Maternal immune activation and adolescent alcohol exposure increase alcohol drinking and disrupt cortical-striatal-hippocampal oscillations in adult offspring

Abstract

Maternal immune activation (MIA) is strongly associated with an increased risk of developing mental illness in adulthood, which often co-occurs with alcohol misuse. The current study aimed to begin to determine whether MIA, combined with adolescent alcohol exposure (AE), could be used as a model with which we could study the neurobiological mechanisms behind such co-occurring disorders. Pregnant Sprague-Dawley rats were treated with polyI:C or saline on gestational day 15. Half of the offspring were given continuous access to alcohol during adolescence, leading to four experimental groups: controls, MIA, AE, and Dual (MIA + AE). We then evaluated whether MIA and/or AE alter: (1) alcohol consumption; (2) locomotor behavior; and (3) cortical-striatal-hippocampal local field potentials (LFPs) in adult offspring. Dual rats, particularly females, drank significantly more alcohol in adulthood compared to all other groups. MIA led to reduced locomotor behavior in males only. Using machine learning to build predictive models from LFPs, we were able to differentiate Dual rats from control rats and AE rats in both sexes, and Dual rats from MIA rats in females. These data suggest that Dual "hits" (MIA + AE) increases substance use behavior and disrupts activity in reward-related circuits, and that this may be a valuable heuristic model we can use to study the neurobiological underpinnings of co-occurring disorders. Our future work aims to extend these findings to other addictive substances to enhance the translational relevance of this model, as well as determine whether amelioration of these circuit disruptions can reduce substance use behavior.

Fig. 1. Experimental timelines.

Dams were exposed to polyI:C or saline on gestational day (GD) 15. Half of the offspring were then exposed to continuous alcohol from postnatal day (P) 28-42. Behavioral and electrophysiological experiments began in adulthood (>P 70).

Fig. 2. The impact if polyI:C on dams.

A PolyI:C did not impact the number of days of gestation compared to saline-treated dams (controls) (p > 0.05; n = 9/group). B PolyI:C did not impact the number of pups born or M/F pup ratio compared to control dams (p > 0.05; n = 9/group). C Dams treated with polyI:C ate less food than control dams overall (p = 0.002; n = 9/group). D Dams treated with polyI:C drank less water than control dams 24 hours after injection (p < 0.05; n = 8/group). E PolyI:C caused a reduction in body weight 24 hours after injection, but an increase 48 hours after injection, compared to control dams (p < 0.05; n = 9/group). F The impact of polyI:C on IL6 and TNFα concentration 2 hours post-injection. Each dot represents an individual dam. PolyI:C significantly enhanced TNFα levels (p = 0.006; n = 4–5/group), but not IL6 levels (p = 0.08; n = 4–5/group).

Fig. 3. The impact of MIA and AE on offspring drinking behavior.

A Average alcohol consumed (g/kg) during adolescence (P 28–42) in male and female offspring from dams exposed to polyI:C (Dual) or saline (AE). There were no significant differences between groups, except during session 2 (p > 0.05; n = 9–11/group/sex from 4 dams). B Average alcohol consumed (g/kg) in a limited access paradigm across 3 weeks in adult control, MIA, AE, and dual rats. Drinking rates increased across time in all groups (p = 0.05), but Dual offspring drank significantly more alcohol than all other groups during weeks 2 and 3 (p < 0.05; n = 8–11/group/sex from 12 dams). Female rats drank more alcohol than males (p < 0.05).

Fig. 4. The impact of MIA and AE on offspring locomotor behavior.

A MIA reduced total distance traveled in locomotor response to novelty task in male rats (p < 0.05). Female rats overall moved more than male rats (p < 0.05; n = 9–11/group/sex from 8 dams). B MIA and/or AE did not impact the number of center entries; or C the time spent in the center (p > 0.05). Overall, female rats spent less time in the center zone compared to male rats (p < 0.05).

Fig. 5. Cortical-striatal-hippocampal LFPs predict MIA and/or AE exposure.

A Histologic representation of lesions caused by electrode cannula in the mPFC (+3.4 mm from bregma), NAcSh (+1.2 mm from bregma), and CA1 (−3.8 mm from bregma). Electrode wires extended 1 mm from the end of the cannula for the NAcSh, CA1, and PL, and 2 mm for the IL. B Schematic representation of the baseline model building. C LFPs predicted Dual rats from control rats better than the “animal detector” in both males and females (5–10/group/sex from 7 dams). D LFPs predicted Dual rats from MIA rats better than the “animal detector” in females, but not in males (n = 5–13/group from 6 dams). E LFPs predicted Dual rats from AE rats better than the “animal detector” in both males and females (n = 5–10/group/sex from four dams).