensitization challenge.

Figure 2.

Figure 2.

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MIA-Ctrl adolescent males displayed disrupted learning in conditioned avoidance response training. Number of avoidance responses made during the ten days of training. *p<0.01 for MIA-Ctrl relative to SAL-Ctrl and MIA-RMS across days.

3.3. Adult conditioned avoidance response training

Similar to adolescent CAR training, the five days of CAR training in adult males improved avoidance response across the training days. There was a main effect of Day, F(4,25) = 45.697, p < 0.001, and a significant MIA × RMS interaction, F(1,28) = 4.792, p = 0.037 (Fig. 3). Post hoc LSD identified a trend of fewer avoidances made by MIA-Ctrl compared to MIA-RMS, p = 0.053, but no differences between MIA-Ctrl compared to SAL-Ctrl or SAL-RMS.

Figure 3.

Figure 3.

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MIA-RMS adolescent males displayed lower number of avoidances during drug-free CAR retraining, but not during OLZ challenge. Number of avoidance responses made by rats during the five OLZ 1.0 mg/kg test days (a). Number of avoidance responses made by rats on the retraining days and the OLZ 0.5 mg/kg sensitization assessment day (b). *p<0.01 for MIA-RMS relative to all other groups.

3.4. Adult repeated OLZ testing and challenge

Similar to adolescent males, adult rats also showed a progressive decrease in avoidance response throughout the five days of OLZ testing (i.e., the induction phase of OLZ sensitization). There was a main effect of Day, F(4,25) = 17.691, p < 0.001 (Fig. 4a). All groups showed increased sensitivity to OLZ across days with stronger suppression of CAR. There was also a main effect of MIA, F(1,28) = 9.804, p = 0.004, with MIA animals displaying higher number of avoidances across days than SAL animals. No significant group differences were seen during the two drug-free retraining sessions or the final OLZ sensitization challenge test (Fig. 4b).

Figure 4.

Figure 4.

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Adult conditioned avoidance response training. Number of avoidance responses made during the five days of training.

4. Discussion

The present study examined the effects of MIA and RMS on CAR learning, acute OLZ effect and OLZ sensitization in a rat model of schizophrenia in both adolescence and adulthood periods. We were particularly interested in whether OLZ sensitization effect would be different in MIA, RMS and MIA-RMS rats compared to normal rats. We demonstrated that MIA disrupted CAR learning in adolescence and adulthood, and reduced OLZ sensitivity in adult males. This was evidenced by the finding that adult MIA rats showed an impairment in the acquisition of CAR and a reduced response to the acute treatment of OLZ (1.0 mg/kg; sc) during the repeated drug test days. RMS had no effect on either the acquisition of CAR or OLZ sensitization, and possibly attenuated the effects of MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. Notably, neither MIA nor RMS significantly altered the magnitude of OLZ sensitization in the challenge test, suggesting that the expression of OLZ sensitization was rather robust.

In this study, we demonstrated behavioral sensitization to repeated OLZ exposure in MIA and RMS offspring using the CAR test, as we have previously shown in normal animals [12]. As most patients on APD receive chronic treatments, preclinical studies addressing chronic APD use are critical in understanding how the treatment efficacy changes over time and the relevant mechanisms. We previously showed that repeated APD exposure can alter the behavioral sensitivity of animals to subsequent treatments, and this phenomenon is persistent from adolescence to adulthood [12], [16]. Here we confirmed that this sensitization is independent of pre- and postnatal early life stress, and that chronic APD-induced changes occur in these individuals. One interesting finding is that adult MIA rats showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days in comparison to control rats, as they showed less decrease in avoidance responding than normal rats, indicating a disruption of the induction of OLZ sensitization. This observation is in agreement with clinical observations that patients with schizophrenia can tolerate higher doses of antipsychotic treatment than healthy controls, who often experience significant adverse events at dose levels that are well tolerated by schizophrenic patients due to the differences in tolerability, bioequivalence and pharmacokinetic parameters [33].

No prior work has shown that in utero PolyI:C disrupts offspring CAR learning. Our previous work using a single G 15 PolyI:C 4.0 mg/kg treatment demonstrated a slight disruption in CAR learning during the first two days of training in PND 31 males, but was not significant overall [34]. Similarly, a previous study incorporating active avoidance learning for latent inhibition assessment found no disruption in avoidance learning in G 15 PolyI:C 4.0 mg/kg MIA adults [35]. This is likely due to the sensitive nature of PolyI:C timing and age dependent phenotypic expression. MIA effects are highly dependent upon procedural factors, and various studies have shown differences in MIA procedures and age of assessment as sources of discrepancies [36]. For example, a study assessing PolyI:C timing clearly indicated differential adult offspring phenotype depending on the period of gestational exposure [37]. Other work have also shown differences in behavioral expression when assessing adolescents versus adults [1]. These discrepancies suggest that while MIA is an important animal model, different manipulations can produce variable results. Here, our findings of MIA disruption in CAR learning may be attributed to a G 13 and 15 MIA regimen that produced developmental alterations sufficient to manifest abnormal active avoidance learning. This impairment was most notable in PND 43 males, while the effect was more attenuated in adulthood, supporting the idea that the timing of early life insults differentially alters developmental outcomes.

Most animal work shows that adult rats who have been reared in a maternal separation condition tend to exhibit increased sensitivity to stress [38]–[40] and increased anxiety or fearlike behavior [41]–[43], mimicking the long-term effects of early childhood trauma and maternal neglect on depression and anxiety disorders [44]–[46]. In the present study, a similar RMS procedure produced no behavioral disruptions, but rather possibly attenuated MIA-induced deficits. This supported a previous finding of prenatal restraint stress-induced PPI alteration being normalized by postnatal RMS exposure [19]. The results here add to the theory of temporally distinct environmental stressors interacting to modulate behavioral outcomes of the offspring.

While our work increased insights into the effects of early stress on learning and APD response, the complex nature of differential behavioral expressions in offspring based on MIA and RMS regimens remains a factor difficult to untangle. Another concern to address in examining the effects of early stress on APD response is the need for validation with other early life stress paradigms in order to increase generalizability. Given differences in APD receptor pharmacology, future work exploring these paradigms using other APD agents would be necessary as well. In summary, results from the current study provided novel and clinically relevant findings. We verified that OLZ behavioral sensitization does occur in both rodent MIA and RMS models of schizophrenia, confirming the phenomenon to be independent of these rodent models of early stress and psychiatric disorders. These findings provide an incentive to investigate such a sensitization effect in human subjects. This may help understand the behavioral and neurobiological mechanisms underlying antipsychotic effects.

Figure 5.

Figure 5.

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MIA-Ctrl adult males displayed reduced sensitivity to OLZ during repeated drug testing, but not during OLZ challenge. Number of avoidance responses made by rats during the 5 OLZ 1.0 mg/kg test days (a). Number of avoidance responses made by rats on the retraining days and the OLZ 0.5 mg/kg sensitization assessment day (b). *p<0.01 between drug treatment conditions.

Acknowledgements

This study was funded in part by the NIMH grant (R03HD079870) to Professor Ming Li.

Footnotes

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Conflict of interest

The authors declare no conflict of interests.

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