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. Author manuscript; available in PMC: 2023 May 1.
Published in final edited form as: Alcohol Clin Exp Res. 2022 Apr 18;46(5):891–906. doi: 10.1111/acer.14818

Prenatal ethanol exposure impairs sensory processing and habituation of visual stimuli, effects normalized by postnatal environmental enrichment

Ruixiang Wang 1, Connor D Martin 1, Anna L Lei 1, Kathryn A Hausknecht 1, Marisa Turk 1, Veronika Micov 1, Francis Kwarteng 1, Keita Ishiwari 1, Saida Oubraim 1, An-Li Wang 1, Jerry B Richards 1, Samir Haj-Dahmane 1, Roh-Yu Shen 1,*
PMCID: PMC9122102  NIHMSID: NIHMS1793191  PMID: 35347730

Abstract

Background.

Individuals with fetal alcohol spectrum disorders (FASD) often show sensory processing deficits in all sensory modalities. Using an operant light reinforcement model, we tested if prenatal ethanol exposure (PE) could alter operant responding to elicit a contingent sensory stimulus - light onset (turning on light) and habituation of this behavior in rats. We also explored if postnatal environmental enrichment could ameliorate PE-induced deficits.

Methods.

Pregnant Sprague Dawley rats were gavaged twice/day with 0 or 3 g/kg/treatment ethanol (15% w/v) during gestational days 8–20, mimicking second-trimester heavy PE in humans. The offspring were reared in the standard housing condition or an enriched condition. Adult male and female offspring underwent an operant light reinforcement experiment with either a short-access or a long-access procedure. A dishabituation test was also conducted to further characterize the habituation process.

Results.

In the short-access procedure, PE led to increased operant responding to the contingent light-onset in both sexes reared in the standard housing condition. Such an effect was not observed in rats reared in enriched condition due to an overall decrease in responding. Moreover, rats reared in enriched condition showed greater short-term habituation. In the long access procedure, PE rats showed increased responding and impaired long-term habituation. The long-access procedure facilitated both short-term and long-term habituation in control and PE rats.

Conclusion.

Prenatal ethanol exposure increases responding to contingent light-onset and impairs the long-term habituation process. The PE-induced deficits could be ameliorated by rearing in the enriched environment and increasing the duration and frequency of exposure to light-onset. The PE-induced effects are similar to increased sensation-seeking, a subtype of sensory-processing deficits, which is often observed in individuals with FASD. Our findings could inform a suitable animal model for investigating the underlying mechanisms as well as possible intervention strategies for these deficits in FASD.

Keywords: fetal alcohol spectrum disorders, light reinforcement, habituation, dishabituation, sensation-seeking, stimulus generalization

Introduction

Prenatal ethanol exposure (PE) causes many physical, behavioral, and cognitive deficits, referred to as fetal alcohol spectrum disorders (FASD). There is a high prevalence of FASD: an estimated 2 – 5% of school-aged children in the US are affected by FASD (May et al., 2009, May et al., 2014). A group of commonly observed deficits in FASD is impaired sensory processing (Jirikowic et al., 2020; Schneider et al., 2011). Sensory processing refers to the complex processes in the central nervous system linking sensory inputs and the corresponding behavioral output, the deficits of which in individuals with FASD are mainly characterized by over responsiveness to innocuous or irrelevant stimuli, impaired habituation, or difficulty in transitioning to a different/novel environment (Franklin et al., 2008, Stade et al., 2006, Jirikowic et al., 2008, Wengel et al., 2011, Fjeldsted and Xue, 2019, Jirikowic et al., 2020).

Tactile over responsiveness has been studied in primate models of FASD (Schneider et al., 2008; Schneider et al., 2017). Reduced habituation to olfactory stimuli has been shown in rodent models of FASD (Barron and Riley 1992). In contrast, to our knowledge, there are no animal studies investigating how PE impacts visual sensory processing, deficits of which are observed in clinical studies, nonetheless (Streissguth et al., 1983). The goal of the present study was to bridge the gap, using an established operant light reinforcement paradigm with the contingent light-onset (turning on light) as a visual sensory reinforcer. It has been observed that sensory stimuli, such as the contingent light-onset has rewarding properties and can serve as moderate primary reinforcers compared to other rewards (e.g., food, water, and drugs) to elicit responding (Lloyd et al., 2012a, Lloyd et al., 2014, Wang et al., 2018a, Redgrave and Gurney, 2006). There are several advantages of using an operant light reinforcement paradigm to investigate how sensory stimuli are processed including the habituation process. First of all, it allows focusing on a specific visual stimulus instead of unspecific stimuli in a novel environment. It can also adapt to multi-session testing with various reinforcement schedules. The operant paradigm directly investigates behavioral responses as a result of sensory stimulation. In addition, the light reinforcement paradigm has been suggested as a rodent model for sensation-seeking, i.e., being exceedingly active in responding (Olsen and Winder, 2009, Gancarz et al., 2012), which is a sensory processing deficit found in FASD (Jirikowic et al., 2008, Wengel et al., 2011). The light reinforcement paradigm is especially suitable for investigating the unique features of habituation to specific visual stimuli (Wang et al., 2018a, Lloyd et al., 2012a). As such, both short-term and long-term habituation as well as the dishabituation process after PE were investigated in the present study. Although habituation is the simplest form of learning, the PE effects on this process are not well known. The results from the present study will characterize PE-induced deficits in the habituation process.

Although there are few treatment options for FASD (Murawski et al., 2015), significant improvements of various deficits have been observed in children with FASD who are raised in favorable environments (Petrenko, 2015). These observations are consistent with animal studies showing that environmental enrichment could ameliorate various PE-induced deficits (Gursky and Klintsova, 2017, Hannigan et al., 2007, Hamilton et al., 2014, Hannigan and Berman, 2000). In our laboratory, we have applied the environmental enrichment approach to effectively ameliorate PE-induced cellular and cognitive/behavioral deficits including deficits in executive function and increased addiction risk (Wang et al., 2018a, Wang et al., 2018b, Aghaie et al., 2020). This approach consists of neonatal handling before weaning (Raineki et al., 2014) and complex housing after weaning (Wang et al., 2018a, Wang et al., 2018b, Aghaie et al., 2020). Such combined method has produced additive beneficial effects previously (Escorihuela et al., 1994, Fernández-Teruel et al., 2002, Pham et al., 1999). Importantly, this intervention strategy has shown to reduce responding to contingent light-onset and improve the habituation process (Wang et al., 2018a). Therefore, we investigated if possible PE-induced deficits in sensory processing including habituation could be ameliorated by postnatal environmental enrichment.

Materials and Methods

Animal breeding and prenatal ethanol treatment

Rats were bred in house to control the prenatal environment and eliminate potential prenatal stress caused by transportation (Prager et al., 2011). The breeding procedure has been described previously (Wang et al., 2019). In brief, male and 3-month-old virgin female Sprague-Dawley rats (Envigo, Indianapolis, IN, USA) were paired until copulatory vaginal plugs were spotted (on gestational day/GD 0). Pregnant dams were then randomly assigned to the control or PE group and singly housed in standard plastic cages. The colony room was maintained with temperature at 20 – 26°C and humidity at 40 – 60%.

During gestational day (GD) 8 – 20, pregnant dams were administered twice (5 – 6 h apart) with 3 g/kg/treatment ethanol (15% w/v in 0.9% saline) or vehicle (22.5% w/v sucrose in 0.9% saline, isocaloric to ethanol) via intragastric gavage every weekday. A single daily treatment with 4 g/kg solutions was given on weekends. The blood ethanol concentration was 116.3 ± 10.4 mg/dL, measured 1 hour after the 2nd gavage on weekdays. The PE treatment paradigm in rats is comparable to heavy prenatal alcohol exposure in humans (Eckardt et al., 1998, Shen et al., 1999). In addition, control dams were pair-fed with PE dams on GDs 8 – 20 to equate nutrient intake from rat chow across groups. Food was provided ad lib after GD 20. The dams of both groups also received thiamine-containing vitamin B administrations (containing 8 mg/kg ; i.m.; twice/week during GDs 8 – 20; Super B Complex, Vedco, Saint Joseph, MO) to avoid thiamine deficiency caused by the ethanol treatment or the pair-feeding procedure (Galvin et al., 2010, Kloss et al., 2018, Vedder et al., 2015).

On postnatal day (PD) 1, each litter was culled to 10 pups (with equal numbers of males and females when possible) and the pups born to PE dams were fostered by extra dams that received no treatment and gave birth one day or two earlier. The purpose of this cross-fostering procedure was to prevent maternal negligence or undernutrition caused by alcohol withdrawal in PE dams. The control pups were exchanged between litters.

Rearing conditions

There were two different rearing conditions: standard housing condition and enriched condition. Before weaning, pups reared in the enriched condition underwent neonatal handling, which was a brief (15 min/day) maternal separation and handling procedure on PDs 2 – 20. Neonatal handling served as a complementary enrichment procedure by enhancing maternal behavior during early development (Fernández-Teruel et al., 2002, Van Praag et al., 2000). Pups reared in the standard housing condition were kept undisturbed from the experimenters except for weekly cage changes.

After weaning on PD 21, rats in the enriched condition were group housed (10 – 20/cage; same sex; with the same prenatal treatment) in large 4-level wire cages with internal ramps (L × W × H: 36 × 24 × 48 in; Model: CG-71111; Petco, San Diego, CA, USA) containing 30 pet toys/cage, including wheels, balls, hanging hideouts, ladders, and ropes (Petco). The toys were relocated or changed every weekday to create novelty (see more details in Wang et al. 2018a). In contrast, rats in the standard housing condition were kept in pairs in standard plastic cages (L × W × H: 10.5 x 19 x 8 in.) on direct bedding after weaning. The floor spaces/rat for standard housed rats and enriched rats are 77 in2 and 259 – 518 in2 , respectively. The behavioral experiments were conducted when the rats were 9 – 12 weeks old. The rearing conditions were maintained until the completion of the study.

Apparatuses

Twenty-four locally-made operant boxes (L × W × H: 9.5 × 8.7 × 7.8 in) were utilized in the light reinforcement experiment, which have been described in detail previously (Lloyd et al., 2012b). Each box was situated in a sound-and-light-attenuating chamber. There was a snout poke hole on each of the left and right side-walls. A stimulus light was mounted on the ceiling, midway between the two holes (Fig. 1A). The light could produce an illuminance of 68 lx, as measured in the center of the box. Snout pokes could be detected by infrared photo sensors. An interface (MED Associates, Fairfax, VT, USA) connected the boxes to a desktop computer. The MED PC® language was used for programming.

Figure 1.

Figure 1.

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Light reinforcement experiment paradigm and bodyweight of dams and offspring. (A) Left panel illustrates the operant box used in the light reinforcement experiment. Right panel depicts the short- and long-access procedures of the light reinforcement experiment. (B) Left panel depicts body weight of the dams. The only differences is between foster dams and ethanol treated dams. The middle and right panel depict the offspring bodyweight in males and females, respectively. Significant differences were found between standard housed and enriched conditions. No differences were found between control and PE rats. *: p < 0.05, foster dams vs PE dams bodyweight. ##: p < 0.01; ###: p < 0.001, bodyweight in rats in standard housing vs. enriched condition.

Light reinforcement experiment

The light reinforcement experiment comprised two phases: the pre-exposure phase and the light-onset phase. Most of the rats underwent a short-access procedure in which each experimental phase was composed of six 30-min daily sessions (Fig. 1A). The two snout poke holes were randomly designated as active and inactive holes. In the pre-exposure phase, snout pokes into both holes produced no programmed consequences in unlit boxes. The purpose of having the pre-exposure phase was to let rats acclimate to the testing boxes so that they were less likely to be distracted by other features inside the box when the stimulus light was introduced later (Lloyd et al., 2012b, Leaton et al., 1963). In the light-onset phase, snout pokes into the active hole led to the onset of light illumination for 5 s under a variable-interval schedule (average interval = 1 min), whereas snout pokes into the inactive hole had no programmed consequences.

To investigate if session length and duration can influence the habituation process, a long-access procedure (Fig. 1A) was employed in additional female control and PE rats reared in the standard housing condition. The long-access procedure consisted of ten 60-min sessions in each experimental phase (Wang et al., 2018a).

Additionally, to further characterize the habituation process, a 60-min dishabituation session was scheduled following the light-onset phase in the long-access procedure (Fig. 1A). The dishabituation session was programmed like a regular light-onset session except that during the 31st – 36th min of the session when responding was leveled off, a loud (~90 dB) warbling sound was continuously on (see more details in Wang et al., 2018a). We observed how presentation of this new stimulus could impact animals’ responding to the contingent light-onset. All experimental procedures involving animals were performed in accordance with the University at Buffalo Institutional Animal Care and Use Committee guidelines.

Data Analysis

The contingent light-onset served as a reinforcer in the light reinforcement experiment. To assess reinforcer effectiveness, we compared proportion of active responding (i.e., nose pokes to the active hole to total responding) between groups (Lloyd et al., 2014, Wang et al., 2018a).

We observed habituation of responding within the session (short-term habituation) and between sessions (long-term habituation). To assess habituation, we computed area under the curve (AUC) described in detail previously (Myerson et al., 2001, Wang et al., 2018a). Briefly, to compute AUC for within-session habituation, only the first 18 min from six 3-min epochs of active responses in each session were analyzed because the active responses typically leveled off after this period of time (Wang et al., 2018a). The number of responses in each 3-min epoch was normalized to the maximum number of responses in an epoch of that session which typically occurred in the first epoch. Using the normalized values as y-coordinates, the six epochs were partitioned into five trapezoid areas, and the sum of the five areas was AUC. A smaller AUC indicated a faster decline in responding and thus faster within-session habituation. In the first two sessions during the light-onset phase, fluctuations in responding occurred frequently because rats were acquiring the newly-introduced sensory contingency. As such, light-onset session 1 – 2 were excluded from AUC computation. To analyze long-term between-session habituation patterns, we also computed AUCs using total numbers of active responses/session.

One-, two-, or three-way analysis of variance (ANOVA) was used in statistical analysis. Litter was included as a nested factor in ANOVA to control for potential litter effects because pups were “nested” under litters. This approach has been utilized previously to appropriately report and control litter effects in prenatal ethanol exposed animals by us and others (Aghaie et al., 2020, Wang et al., 2020, Wang et al., 2019, Angelucci et al., 1999). Planned comparisons were employed in pairwise comparisons after ANOVA. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). The significance level was set at α = 0.05. Data are expressed as mean ± SEM unless specified otherwise.

Results

Prenatal ethanol exposure led to slightly lower birthweight; enriched condition consistently reduces adult bodyweight.

The weight of control (n=25), PE (n=26), and foster dams (n=26) during GD 6-20 were analyzed and an interaction effect between group and GD was found (two-way ANOVA with mixed design, F28,1036 = 7.62, p < 0.001; Fig. 1B left panel). The major group difference was between the foster dams and PE dams (planned comparison following two-way ANOVA, p < 0.05). No differences were found between control and PE dams. The results show the pair-feeding procedure effectively controlled the possible nutritional differences between control and PE animals. Prenatal ethanol exposure did not lead to a reduction in litter size (two-way ANOVA; interaction effect between prenatal treatment and sex, F1,53 = 10.56, p < 0.01; Table 1). Interestingly, there were more male pups than female pups in PE litters (male: female = 1.31:1; p < 0.01, planned comparison), but no such difference was observed in control litters. In addition, PE led to a slight but significant reduction (2.15%) in pup bodyweight on PD 1 (two-way ANOVA with litter as a nested factor; main effect of prenatal treatment, F1,638 = 41.41, p < 0.001; main effect of sex, F1,638 = 65.95, p < 0.001; litter effect, F53,638 = 20.26, p < 0.001; Table 1). The bodyweight on PD 1 was also higher (2.68%) in males than in females regardless of prenatal treatment (Table 1). Taken together, PE paradigm in the present study did not lead to major teratogenic effects on litter size or birthweight.

Table 1.

Birth outcome

Control: 27 litters (mean ± SEM) PE: 28 litters (mean ± SEM) P-Value
Litter Size 13.15 ± 0.49 12.14 ± 0.57 0.196
   Number of Male Pups   6.15 ± 0.42   6.89 ± 0.41 0.176
   Number of Female Pups   7.00 ± 0.38   5.25 ± 0.31 <0.01
Pup weight on Postnatal Day 1
   Average Weight (g)   6.54 ± 0.04   6.40 ± 0.04 <0.001
   Average Male Weight (g)   6.74 ± 0.06   6.52 ± 0.05 <0.001
   Average Female Weight (g)   6.37 ± 0.06   6.25 ± 0.06 <0.001
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Note. PE: prenatal ethanol exposure. P-values are based on planned comparisons following ANOVA. Data are expressed as mean ± SEM.

We also recorded the bodyweight of offspring from late adolescence to young adulthood (Fig. 1B). The results confirmed PE did not influence the bodyweight. In males, we did not observe PE effects but a significant effect of the enriched condition. Rats in the enriched condition had lower body weight (planned comparison: p < 0.001 following three-way repeated measures ANOVA with litter as the nested factor: two-way interaction effect between postnatal rearing condition and age, F4,256 = 5.76, p < 0.001; litter effect: F13,61 = 6.52; p < 0.001; control standard housed: n = 18, control enriched, n = 20, PE standard housed, n = 20, PE enriched, n = 20; Fig. 1B, middle panel). In female offspring, no PE effects were observed and rats in the enriched condition also had lower bodyweight (planned comparison: p < 0.001; following three-way repeated measures ANOVA: two-way interaction effect between postnatal rearing condition and age: F4,256 = 5.76, p <0.001; n = 20 in all four groups; Fig. 1B right panel).

In the short-access procedure basal responding during the pre-exposure phase was impacted by PE, sex, and postnatal rearing conditions.

One hundred and twenty rats from 38 litters underwent the short-access light reinforcement procedure (see Table 2 for animal/litter numbers; Fig. 1). In the pre-exposure phase, where the animals were habituating to the operant boxes and responses did not elicit light on-set, there were no differences in mean responses/session (numbers of snout pokes) between the designated active and inactive snout poke holes in any group (one-way repeated measures ANOVA; see Table 2 for percent active responding in each group), indicating that the operant boxes were unbiased.

Table 2.

Animal/litter information and proportions of responses in designated active hole

Sex Prenatal Treatment Rearing Condition # Rats / # Litters % responses from designated active hole
Male Control Standard 14 Rats / 6 Litters 51.69 ± 2.76
PE Standard 16 Rats / 6 Litters 50.64 ± 1.89
Control Enriched 16 Rats / 5 Litters 53.18 ± 2.69
PE Enriched 16 Rats / 5 Litters 50.76 ± 2.35
Female Control Standard 14 Rats / 5 Litters 46.95 ± 2.22
PE Standard 14 Rats / 5 Litters 48.91 ± 2.39
Control Enriched 16 Rats / 3 Litters 52.75 ± 2.65
PE Enriched 14 Rats / 3 Litters 50.80 ± 1.57
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Note. PE: prenatal ethanol exposure. % active response: average proportion of active responses in total responses cross 6 sessions in each phase. Data are expressed as mean ± SEM.

In males, no differences were observed in responses/session to the designated active hole between control and PE groups regardless of postnatal rearing condition. However, rats reared in the enriched condition responded much less than rats reared in the standard housing condition regardless of prenatal treatment (three-way repeated measures ANOVA: prenatal treatment, rearing condition, & sessions, with litter as a nested factor; main effect of rearing condition, F1,40 = 133.30, p < 0.001; main effect of session, F5,290 = 6.45, p < 0.001; Fig. 2A). We also observed that enriched condition led to a reduction in responding to the designated inactive hole in both control and PE rats (Fig. 2A).

Figure 2.

Figure 2.

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Prenatal ethanol exposure (PE) led to increased responding to the contingent light-onset in the short-access light reinforcement procedure, effects normalized by environmental enrichment. (A) depicts numbers of active and inactive responses (nose pokes) in each 30-min session during the pre-exposure and light-onset phases in males. In the pre-exposure phase, there were no differences between control (Ctl) and PE rats in either the designated active or inactive hole regardless of rearing condition. In the light-onset phase, PE rats made more active responses than controls in the standard housing condition, an effect not observed in the enriched condition. Moreover, enriched condition led to reduced responding. (B) Numbers of active and inactive responses in each session in females. In the pre-exposure phase, PE rats made more responses toward designated inactive hole than controls in the standard housing condition, an effect not observed in the enriched condition. In the light-onset phase, PE females made more responses toward both holes than controls in the standard housing condition, effects not observed in rats reared in enriched condition. Enriched condition led to significantly reduced responding in all groups. Data are expressed as mean ± SEM in curve and bar charts. *: p < 0.05; ***: p < 0.001, control vs. PE rats in the same sex and rearing condition. ###: p < 0.001, rats in standard housing vs. enriched condition of the same sex. P-values are based on planned comparisons following ANOVA.

Similarly, in females, enriched condition led to decreased responding to both active and inactive holes regardless of prenatal treatment. Different from male PE rats, female PE rats reared in the standard housing condition responded more than their control counterparts to the designated inactive hole (three-way repeated measures ANOVA with litter as a nested factor; interaction effect between prenatal treatment and rearing condition, F1,42 = 4.52, p < 0.05; interaction effect between rearing condition and session, F5,270 = 5.12, p < 0.001; litter effect, F12,42 = 4.29, planned comparison p < 0.001; control vs. PE females reared in standard housing condition: p < 0.05; Fig. 2B), but not to the designated active hole.

In the short-access procedure, contingent light-onset was an effective sensory reinforcer for all the rats.

In order to confirm that the contingent light-onset indeed had reinforcing effects, we used the proportion of active response as an index for reinforcer effectiveness in the short-access procedure. We compared this index between pre-exposure and light-onset phases in the short-access procedure in both sexes. Rats in all group show significant increase in the mean proportion of active responses in the light-onset phase (three-way repeated measures ANOVA with litter as a nested factor: prenatal treatment, rearing condition, and phase; male: interaction effect between rearing condition and phase, F1,58 = 8.68, p < 0.01; planned comparison: p < 0.001 between phases for control, PE rats in standard housing condition and PE rats in enriched condition; p < 0.01 for controls in enriched condition; female: main effect of phase, F1,54 = 54.13, p < 0.001; planned comparison: p < 0.001 between phases for control, PE rats in standard housing condition and control rats in enriched condition; p < 0.05 for PE rats in enriched condition; Fig. 3 A & B). These results indicate that the contingent light-onset produced reinforcing effects for all rats (Leaton et al., 1963).

Figure 3.

Figure 3.

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Prenatal ethanol exposure (PE) led to increased reinforcer effectiveness of the contingent light-onset in both sexes in the short-access procedure. (A) & (B) left panels depict reinforcer effectiveness, measured by percent active responding, in each session in males and females, respectively. (A) & (B) right panels are scatter plots depicting average reinforcer effectiveness in pre-exposure and light-onset phases in male and female rats. In the pre-exposure phase, the reinforcer effectiveness was around 50% in any group. In the light-onset phase, the reinforcer effectiveness was significantly greater than 50% in all groups, indicating that the contingent light-onset was reinforcing for all rats. In males reared in standard housing condition, PE rats showed increased reinforcer effectiveness than controls. These effects were not observed in females. In addition, in females reared in the enriched condition, PE rats show lower reinforcer effectiveness then controls. Reinforcer effectiveness was reduced by environmental enrichment regardless of prenatal treatment. Data are expressed as mean ± SEM *: p < 0.05; **: p < 0.01, control vs. PE rats in the same sex and rearing condition. ##: p < 0.01; ###: p < 0.001, standard housing vs. enriched rats. P-values are based on planned comparisons following ANOVA.

In the short-access procedure, PE led to increased reinforcer effectiveness only in male rats.

We compared the reinforcer effectiveness between groups using proportion of active responses over total responses in the short-access procedure. In males, the reinforcer effectiveness was greater in PE rats than in their control counterparts reared in standard housing condition (p < 0.01, planned comparison after three-way repeated measures ANOVA with litter as a nested factor: prenatal treatment, rearing condition, and sessions; main effect of treatment, F1,40= 12.41, p < 0.01; main effect of rearing condition, F1,40= 40.54, p< 0.001; litter effect, F18,40= 4.07, p < 0.001; Fig. 3A). In addition, enriched condition led to a reduction in reinforcer effectiveness when compared to the standard housing condition in both control (p < 0.01) and PE (p < 0.001) rats.

Interestingly, in females, the only group difference observed was that PE rats showed lower reinforcer effectiveness than controls reared in the enriched condition (p < 0.05, planned comparison following three-way repeated measures ANOVA with litter as a nested factor; main effect of treatment, F1,40 = 17.51, p < 0.001; main effect of rearing condition, F1,42 = 6.27, p < 0.05; litter effect, F12,42 = 2.90, p < 0.01; Fig. 3B).

In addition, sex differences were observed in PE rats. The reinforcer effectiveness was greater in males than in females regardless of rearing condition (three-way ANOVA on mean percent active responding/session: sex, prenatal treatment, and rearing condition, with litter as a nested factor; sex × treatment interaction effect, F1,82 = 17.76, p < 0.001; sex × rearing condition interaction effect, F1,82 = 6.85, p < 0.05; litter effect, F30,82 = 3.38, p < 0.001; in the standard housing condition, male vs female PE rats, p < 0.001, planned comparison; in the enriched condition, male vs. female PE rats, p < 0.05; Fig. 3).

In the short-access procedure, PE led to greater responding to contingent light-onset in rats reared in standard housing condition but not in rats reared in enriched condition.

In the light-onset phase of the short-access procedure, male PE rats reared in the standard housing condition made more responses to the active hole than their control counterparts (p < 0.001, planned comparison following three-way repeated measures ANOVA: prenatal treatment, rearing condition, & sessions, with litter as a nested factor; prenatal treatment x rearing condition interaction effect, F1,40 = 7.37, p < 0.01; interaction effect between rearing condition and session, F5,290 = 5.66, p < 0.001; litter effect, F18,40 = 11.09, p < 0.001; Fig. 2A), an effect not observed in male rats reared in the enriched condition. The lack of differences could be due to that enriched condition led to a major reduction in responding to the active hole regardless of prenatal treatment (p < 0.001; planned comparison).

Similar effects were observed in females. Specifically, PE resulted in increased responding to the active hole under standard housing condition (p < 0.05, planned comparison following three-way repeated measures ANOVA with litter as a nested factor; interaction effect between prenatal treatment and rearing condition, F1,42 = 7.59, p < 0.01; main effect of session, F5,270 = 2.92, p < 0.05; litter effect, F12,42 = 14.25; Fig. 2B). Environmental enrichment led to a reduction in responding in both control and PE rats (p < 0.001; planned comparison).

For responses to the inactive hole, a similar reduction by enriched condition was observed (p < 0.001; planned comparison after three-way repeated measures ANOVA with litter as a nested factor; prenatal treatment × rearing condition interaction effect, F1,42 = 16.03, p < 0.001; litter effect, F12,42 = 5.50, p < 0.001; Fig. 2C & D ; Fig. 2A).

Lastly, PE female rats reared in the standard housing condition made more responses to the inactive hole than controls (p < 0.001, planned comparison following three-way repeated measures ANOVA with litter as a nested factor; prenatal treatment × rearing condition interaction effect, F1,42 = 16.03, p < 0.001; litter effect, F12,42 = 5.50, p < 0.001; Fig. 2B).

In the short-access procedure, PE did not alter within-session habituation to the contingent light-onset but environment enrichment facilitated it.

Within-session/short-term habituation to the contingent light-onset was quantified with AUC in the short-access procedure. In males, no differences in AUC were observed between control and PE rats regardless of rearing condition (Fig. 4). However, relative to the standard housing condition, enriched condition led to a reduction in AUC in both control and PE rats, indicating faster within-session habituation (three-way repeated measures ANOVA: prenatal treatment, rearing condition, and light-onset sessions 3 – 6, with litter as a nested factor; main effect of rearing condition, F1,40 = 152.90, p < 0.001; main effect of session, F3,174 = 6.81, p < 0.001; Fig. 4).

Figure 4.

Figure 4.

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In the short-access procedure, prenatal ethanol exposure (PE) did not alter within-session/short-term habituation. Enriched condition facilitated within-session/short-term habituation. (A) Active responses in the first 18 min of each session during the light-onset phase in both sexes. (B) Average area under the curve (AUC) data measuring within-session/short-term habituation from session 3 - 6. (C) Scatter plots summarize group comparisons, using mean AUCs across sessions shown in (B). No differences in AUC were observed between control (Ctl) and PE rats of either sex reared in the standard housing condition. Environmental enrichment led to decreased AUC indicating faster habituation regardless of sex or prenatal treatment. Moreover, in female rats reared in enriched condition, PE rats had lower AUC/faster habituation than controls. Data are expressed as mean ± SEM (B) & (C). ***: p < 0.001, control vs. PE in enriched female rats. ###: p < 0.001, standard housing vs. enriched condition of the same sex. P-values are based on planned comparisons following ANOVA.

Similar effects were observed in females (Fig. 4). Faster habituation was observed rats reared in enriched condition regardless of prenatal treatment (three-way repeated measures ANOVA with litter as a nested factor; interaction effect between prenatal treatment and rearing condition, F1,42 = 7.39, p < 0.01; main effect of session, F3,162 = 7.23, p < 0.001; litter effect, F12,42 = 2.02, p < 0.05; Fig. 4B & C). Furthermore, in females with environment enrichment, within-session AUCs were reduced in PE rats compared to controls, indicating faster habituation (p < 0.001, planned comparison; Fig. 4B & C).

In the long-access procedure, PE led to greater responding to contingent light-onset.

To further characterize the PE effects on sensory and the habituation process to sensory stimuli, we also conducted the a long-access procedure consisting longer session duration and more sessions. These effects were conducted in additional female rats reared in the standard housing condition (control: n = 22 rats/8 litters; PE: n = 14 rats/5 litters). We chose to test females only since there was no sex effects in these parameters in the short-access program. Several effects in the long-access procedure were similar to those observed in the short-access procedure. First, mean proportion of active responses (from 10 sessions) between increased significantly in the light-onset phase for both control and PE rats, confirming the reinforcer effectiveness of light-onset (three-way repeated measures ANOVA with litter as a nested factor: prenatal treatment, rearing condition, and phase; main effect of phase, F1,34 = 406.19, p < 0.001; planned comparison: p < 0.001 between phases for both control and PE rats). PE also led to an overall increase in responding to the contingent light-onset (two-way repeated measures ANOVA with litter as a nested factor; main effect of prenatal treatment, F1,23 = 28.36, p < 0.001; main effect of session, F9,306 = 22.57, p < 0.001; litter effect, F11,23 = 10.81, p < 0.001; Fig. 5A). Increased responding to the inactive hole was also observed in PE rats during both pre-exposure and light-onset phases (p < 0.001; Fig. 5A). Furthermore, PE did not alter reinforcer effectiveness of the contingent light-onset assessed by percent active responding (Fig. 5B). Interestingly, a gradual reduction in reinforcer effectiveness across sessions was observed in both control and PE rats (session 1 vs. session 10 in controls: p < 0.01, planned comparison; session 1 vs. session 10 in PE rats: p < 0.05 following two-way repeated measures ANOVA: prenatal treatment & session 1 vs. session10, with litter as a nested factor; main effect of session, F1,34 = 12.31, p < 0.01; Fig. 5B).

Figure 5.

Figure 5.

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In the long-access procedure. Prenatal ethanol exposure (PE) led to increased responding, decline in reinforcer effectiveness, and greater dishabituation. (A) In the long-access procedure, PE led to an increase in responses/session in both pre-exposure (designated inactive side) and light-onset phases in female rats reared in standard housing condition, similar to that observed in the short-access procedure. (B) Prenatal ethanol exposure did not alter reinforcer effectiveness of the contingent light-onset (assessed by percent active responding) in female rats, which replicated the observation in the short-access procedure. However, longer access to the testing environment led to a reduction in reinforcer effectiveness in both control (Ctl) and PE rats. (C) In the dishabituation test, the presentation of a loud sound/noise for 6 min (shown in the shaded area) induced surges in active responses to the contingent light-onset in both control and PE rats. However, the effect was greater in PE rats than in controls. Data are expressed as mean ± SEM in curve and bar charts. ***: p < 0.001, control vs. PE rats. ###: p < 0.001; ##: p < 0.01, session 1 vs. session 10 in % active response in control and PE rats, respectively (B). %: p < 0.001, epoch 5 vs. epoch 6 in (C). P-values are based on planned comparisons following ANOVA.

Prenatal ethanol exposure led to greater dishabituation.

Dishabituation is a feature of habituation depicting recovery of already reduced (habituated) responses when the environment is disturbed. The dishabituation test was performed right following the completion of the long-access procedure (Fig. 1B). In the 5th epoch of a light reinforcement session, the responding levels in both control and PE were low and did not differ, indicating reaching maximal within-session habituation (Fig. 5C). The presentation of a loud noise during the next epoch induced a significant increase in responding in both and PE rats, demonstrating the dishabituation process (planned comparisons: epoch 5 vs. epoch 6, p < 0.001 in both controls and PE rats following two-way repeated measures ANOVA: prenatal treatment, epochs, with litter as a nested factor; main effect of epoch, F1,34 = 56.03, p < 0.001;). In addition, PE rats showed greater increase in responding than controls indicating greater dishabituation (planned comparison, control vs. PE in epoch 6, p < 0.05; Fig. 5C).

In the long-access procedure, prenatal ethanol exposure did not alter within-session habituation but impaired between-session habituation.

To assess if the long-access procedure could facilitate within-session/short-term habituation, we also compared within-session AUC. Similar to the observations in the short-access procedure, PE did not alter within-session habituation (light-onset session 3 – 10; Fig. 6A & B left panel). However, we observed a reduction in within-session AUC across sessions in both control and PE rats (two-way repeated measures ANOVA: prenatal treatment & session – 3 &10, with litter as a nested factor; main effect of session, F1,34 = 16.07, p < 0.001; session 3 vs. session 10 in both control and PE rats: p < 0.01, planned comparisons; Fig. 6B left & middle panels).

Figure 6.

Figure 6.

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Prenatal ethanol exposure (PE) led to impaired long-term habituation, shown by greater between-session recovery of responding in the long-access procedure. (A) depicts numbers of active responses in the first six 3-min epochs of light-onset sessions. (B) Prenatal ethanol exposure did not alter short-term habituation, but impaired long-term habituation. The short-term/within-session habituation was assessed by within-session area under the curve (AUC). The left panel depicts within-session AUCs in light-onset sessions 3 – 10. The middle panel shows that longer access to the testing environment facilitated within-session habituation in both control and PE rats, reflected by a reduction in AUC from session 3 to session 10. The right panel depicts PE-impaired long-term habituation, reflected by elevated between-session recovery of responding. Specifically, PE rats made more active responses than controls in the first two 3-min epochs but not in the following epochs throughout light-onset sessions 3 – 10. Data are expressed as mean ± SEM in (B). ***: p < 0.001, control vs. PE rats. ##: p < 0.01, session 3 vs. session 10. P-values are based on planned comparisons following ANOVA.

Between-session recovery is a feature of long-term habituation which describes the resumption of responding following stimuli are withheld over time and available again (Rankin et al., 2009). PE rats showed stronger between-session recovery reflected by augmented responding in the first two 3-min epochs (two-way repeated measures ANOVA with litter as a nested factor: prenatal treatment & mean responses of epochs 1 – 6 across session 3 – 10; interaction effect between prenatal treatment and epoch, F5,170 = 7.68, p < 0.001; litter effect, F11,23 = 22.59, p < 0.001; control vs. PE; p < 0.001 for both epoch 1 and epoch 2, planned comparisons; Fig. 6B right panel).

Compared to the short-access procedure, long-access procedure decreased responding to contingent light-onset and facilitated within- and between-session habituation.

Compared to the short-access procedure, the long-access procedure led to a reduction in responding in both control and PE rats reflected in decreased number of active responses in the initial 30 min of the first six light-onset sessions (three-way repeated measures ANOVA: access procedure, prenatal treatment, & sessions, with litter as a nested factor; main effect of access procedure, F1,41 = 52.60, p < 0.001; main effect of prenatal treatment, F1,41 = 18.00, p < 0.001; main effect of session, F5,300 = 11.01, p < 0.001; litter effect, F19,41 = 10.37, p < 0.001; Fig. 7A). The long-access procedure facilitated within-session/short-term habituation in both control and PE rats, reflected by decreased within-session AUCs compared to those in the short-access procedure (three-way repeated measures ANOVA: access procedure, prenatal treatment, & sessions 3 – 6, with litter as a nested factor; main effect of access procedure, F1,41 = 12.20, p < 0.01; main effect of session, F3,180 = 4.05, p < 0.01; litter effect, F19,41 = 2.33, p < 0.05; Fig. 7B left and middle panels). In comparison to the short-access procedure, the long-access procedure also led to faster between-session/long-term habituation measured by between-session AUC from session 1 to session 6) in both control and PE rats (two-way ANOVA: access procedure & prenatal treatment, with litter as a nested factor; main effect of access procedure, F1,41 = 9.88, p < 0.01; Fig. 7C). The effect is shown as faster decline in responding across sessions.

Figure 7.

Figure 7.

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Longer exposure to the testing environment led to a reduction in responding and more rapid within-session habituation. (A) Compared to the short-access procedure, the long-access procedure led to lower responding, regardless of prenatal treatment. The left panel depicts numbers of active responses during the first 30 min in each of the light-onset sessions. The right panel summarizes the reduction in responding shown in both the short- and long-access procedure using mean active responses across the first six light-onset sessions. PE led to an overall increase in responding. Long-access procedure also led to a decrease in responding. (B) Relative to the short-access procedure, the long-access procedure led to faster within-session/short-term habituation (assess by within-session AUC), regardless of prenatal treatment. The left panel depicts within-session AUCs in light-onset sessions (sessions 1 – 2 were not included because no clear habituation patters were displayed). The middle panel shows mean within-session AUCs across sessions 3 – 6. The right panel shows that the long-access procedure led to faster between-session/long-term habituation in both control (Ctl) and PE rats, assessed by between-session area under the curve (AUC) from session 1 to session 6. Data are expressed as mean ± SEM in curve and bar charts. *: p < 0.05; ***: p < 0.001, short-access vs. long-access procedure with the same prenatal treatment. ###: p < 0.001, control vs. PE rats. P-values are based on planned comparisons following ANOVA.

Discussion

Using a second trimester-equivalent binge-drinking PE model in rats, we have demonstrated that without causing major teratogenic effects, PE leads to increased operant responding to elicit sensory stimuli in both sexes. Specifically, the PE effects are manifested as 1. augmented responding to a distinct visual stimulus (i.e., light-onset; turning on light), 2. higher between-session spontaneous recovery, and 3. increased responding when the environment is disturbed by a loud noise. The PE-induced effects can be ameliorated by rearing rats in an enriched condition which greatly decreases responding in both control and PE rats. The PE-induced increases in responding can also be reduced by increasing exposure to contingent light-onset via augmented duration and number of sessions. These strategies lead to the facilitation of both short-term and long-term habituation to the contingent light-onset.

In the short-access light reinforcement experiment, we have observed greater reinforcer effectiveness of the contingent light-onset (measured by proportion of active responses) in male PE rats reared in the standard housing condition, suggesting that the increases in active responses to the light-onset could be due to enhanced reinforcer effectiveness. Namely, male PE rats find the contingent light-onset more reinforcing than their control counterparts. Such an effect is not observed in females. However, similar to males, female PE rats reared in the standard housing condition show increased active responses to the contingent light-onset compared to their female control counterparts. But PE does not lead to greater reinforcer effectiveness. In addition, female PE rats reared in the standard housing condition respond more than controls during the pre-exposure phase when the light never turns on. They also respond more to the inactive hole during the light-onset phase. This response pattern is observed in female rats in the long-access procedure too. As such, it appears that in females, PE could lead to a general increase in responding to the novel environment as well as to specific novel sensory stimuli without showing greater reinforcer effectiveness. This is an interesting observation of sex differences in PE effects on sensory processing.

Prenatal ethanol exposure-induced increases in responses to contingent visual stimuli are observed in rats reared in the standard housing condition but not in rats reared in the enriched condition. In fact, postnatal environment enrichment leads to major decreases in all categories of responses. The most prominent effect is the decrease in active responses to the contingent light-onset. As a result, no group differences are observed between control and PE rats reared in the enriched condition. This observation is similar to previous studies (Wang et al., 2018a, Aubert et al., 2004, Cain et al., 2006) showing that postnatal environment enrichment can profoundly reduce responses to the contingent light-onset in naïve rats (by 71.9% on average). The lower responses are not attributed to slow movement due to increased bodyweight as we show that enriched rats have lower bodyweight. Previous studies have also shown postnatal environment enrichment does not impact motor function (Urakawa et al., 2007). Instead, the reduced responses in the light reinforcement task have been attributed to decreased reinforcer effectiveness which is consistent with the results of the present study (Wang et al., 2018a; Cain et al., 2006). We and others have also observed an overall decrease in locomotor activity in a novel environment in rats reared in the enriched condition and attributed this effect to fast habituation to novelty and reduced anxiety (Wang et al., 2018b; Zimmermann et al., 2001, Hughes and Collins, 2010). Indeed, environmental enrichment can effectively reduce stress and corticosterone levels (Segovia et al., 2009). In the present study, the rats reared in the enriched condition have undergone both neonatal handling before weaning and complex housing after weaning. Each approach independently has been shown beneficial effects in PE animal models (Hannigan et al., 2007). The individual contribution of these two intervention approaches in the present study remains to be elucidated.

An important feature of sensory stimuli as primary reinforcers is that after repeated presentation of the sensory stimuli, the responses undergo habituation leading to declined response rates within a short period of time. In order to exclude the possibility of sensory adaptation or motor fatigue for declined responses, a dishabituation test could be run to introduce major disturbances in the environment. A recovery of the already declined responses would validate the habituation process (Rankin et al., 2009). This is indeed what we have observed during the dishabituation test which confirms that the within-session decline in responding to contingent light-onset is indeed due to the short-term habituation process (Lloyd et al., 2014, Lloyd et al., 2012a, Wang et al., 2018a). Importantly, we observe that PE facilitates the dishabituation process reflected in a greater increase in responding to contingent light-onset during the noise exposure.

Habituation has been suggested to be the simplest form of non-associative learning (Best et al., 2008, McDiarmid et al., 2019) which is characterized by reduced responding to repetitive, redundant, or irrelevant stimuli and serves as a protective mechanism against information overload. As such, habituation can facilitate other forms of learning because it allows individuals to filter out irrelevant information and focus on critical stimuli (Fagan et al., 1983, Schneider et al., 2011, Fenckova et al., 2019, Best et al., 2005, McDiarmid et al., 2019). Impaired habituation is a prevalent symptom in multiple neurological and psychological disorders (McDiarmid et al., 2019, McDiarmid et al., 2017). Prenatal ethanol exposure also impairs habituation to sensory stimuli in novel environments and has been regarded as part of the sensory processing deficits (Schneider et al., 2011). Interestingly, impaired habituation in FASD is opposite to facilitated habituation in individuals with attention deficits/hyperactivity disorders (Abele-Webster et al., 2012). Impaired habituation caused by PE has been observed as early as the fetal period (Hepper et al., 2012). Human infants and neonatal rats with PE both exhibit slowed habituation to sensory stimuli (Streissguth et al., 1983, Barron and Riley, 1992). The light reinforcement paradigm in the present study allows us to study the impact of PE on habituation of responses to specific visual stimuli. To that end, we investigated how PE impacts both short-term and long-term habituation. To our surprise, we have not observed PE impacts the short-term habituation of either sex reared in the standard housing condition. On the other hand, we observe that rearing in the enriched condition greatly facilitates the within-session habituation. These observations indicate that rearing in the enriched condition facilitates the short-term habituation to sensory stimuli across groups.

The lack of PE effects in within-session/short-term habituation in the short-access procedure appears to be inconsistent with reports showing that PE impairs habituation in clinical settings. We suspect that the short-access procedure may be limited in detecting possible PE effects on habituation. Therefore, we increase the duration of pre-exposure and the magnitude of stimulus presentation using the long-access procedure which has longer session duration and an increased number of sessions. Interestingly, we still have not detected PE effects on within-session habituation . However, compared to the short-access procedure, the long-access procedure facilitates within-session/short-term habituation in both control and PE rats. Moreover, the long-access procedure also facilitates between-session/long-term habituation which is measured by a sharper decline in overall responses between sessions in both control and PE rats . These effects are consistent with a major feature of habituation that longer and more frequent exposure to the novel environment/stimuli can potentiate short-term habituation to the same environment/stimuli (Rankin et al., 2009).

The results from the long-access procedure has also revealed several unique PE effects on the habituation processes. First, PE leads to greater spontaneous between-session recovery of responding, which is a feature of the between-session/long-term habituation process observed after the sensory stimuli are withheld over time (Rankin et al., 2009). This effect is reflected by increased responding in the first 6 min of each session. The facilitated spontaneous recovery of responding along with the greater dishabituation (i.e., heightened responding in PE rats during the dishabituation process) show that PE rats respond more to sensory stimuli when the stimuli are withheld for a period of time or when there is a change or disturbance in the environment.

Another important feature of habituation is stimulus generalization, which states that the habituation process can be generalized to sensory stimuli within the same modality (Rankin et al., 2009). It is obvious that the enriched rearing condition provides the rats with ample opportunities of repeated exposure to various sensory stimuli. It is tempting to speculate that through the stimulus generalization process, rats reared in the enriched condition have experienced intense habituation process to many more sensory stimuli compared to standard housed rats. Therefore, they exhibit significantly reduced responses to the operant box during the pre-exposure phase as well as responses to contingent light-onset during the light-onset phase. This effect leads to low responding and a lack of differences between control and PE rats reared in the enriched condition. At the present time, there is no direct evidence to support this notion. However, environmental enrichment has been found to cause a global increase in the spontaneous activity and excitation in responses to different whisker stimulation paradigms in all layers of sensory cortex. It is proposed that such changes promote plasticity (Alwis and Rajan, 2013). Such global changes in neuronal activity and improved plasticity might be associated with mechanisms underlying stimulus generalization. Future research is required for elucidating the stimulus generalization hypothesis and the cellular mechanisms underlying reduced operant responses to sensory stimuli after enrichment.

The results demonstrated in the present study – PE facilitates overall increases in responses to novel visual stimuli, increased spontaneous recovery, and increased responses when the environment is reintroduced or disturbed are similar to clinical observations of sensory processing deficits in individuals with FASD (Jirikowic et al., 2008, Franklin et al., 2008, Carr et al., 2010, Long et al., 2018, Wengel et al., 2011). Earlier studies have shown PE-induced deficits in processing visual information (Coles et al., 2002, Mattson and Roebuck, 2002). A recent study further confirms that the majority of individuals with FASD have sensory processing deficits in auditory, tactile, and visual modalities (Jirikowic et al., 2020). Specific deficits in visuospatial processing has been reported (Kable et al., 2016). A subtype of sensory processing deficits is augmented sensation-seeking (Norbury and Husain, 2015) which describes that individuals actively and continuously seek sensory inputs due to high threshold and poor registration of sensory stimuli (Dunn, 1999). Increased sensation seeking has been documented in children with FASD (Wengel et al., 2011) across all sensory modalities. In rodents, sensation-seeking is often modeled by increased locomotor responding in a novel environment (Dellu et al., 1996). The light reinforcement paradigm used in the present study has also been proposed to model sensation seeking using contingent light onset as the specific novel visual stimulus (Olsen and Winder, 2009, Gancarz et al., 2012). The high sensation seekers in the rodent model indicated by higher responses to novelty/novel stimuli are associated with increased addiction risk (Cain et al., 2005, Gancarz et al., 2011). Indeed, we have shown PE leads to elevated locomotor response to novelty as well as increased amphetamine self-administration in rats with PE (Wang et al., 2019). In addition, high sensation seeking is associated with potentiated dopaminergic (DA) neurotransmission in the midbrain DA neurons, which possibly underlies increased responses to both sensory stimuli and addictive drugs (Norbury and Husain, 2015). Interestingly, evidence also shows light signals activate midbrain DA neurons and this action has been proposed to underlie the reinforcing properties of the contingent light-onset (Redgrave and Gurney, 2006). The response to contingent light-onset is also increased when a psychostimulant is administered (Lloyd et al., 2012b). In our laboratory, we have consistently observed that PE leads to altered neurotransmission in midbrain DA neurons in both the substantia nigra and the ventral tegmental area (VTA). In VTA DA neurons, the origin of the mesolimbic system, we find persistent increase in glutamate neurotransmission onto VTA DA neurons including increased glutamatergic synaptic strength, enhanced long-term potentiation, and weakened long-term depression (Hausknecht et al., 2015, Hausknecht et al., 2017). These effects might paradoxically mediate overexcitation/depolarization block of VTA DA neurons observed in vivo and lead to allostatic adaptation in the mesolimbic DA pathway (Shen et al., 1999). These neuroadaptations after PE could underlie PE-induced increase in sensation seeking, manifested as both greater responses to contingent sensory stimuli and higher drug addiction risk. These possibilities need to be investigated in the future.

We have also shown that several PE-induced behavioral deficits that could be mediated by midbrain DA neuron function – increased locomotor responding to novelty, increased addiction risk, and increased responding/impaired habituation to sensory stimuli –can all be normalized by rearing rats in the enriched condition (Wang et al., 2018a, Wang et al., 2018b). Therefore, PE-induced dysfunction in the midbrain DA system could be a common neuronal mechanism for several behavioral deficits caused by PE. Environmental enrichment might ameliorate these deficits through normalizing midbrain DA functions.

In conclusion, PE leads to increased responding to contingent light-onset in rats of both sexes reared in the standard housing condition. PE also leads to impaired long-term but not short-term habituation to contingent light-onset. Lastly, PE facilitates responding to sensory stimuli when there is a change or disruption in the environment. The results are consistent with the clinical observations that individuals with FASD exhibit increased sensation seeking to sensory stimuli. Importantly, we show that rearing rats in complex, enriched environment can ameliorate PE induced deficits. In addition, longer duration of exposure and more frequent exposure to novel sensory stimuli can facilitate the long-term habituation and reduce increases in responses to sensory stimuli in PE animals. The findings could inform treatment/intervention strategies for sensory processing deficits especially the sensation seeking phenotype in FASD. The light reinforcement paradigm could serve as an animal model for cellular/molecular studies to elucidate neural mechanisms underlying PE-induced deficits in sensory processing and habituation.

Supplementary Material

fS1
fS2

Acknowledgments

The authors thank Mark Kogutowski for his technical support, and Anthony Trinh, Aaron Anderson, and Lovina John for their help in animal breeding and data collection.

Funding sources:

The National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (Grants AA019482 and AA026421 to R.S.)

Footnotes

Conflict of Interest

All the authors declare no conflict of interest.

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fS1
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fS2
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