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. 2019 May 31;46(1):54–67. doi: 10.1093/schbul/sbz043

Assessing Reality Testing in Mice Through Dopamine-Dependent Associatively Evoked Processing of Absent Gustatory Stimuli

Benjamin R Fry 1,#, Nicollette Russell 1,2,#, Ryan Gifford 1, Cindee F Robles 1, Claire E Manning 2, Akira Sawa 3,4, Minae Niwa 3,✉, Alexander W Johnson 1,2,✉
PMCID: PMC6942166  PMID: 31150554

Abstract

Impairments in reality testing are core features of numerous neuropsychiatric conditions. However, relatively few animal models have been developed to assess this critical facet of neuropsychiatric illness, thus impeding our understanding of the underlying central systems and circuits. Using mice in which dominant-negative Disrupted-in-Schizophrenia-1 is expressed throughout central nervous system circuitry (DN-DISC1-PrP), the capacity for an auditory conditioned stimulus (CS) to evoke perceptual processing of an absent sucrose solution was examined. At test, during CS presentations, DN-DISC1-PrP mice consumed more water and displayed a licking profile that is more typically revealed while ingesting a sweet-tasting solution. DN-DISC1-PrP mice also displayed greater c-fos expression in the insular (gustatory) cortex when consuming water in the presence of the CS. This capacity for the CS to more readily substitute for the taste features of the absent sucrose solution in DN-DISC1-PrP mice was attenuated following systemic treatment with the antipsychotic haloperidol. Conversely, social isolation during adolescence promoted the manifestation of these effects. These results provide strong validation for using associative learning procedures to examine dopamine-mediated reality testing associated with insular cortex activation.

Keywords: delusions, hallucinations, reward, neuropsy- chiatric illness, neuroleptics

Introduction

Schizophrenia is a chronically debilitating disease that throughout the world affects roughly 7 individuals per 1000 of the adult population.1 Animal models have been relatively successful in mimicking endophenotypes associated with either negative2,3 or cognitive4,5 symptoms; however, positive symptoms have received significantly less attention as they are more typically viewed as uniquely human phenomena.6 Although disruptions in dopamine (DA) have long been attributed to the pathophysiology associated with positive symptoms of schizophrenia,7–9 10%–30% of patients show treatment resistance to antipsychotics; furthermore, those successfully treated often suffer from unintended severe side effects.10 This is due to the serendipitous discovery of these pharmacotherapies and a lack of understanding of the detailed neurobiology owing to a dearth of appropriate animal behavioral models.6

To examine and validate psychotic-like behaviors in mice, we made use of a transgenic Disrupted-in-schizophrenia-1 (DISC-1) mouse model. DISC-1 was originally identified in a Scottish pedigree wherein a balanced translocation in chromosomes 1 and 11 resulted in enhanced risk for neuropsychiatric conditions.11 Although more recent genome wide association studies have failed to identify common variants of the DISC-1 gene with schizophrenia,12 this model remains a useful tool to elucidate biological mechanisms of schizophrenia and other related disorders.13 DISC-1 plays a critical role in neuronal processes driving the formation of neuronal network development and function,14 with its protein network playing crucial roles in pathogenesis related to severe neuropsychiatric conditions.15 A number of genetically engineered mouse models have been developed and mirror many of the core brain16 and behavioral4 endophenotypes17 seen with human psychiatric conditions.18

In both humans and animals, reality testing has been examined via associative learning,19 where a stimulus can be associated with multiple components of the event that it predicts, including its hedonic and perceptual features.20,21 Studies have revealed that these associations can be particularly efficacious early on in training21 such that a food-paired conditioned stimulus (CS) can, in the absence of food, both establish new learning to the food22,23 and evoke sensory responses that are typically only seen in the presence of the food itself.24,25 This difficulty in distinguishing between real and abstract representations of food quickly dissipates with more extensive training, where it is posited that reward expectancies and incentive motivational systems control behavior.21,22

In the current study, transgenic mice with dominant negative expression of DISC-1 under the control of the prion protein promoter (DN-DISC1-PrP)26,27 received Pavlovian conditioning with an auditory CS paired with sucrose solution. Subsequently, we examined whether this CS would evoke a highly detailed perceptual and evaluative image of a motivational event (ie, sweet taste of sucrose), even though the event itself was not presented.28 This was assessed by the capacity of the CS to evoke evaluative hedonic licking responses to water that are typically seen with sweet-tasting solutions.29 DN-DISC1-PrP mice were significantly more vulnerable to perceiving and responding to the absent sucrose, an effect that was particularly prominent when the extensively trained CS was presented. Strikingly, this enhanced vulnerability was reduced to the level of control mice by systemic injections of the antipsychotic haloperidol, and was augmented when DN-DISC1-PrP mice received mild social isolation during adolescence. Moreover, when we examined neuronal activation in the insular (gustatory) cortex—a region known to express DISC-130 and contain taste-responsive neurons31—the CS was capable of evoking significantly greater neuronal activation in the absence of direct gustatory sensory input in DN-DISC1-PrP mice. Collectively, these findings support and validate the use of associative-learning methodologies to examine perceptual processes that reflect DA-mediated reality testing and insular activation in animals.

Methods

Animals

Breeding pairs of DN-DISC1-PrP mice were generated at the Transgenic Core Laboratory of the Johns Hopkins University as described previously26 and transferred to Michigan State University. Details on housing conditions and food deprivation can be found in the supplementary methods. All studies were under the auspices of the Michigan State University Institutional Animal Care and Use Committee.

Behavioral Procedures

Experiment 1

Behavioral testing took place in 4 individual conditioning chambers, each containing a food well and lickometer29 (Med Associates). At the start of each consumption session, 50 μl of 0.2 M sucrose was available in the food cup and additional 12 μl deliveries occurred every 10 licks as mice consumed the liquid. Wild-type (♂ n = 8; ♀, n = 8) and transgenic (♂ n = 17; ♀ n = 5) mice received single daily 10 min consumption tests with 0.2 M sucrose until a stable baseline number of licks was reached.32 Subsequently, mice received consumption tests with water and varying sucrose concentrations (0.1, 0.2 , and 1 M), each tested on a separate day and in a counterbalanced latin square design. During these tests, individual licks were time stamped and the temporal distribution of pauses in licking behavior were recorded for subsequent analysis of licking microstructure. We examined the size (mean number of licks made with <500 ms pause between the end of one lick and the start of the next) and number (licking behavior initiation following a ≥500 ms pause) of clusters, which reflect the palatability (taste) of food and post-ingestive inhibitory consequences, respectively.29,33

Experiment 2

Mice (n = 68) received 2 food cup training sessions, separated by 24 h. At the start of each session, 50 μl of 0.2 M sucrose solution was made available prior to the mouse being placed into the conditioning chamber. Upon entering the food cup, the mouse initiated the first of 16 trials during which 50 μl of 0.2 M sucrose solution was delivered. This delivery occurred according to a random-time 120 s schedule and each session took approximately 30–45 min to complete. Subsequently, mice received single 32 min Pavlovian conditioning sessions for a total of 8 days. In these sessions, wild-type (n = 30) and transgenic (n = 30) mice received 14 presentations of 1 CS (extensively trained CS) and 2 presentations of a second CS (minimally trained CS), each 10 s in duration and pseudo-randomly presented with a variable intertrial interval (ITI) of 120 s. Thus, the amount of CS training was manipulated, as previous studies suggest, this is a critical variable that determines whether an animal can distinguish the CS from the actual presentation of the reward.21,22,25 For half the mice, the extensive CS was a 1500 Hz tone and the minimal CS was white noise; for the remaining mice these contingencies were reversed. Each CS was presented for 10 s, with the final 5 s occurring with delivery of the sucrose solution unconditioned stimulus (US). An additional unpaired control group of wild-type (♂ n = 2, ♀ n = 4) and transgenic (♂ n = 3, ♀ n = 1) mice received the same number of presentations of the CS; however, the delivery of the US occurred in a random manner throughout the session,34 with the criterion that 16 presentations of the sucrose occurred by the end of the session. After the completion of training, all mice received a single 16 min test session that included 8 presentations of one of the CSs separated by a fixed 2 min ITI. Mice were tested with either the extensive (wild-type, ♂ n = 9, ♀ n = 8; transgenic, ♂ n = 8, ♀ n = 6) or minimal CS (wild-type, ♂ n = 6, ♀ n = 7; transgenic, ♂ n = 8, ♀ n = 6). Unpaired mice from both genotypes were tested with the extensively presented CS. For each CS, unflavored deionized water was delivered, and the number of licks during the pre-CS, CS and the post-CS period was subjected to analyses of licking microstructure, as described in Experiment 1.

Experiment 3

Training and testing were similar to experiment 2, with the one exception that mice were tested with the extensive noise CS. This contingency was chosen as the extensive noise CS was particularly effective at evoking a pattern of licking behavior consistent with increases in the hedonic evaluation of water (Figure 2e; supplementary figure S1). Approximately 30 min prior to testing with the extensive noise CS, mice received an intraperitoneal injection of either 0.1 mg/kg (wild-type, ♂ n = 3, ♀ n = 5; transgenic, ♂ n = 3, ♀ n = 5) or 0.25 mg/kg (wild-type, ♂ n = 6, ♀ n = 4; transgenic, ♂ n = 10, ♀ n = 2) haloperidol (Sigma-Aldrich) at a volume of 10 ml/kg (supplementary figure S2). The remaining mice from each genotype (wild-type, ♂ n = 10, ♀ n = 4; transgenic, ♂ n = 9, ♀ n = 5) were injected with vehicle (10% Tween 80 in 0.9% sterile saline).

Experiment 4

Naïve wild-type (♂ n = 4, ♀ n = 5) and transgenic (♂ n = 4, ♀ n = 5) mice received social isolation where they were removed from group housing and isolated in individual cages from 5 weeks of age until the completion of behavioral testing (≈8 weeks of age).26 A separate group of age-matched wild-type (♂ n = 3, ♀ n = 7) and transgenic (♂ n = 4, ♀ n = 5) mice remained grouped housed for this duration. Behavioral training and testing were conducted in the same manner as experiment 3.

Immunohistochemistry and c-fos Quantification

Immunohistochemistry was completed as previously described35 (see, supplementary methods). Bilateral nuclei were analyzed from coronal brain sections from wild-type (n = 6) and transgenic (n = 5) mice tested with the extensive CS, together with wild-type (n = 4) and transgenic (n = 4) mice tested with the unpaired CS. c-fos positive cells were quantified from 4 sections of the insular cortex from bregma (+1.18 mm; 1.42 mm; 1.7 mm; 1.94 mm; 2.1 mm) and 3 sections of the nucleus accumbens (ACB; +0.98 mm; 1.42 mm; 1.94 mm). Quantitative analysis of c-fos immunoreactivity was performed by 3 separate scorers, where the mean number of c-fos counts for each area were quantified and analyzed.

Data Analysis

Data were subjected to repeated measures analysis of variance (ANOVA). All significant 3-way and 2-way interactions were followed up by repeated measures ANOVA and simple main effects analyses to examine the nature of these interactions. Post hoc comparisons were analyzed using Bonferroni tests. The α level for significance was .05, and all analyses were conducted using Statistica (Statsoft).

Results

Experiment 1

For both wild-type and DN-DISC1-PrP mice, the overall intake of the sucrose solutions displayed an inverted-U-shaped function29,33 with the highest intake being revealed at the intermediate sucrose concentration (0.2 M; figure 1a). ANOVA revealed a main effect of concentration (F(3,108) = 79.38, P < .0001) and no differences between the groups or interactions (Fs < 1; Ps > .86). The pattern of licking for each concentration of sucrose was also comparable between groups (Fs < 1), as was the first minute lick rate, which reflects similar orosensory positive feedback to the sucrose solution prior to accumulation of fluid in the gastrointestinal tract33 (figure 1b and c). The analysis of licking microstructure further supported intact gustatory detection in transgenic mice, as the mean cluster size displayed a monotonic relationship with increases in tastant concentration (F(3,108) = 86.28, P < .0001). No differences between the groups during either test were noted (Fs < 1; Ps > .77; figure 1d). Similarly, both groups of mice displayed a comparable inverted-U-shaped function in cluster number (F < 1; figure 1e), indicating intact post-ingestive inhibition resulting from the colligative and caloric properties of the ingested sucrose solution.33

Fig. 1.

Fig. 1.

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Experiment 1 sucrose consumption and licking microstructure analysis. Wild-type and DN-DISC1-PrP mice showed intact (a) acceptance and (b and c) comparable pattern of licking for a range of sucrose concentrations during each 10 min consumption session. Both groups of mice showed a monotonic increase of (d) cluster size, and a (e) decrease in cluster number at the highest sucrose concentration. Error bars indicate standard error of the mean (SEM).

Experiment 2

Similar to performance in training (supplementary figure S3a and b), wild-type, and DN-DISC1-PrP mice displayed a comparable pattern of food cup responding during the test stage (figure 2a–c). Analysis of these data revealed a period (Pre-CS, CS, post-CS) × condition interaction (F(2,62) = 15.53, P < .0001) due to significant differences between mice in the extensive condition and the 2 other groups during the CS (Ps < .0001) but not pre-CS or post-CS periods (Ps ≥ .38). In addition, no effect of genotype or interaction with other variables was noted (Fs < 1.18; Ps > .32). However, the data of primary interest from this experiment revealed clear differences between genotypes in licking to the unflavored water, which during the CS was significantly greater in DN-DISC1-PrP mice tested with the extensive CS (figure 2e). Due to a general lack of licking, together with the small number of animals and absence of any genotype differences in the unpaired mice, responding for these animals was excluded from further analysis. For the remaining mice, a significant 3-way genotype × condition × period ANOVA was revealed (F(1,54) = 8.81, P = .004). Follow-up genotype × condition ANOVAs for each period revealed a similar pattern of licking during the pre-CS for all mice (Fs < 1), whereas during the CS period a significant genotype × condition interaction was revealed (F(1,54) = 6.55, P = .01) due to significant elevation in lick rate for DN-DISC1-PrP extensive mice compared to all other groups (Ps ≤ .01). During the post-CS period (figure 2f), wild-type mice tested in the extensive condition showed reduced licking relative to minimal wild-type (F(1,54) = 5.81, P = .01), which showed comparable lick rate to transgenic mice in both conditions (Fs < 1; Ps > .54).

Fig. 2.

Fig. 2.

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Experiment 2 conditioned food cup and licking test responses. Wild-type and DN-DISC1-PrP mice showed comparable low levels of (a) conditioned food cup approach and (d) licking behavior during the pre-CS irrespective of whether they were tested with the extensive, minimal, or unpaired CS. During the CS, (b) food cup approach behavior was similarly elevated in both groups of mice tested with the extensive CS, relative to mice tested with the minimal CS. Responses to the unpaired CS were negligible in all mice. However, (e) DN-DISC1-PrP mice tested with the extensive CS displayed significantly greater licking for the water during the cue presentation compared to all other mice. ★ indicates genotype × condition interaction (P = .01) due to significant elevation in lick rate for DN-DISC1-PrP extensive mice compared to all other groups (*Ps ≤ .01). Although (c) food cup approach was comparable during the post-CS period in extensive and minimal mice from both genotypes, (f) licking behavior was lower in wild-type mice tested with the extensive CS compared to all other groups. *indicates significant difference between wild-type mice tested with extensive and minimal CS (P = .01), and trend level significance between genotypes in mice tested with extensive CS (#P = .07). Data are presented in (a–c) responses per minute or (d–f) licks per minute during the pre-CS (10 s prior to CS), CS, and post-CS (10-s interval immediately following CS termination). CS, conditioned stimulus.

The analysis of licking microstructure suggested that the elevated licking responses in DN-DISC1-PrP extensive mice was attributable to measures of palatability (ie, mean cluster size;33figure 3b). ANOVA revealed a significant 3-way interaction (F(1,54) = 10.06, P = .002), with a significant genotype × condition interaction (F(1,54) = 7.81, P = .007) during the CS (not pre-CS or post-CS; Ps ≥ .15) due to elevated cluster size in DN-DISC1-PrP extensive mice compared to all other groups (Ps ≤ .01). It is worth noting that the elevated cluster size to the water in DN-DISC1-PrP mice tested with the extensive CS (4.92 ± 0.68 licks) was significantly higher than that observed when transgenic mice consumed water in experiment 1 (figure 1d; 3.47 ± 0.32 licks, P < .05); thus, testing under these conditions enhanced the palatability of water significantly above that observed during normal intake conditions. Analyses of cluster number revealed a main effect of period, condition, and a period × condition interaction (Ps ≤ .05); however, neither effects of genotype nor interaction among any of the variables was revealed (Ps ≥ .18).

Fig. 3.

Fig. 3.

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Experiment 2 licking microstructure analysis. (a–c) Elevated cluster size during the CS compared to the pre-CS and post-CS, with DN-DISC1-PrP mice tested with the extensive CS showing the highest mean cluster size relative to all other mice. ★ indicates significant genotype × condition interaction, P = .007, due to elevated cluster size in DN-DISC1-PrP extensive mice compared to all other groups (*Ps ≤ .01). (d–f) Cluster number was typically higher during the post-CS for all mice tested with the extensive CS independent of genotype. CS, conditioned stimulus.

Consistent with the idea that the CS gained access to perceptual processing typically activated by the sucrose alone, DN-DISC1-PrP mice tested with the extensive CS also displayed enhanced c-fos immunoreactivity in putative taste responsive neurons in the insular compared to their wild-type counterparts (figure 4b). Genotype × condition ANOVA revealed a main effect of condition only (F(1,15) = 4.75, P < .05). Elevated immunoreactivity was revealed in DN-DISC1-PrP mice tested with the extensive CS compared to wild-type counterparts (P < .05), and a tendency for the former group to show greater c-fos expression compared to transgenic (P = .07) and wild-type (P = .05) mice tested with the unpaired CS. Conversely, in wild-type mice that were tested with the extensive CS and showed no evidence of elevated licking or palatability responses to the unflavored water, insular c-fos immunoreactivity was comparable to both transgenic and wild-type mice tested with the unpaired CS (Ps ≥ .41). On the other hand, in the ACB, irrespective of genotype, mice tested with the extensive CS displayed greater c-fos immunoreactivity compared to unpaired mice. ANOVA revealed a main effect of condition only (F(1,15) = 10.95, P < .01), with wild-type mice tested with the extensive CS showing elevated c-fos compared to unpaired wild-type mice (F(1,15) = 7.00, P = .01) and a tendency for a similar pattern with transgenic mice (F(1,15) = 4.18, P = .05). There were no differences in immunoreactivity between genotypes from either the extensive or unpaired conditions (Fs < 1; Ps > .66).

Fig. 4.

Fig. 4.

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Experiment 2 c-fos immunohistochemistry. (a) Representative photomicrographs of insular cortex quantified sections in wild-type (top) and DN-DISC1-PrP mice (bottom). (b) C-fos immunoreactivity quantified in the insular revealed significantly elevated expression in DN-DISC1-PrP mice tested with the extensive CS compared to wild-type mice. Both DN-DISC1-PrP and wild-type mice showed comparable low levels of insular c-fos expression following testing with the unpaired CS. (c) C-fos expression in the nucleus accumbens was comparably higher in both wild-type and DN-DISC1-PrP mice tested with the extensive CS compared to respective unpaired conditions. *Ps < .05; #Ps ≤ .07. CS, conditioned stimulus.

Experiment 3

During the test stage, haloperidol led to a comparable reduction in approach behavior to the food cup during both the pre-CS, CS, and post-CS periods in wild-type and DN-DISC1-PrP mice (figure 5a–c). A genotype × drug (saline, 0.1 mg/kg haloperidol, 0.25 mg/kg haloperidol) × period ANOVA revealed a main effect of drug (F(2,60) = 9.84, P < .001), period (F(2,60) = 65.12, P < .0001), and a trend for an interaction between the 2 variables (F(4,120) = 2.24, P = .07). No effects of genotype nor interaction among any of the variables were revealed (Fs<1; Ps > .68). Separate genotype × drug ANOVAs for each period also revealed no effects of genotype or interaction, though significant effects of haloperidol were noted at each interval (Ps ≤ .01).

Fig. 5.

Fig. 5.

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Experiment 3 conditioned food cup and licking test responses. (a–c) Haloperidol led to a similar reduction in food cup approach behavior in wild-type and DN-DISC1-PrP mice. (d–f) The licking behavior in DN-DISC1-PrP mice to unflavored water was normalized to the level of wild-type mice by haloperidol treatment. Specifically, (e) licks per minute were significantly elevated in DN-DISC-1-PrP vehicle mice compared to both wild-type vehicle mice (*P = .01) and transgenic mice treated with 0.25 mg/kg haloperidol (*P = .001). A similar pattern was also observed during the (f) post-CS period, with DN-DISC-1-PrP vehicle mice displaying greater lick rate compared to wild-type vehicle (*P = .02), and both 0.1 mg/kg (*P < .05) and 0.25 mg/kg (*P < .001) transgenic conditions. CS, conditioned stimulus.

When licking to the unflavored water was examined (figure 5d–f), vehicle-treated transgenic mice tested with the extensive CS displayed the highest lick rate; however, haloperidol treatment was able to normalize this elevated lick rate in DN-DISC1-PrP to that observed in wild-type mice. Three-way ANOVA revealed a main effect of drug (F(2,60) = 6.20, P < .01), period (F(2,120) = 43.39, P < .001), and a significant drug × period interaction (F(4,120) = 3.13, P = .01). No effects of genotype nor interaction among the variables were revealed (largest F-value; genotype, F(1,60) = 2.48, P = .12). Genotype × drug condition ANOVAs for each period revealed no effects of genotype, though a main effect of drug dose during the CS and post-CS periods (Ps ≤ .02) was noted due to a significant reduction in lick rate between vehicle and 0.25 mg/kg drug conditions for both periods (Bonferroni post hoc comparison, Ps < .01).

An examination of cluster size (figure 6a–c) revealed that haloperidol treatment normalized licking in transgenic animals, resulting in a dose-dependent reduction in this measure of stimulus palatability comparable to that seen in wild-type controls. Three-way ANOVA revealed a main effect of drug (F(2,60) = 3.76, P < .05) and period (F(2,120) = 25.9, P < .0001) only. Separate genotype × drug ANOVAs for each period revealed for the pre-CS period no significant main effects or interactions; however, during the CS (F(2,60) = 3.15, P = .05) and post-CS (F(2,60) = 2.61, P = .08), a trend for a main effect of drug dose only was noted. Collectively, these findings suggest that haloperidol effects were generally specific to the CS and post-CS periods and led to comparable responding in DN-DISC1-PrP and wild-type mice, in a manner that was distinct from that observed during standard consumption tests (supplementary figure S2). A genotype × drug × period ANOVA for burst number (figure 6d–f) revealed a significant drug × period interaction (F(4,120) = 3.67, P < .01). Separate genotype × drug ANOVAs for each period revealed a main effect of drug (F(2,60) = 4.96, P = .01) during the post-CS period. No other effects or interactions were noted (Fs < 2.49; Ps > .09). Finally, to examine whether haloperidol led to changes in oromotor function, we examined interlick intervals (ILIs) <250 ms, which are under the control of a central pattern generator in the hindbrain and reflect rhythmic tongue movements independent of stimulus palatability.33 During the CS, ILIs < 250 ms were comparable for all mice treated with either vehicle or 0.1 mg/kg haloperidol (wild-type vehicle = 35.78 ± 12.19; wild-type 0.1 mg/kg = 35.5 ± 12.50; DN-DISC1-Prp vehicle = 75.71 ± 27.2; DN-DISC1-Prp 0.1 mg/kg = 52.25 ± 15.31 licks) (F < 1). At the highest dose of haloperidol, evidence of nonspecific motoric effects on oromotor function was noted; ILIs < 250 ms for both wild-type (16.2 ± 4.20 licks) and DN-DISC1-Prp (14.08 ± 5.46 licks) mice treated with 0.25 mg/kg haloperidol were significantly lower than vehicle conditions (F(1,46) = 5.89, P = .01).

Fig. 6.

Fig. 6.

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Experiment 3 licking microstructure analysis. Haloperidol normalized (a–c) cluster size in DN-DISC-1-PrP mice. * indicates significant elevation of cluster size (P = .008) in vehicle compared to 0.25 mg/kg DN-DISC-1-PrP mice, and trend level significance difference between DN-DISC-1-PrP mice and wild-type from vehicle conditions (#P =.05). Similarly, (e–f) cluster number in DN-DISC1-PrP mice was normalized following haloperidol treatment, with significant elevation with this measure during the post-CS in vehicle DN-DISC-1-PrP mice compared to other conditions. *Ps ≤ .02. CS, conditioned stimulus.

Experiment 4

Mild isolation stress during adolescence27 had no effect on conditioned approach behavior in DN-DISC1-PrP mice (figure 7a). Two-way housing condition (grouped, isolated) × period ANOVA revealed a main effect of period only (F(2,60) = 154.70, P < .0001). When applied to licking for the unflavored water, ANOVA revealed a main effect of genotype (F(1,30) = 25.0, P < .0001), period (F(2,60) = 181.6, P < .0001), and a significant interaction between the 2 variables (F(2,60) = 10.1, P < .001). This reflected that during the CS and post-CS, DN-DISC1-PrP mice displayed greater licking than wild-type mice (Ps ≤ .001). In addition, isolated transgenic mice showed greater licking during the CS relative to their group-housed counterparts (F(1,30) = 4.21, P < .05), and displayed greater licking relative to isolated wild-type mice during both the CS and post-CS (Ps < .01). When cluster size was examined (figure 8a–c), a period × genotype interaction was also noted (F(2,60) = 10.1, P < .001) due to significant elevation of cluster size in DN-DISC1-PrP mice during both the CS (F(1,30) = 4.41, P < .05) and post-CS periods (F(1,30) = 6.43, P = .01). For cluster number (figure 8d–f), an elevation was noted in DN-DISC1-PrP mice during the post-CS period alone (F(1,30) = 7.99, P < .01).

Fig. 7.

Fig. 7.

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Experiment 4 conditioned food cup and licking test responses. Mild social isolation stress had no effect on (a–c) food cup approach behavior. However, (e–f) lick rates for the water were significantly elevated in DN-DISC-1-PrP compared to wild-type mice (★Ps < .001). Moreover, (e) during the CS, DN-DISC-1-PrP isolated mice displayed the highest rate of licking with significant differences noted compared to both wild-type conditions (*Ps < .01) and between the transgenic conditions (*P < .05). (f) Similarly, during the post-CS, DN-DISC-1-PrP mice displayed greater rate of licking compared to wild types (Ps < .01). CS, conditioned stimulus.

Fig. 8.

Fig. 8.

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Experiment 4 licking microstructure analysis. With respect to (a–c) cluster size, during the (b) CS and (c) post-CS period, DN-DISC1-PrP mice displayed elevated mean cluster size relative to wild-type mice (★Ps < .05). During (c) the post-CS period, significant elevations in cluster size were noted between DN-DISC1-PrP and wild-type mice from the isolated conditions (*P < .01). For (d–f) cluster number, this measure was elevated in DN-DISC1-PrP mice during the (f) post-CS period alone (★P < .01), with significant differences in this measure between DN-DISC1-PrP and wild-type mice from the isolated conditions (*P < .01). CS, conditioned stimulus.

Discussion

In these studies, a CS that was extensively paired with sucrose during training evoked at test enhanced licking for water in DN-DISC1-PrP mice. These effects reflect a CS-evoked substitution of the sucrose solution, resulting in a more detailed perception of the absent (sucrose) event21,22,25 in transgenic mice. In support of this account, the enhanced lick rate to the water in response to CS presentation specifically reflected an increase in the mean number of licks in a cluster—a measure of licking microstructure that reflects stimulus palatability33—and was attenuated following systemic antipsychotic treatment. The enhanced rate of licking to water was further exaggerated in DN-DISC1-PrP mice following exposure to mild isolation stress during a critical adolescent window.27 Finally, the CS also led to greater c-fos activity in the insular cortex, an area that contains taste-responsive neurons and was more readily activated in DN-DISC1-PrP mice in the absence of sweet-taste stimulation. These findings cannot be accounted for based on broad differences in licking or other nonspecific influences on motoric behavior. During training, wild-type and DN-DISC1-PrP mice showed comparable licking and conditioned approach behavior to the food source in the presence of a CS and normal extinction when licking behavior was used as an instrumental response (supplementary figure S4). Similarly, food cup approach behavior was comparable within each testing condition for both genotypes, as were licking and approach responses when mice were tested with either minimally trained or unpaired CSs. Moreover, during short-term consumption tests, DN-DISC1-PrP mice showed normal licking and intact palatability detection of sucrose.33

These findings significantly advance the body of studies that have examined impaired reality testing in animals.36–39 Using a neurodevelopmental model of schizophrenia, lesions of the ventral hippocampus between PD6 and PD8 were found in adult rats to subsequently enhance a representation-mediated taste aversion (RMTA).36 Similar enhancements in susceptibility to RMTA have also been reported in phospholipase C β1 knockout mice (PLCβ1−/−)37 as well as a ketamine mouse model of schizophrenia.38 In these studies, presentation of the CS may cause the animal to “taste” the absent food, which when paired with LiCl leads to RMTA. However, the RMTA is only observed when rodents are tested sometime (eg, 24 h) afterwards, at which point they consume less of the actual food. Thus, with these models the behavioral change that is examined follows the processing of the putative imagined representations. By comparison, we show that one can observe processing of the absent food as the CS was presented. Accordingly, the current approach provides a more concurrent observation of impaired reality testing in animals. We also show that these CS-evoked licking effects can be ameliorated in DN-DISC1-PrP mice with the same antipsychotics used to treat positive symptoms in humans. Conversely, adolescent isolation stress that has previously been shown to induce epigenetic alterations in dopaminergic neurons27 further augmented these CS-evoked effects in DN-DISC1-PrP mice.

The pattern of c-fos expression in DN-DISC1-PrP mice also offers preliminary insight into how the imagined representation of the absent food is activated within the central nervous system. When DN-DISC1-PrP mice were tested with an extensively trained CS that promoted intake and hedonic responses to water, enhanced activity in the insular was observed. This region is critical for numerous taste-related behaviors and is activated in response to primary taste processing.31,40 Given that this activation occurred in the absence of a primary gustatory stimulation, this is consistent with the idea that in DN-DISC1-PrP mice the CS alone was able to more effectively evoke perceptual taste features of the sucrose. This enhanced immunoreactivity reflected the presentation of the extensively trained CS as c-fos expression was significantly lower in both DN-DISC1-PrP and wild-type mice tested with the unpaired CS. Moreover, the enhanced insular activity was not seen in the ACB, which is known to encode reward value.41 Both DN-DISC1-PrP mice and wild-type mice displayed a similar elevation in c-fos expression in the ACB, when compared to their respective unpaired control conditions.

Our findings are also consistent with more contemporary hypotheses of DA function. Traditionally, the firing of midbrain DA cells is thought to reflect a value-based reinforcement signal that is evoked in response to discrepancies between observed and anticipated rewards.42 These model-free learning systems have the advantage of efficient computation of cached value signals that can be used to update reward expectancies; however, they do not include encoding of detailed features of reinforcement.43,44 Accordingly, the dependence on DA signaling for the retrieval of CS-evoked sensory and evaluative palatability responses (eg, mean cluster size) in transgenic mice is difficult to reconcile within this account. More recently, studies have shown DA cells respond to changes in detailed sensory features of outcomes independent of value per se.45 In addition, DA transients are necessary for identity unblocking,46 and also learning of stimulus—stimulus associations in sensory preconditioning.47 These facets of learning are more readily accounted for by sensory-prediction errors that are used to establish a predictive map (ie, successor representation;48,49); or through model-based learning systems,50 which while more computationally expensive, provides the agent with an inherently more flexible and detailed representational architecture to control behavior.48 Perhaps this enhanced activity of the DA system51,52 could facilitate the capacity for stimuli to evoke detailed sensory features of external events (eg, via stimulus—stimulus learning;47) including perceptual processing.

More broadly, the current findings are consistent with a venerable research history that relates psychosis to a failure to amalgamate sensory input and learned expectations.18,53 These ideas have more recently been conceptualized within a predictive coding account of psychosis that posits an imbalance between predictions (priors) and sensory input (likelihood), evoking particularly strong weighting of prediction errors that can imbue aberrant percepts.54 This model is grounded in Bayesian computational inference and the neurobiological underpinnings include top-down modulation of predictive signals via NMDA-receptor signaling together with dopaminergic and cholinergic modulation of likelihood.54 Given their nature, associative learning studies are particularly useful for exploring the phenomenology and neurobiology of psychosis, particularly within a context of predictive encoding.54–57 For instance, following initial compound presentation of visual and auditory stimuli, individuals who hear voices (including those with psychosis) were more vulnerable to perceiving the presentation of a tone when the visual stimulus alone was presented.57 These conditioning-induced hallucinations were perceptual in nature as they engaged activity in the brain that overlapped with the same auditory cortex activation elicited when the tone stimulus was presented. Moreover, they evoked activity in numerous areas important for prediction and sensory encoding, including superior temporal sulcus, caudate, cingulate, and insula cortex. When the computational mechanisms were modeled, participants with stronger hallucinations displayed robust beliefs, consistent with the idea that strong priors cause a percept in the absence of input, an effect that was associated with strong insula activation.57 Together with the current findings, these and other data raise the interesting possibility that both an overreliance on top-down (eg, insular) processing,54,57,58 together with abnormally strong DA-mediated stimulus–stimulus encoding47 and weighting of sensory prediction error48,49 could lead to aberrant generation of percepts.

Our findings support the use of associative learning procedures to examine DA-dependent reality testing that is associated with activation of the insula cortex. However, a number of limitations should be acknowledged. First, previous studies have shown that in normal animals, minimally but not extensively trained CSs gain access to perceptual processing normally activated by the food itself.21–25 In this study, only partial support for this transfer was obtained in wild-type mice (ie, during the post-CS period; figure 2). Second, the pattern of licking (particularly during the post-CS period) was not consistent across experiments. Although it is currently unclear why these inconsistencies were revealed, they may be attributable to the type of CS used at test (ie, tone, noise) and/or subtle variations in testing conditions (eg, experiment 3, injection stress; experiment 4, younger age of animals59,60). Third, the effects of social isolation in DN-DISC1-PrP mice elevated overall lick rates compared to their group-housed counterparts; however, there was no evidence that this reflected an increased in palatability responses. Nevertheless, a general pattern emerged across experiments 2–4: during presentation of the extensively trained CS, the increased rate of licking to water in transgenic mice was accounted for by a pattern of licking behavior that is more typically seen with sweet-tasting solutions33—consistent with the idea that the CS gained control of sensory-evaluative taste responses normally evoked by the sucrose alone.21–25 In addition, it may be worthwhile considering that the testing conditions in these experiments were somewhat comparable to brief access taste response tests in which a tastant is available for a short time—in these tests, the rate of licking itself is thought to indicate orosensory detection (eg, Eylam et al61). Finally, an important feature of our findings is that the increase in palatability responses during the extensive CS was in transgenic mice associated with activation of putative taste responsive neurons31 and greatly attenuated following neuroleptic treatment.

In sum, the current approach provides the opportunity to examine the microcircuitry62 underlying false percepts and concepts, as well as the specific neurobiology mediating the effects of hallucinogenic compounds.63 To date, although antipsychotics are effective, many patients struggle with unintended residual symptoms and complications (eg, increased risk of suicide64) and low levels of adherence.65 A clearer understanding of circuitry underlying aberrant learned associations may allow for the development of pharmacotherapeutic strategies to improve the quality of life of individuals suffering from positive symptoms and potentially reduce the severe side effects associated with the use of antipsychotics.

Funding

Silvio O. Conte Center National Institutes of Health (NIH) grant (P50MH094268 to Sawa); NIH grants (MH092443 to Sawa, MH105660 to Sawa, MH107730 to Sawa, DK111475 to Johnson); startup funds provided by the Department of Psychology at Michigan State University (to Johnson).

Conflict of Interest

The authors have declared that there are no conflicts of interest in relation to the subject of this study.

Supplementary Material

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sbz043_suppl_Supplementary_Figure-2
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sbz043_suppl_Supplementary_Figure-3
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sbz043_suppl_Supplementary_Figure-4
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sbz043_suppl_Supplementary_Material
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Supplementary Materials

sbz043_suppl_Supplementary_Figure-1
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