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

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.

Using internal memory representations in associative learning to study hallucination-like phenomenon

“…The same mice when treated with the antipsychotic risperidone showed both reduced hyperresponsiveness to amphetamine and an attenuated tendency for representation-mediated learning, suggesting that conditioned hallucinations as conceptualized here may be due, at least in part, to dopamine hyperfunction (Koh et al, 2018a). Further substantiating those findings, treatment with haloperidol, which exhibits high affinity dopamine D 2 receptor antagonism, also effectively reduced the tendency to evoke internal representations in DISC-1 transgenic mice (Fry et al, 2019). A role for dopaminergic function demonstrated in those studies is consistent with the view that internal representations elicited in the context of mediated learning approximates hallucinations in patients insofar that hallucinations have also shown some sensitivity to antipsychotics that target dopamine function, and that hallucinations might arise from a dysregulation of the dopamine system causing misattribution of salience to internal representations of percepts and memories (Kapur, 2003).…”

“…We found that the previously taste-associated odor induced a stronger neural activation in the insular taste cortex in mice exposed to ketamine during adolescence than control mice. Using DISC-1 transgenic mice, Fry et al, (2019) similarly found those mice to display a greater c-fos expression in the insular cortex in response to an auditory cue previously paired with a taste. Taken together with the behavioral studies, the neural activation data further strengthened the assertion that animals used to model symptoms of schizophrenia, which do not exhibit any general alteration in simple associative conditioning (Johnson et al, 2013;Koh et al, 2018, Fig.…”

“…Compared to control mice, the mice with a history of ketamine exposure during adolescence showed a more pronounced taste aversion, suggesting (1) a heightened tendency to activate an internal representation from a prior associative experience (i.e., odor activates taste representation during conditioning), and/or (2) a stronger propensity to associate an internal representation with another stimulus or event (i.e., taste representation associates with illness). Recent work using mice with dominant negative expression of Disrupted-In-Schizophrenia-1 (DISC-1), a mutation that increased the risk for neuropsychiatric conditions, shed some light on these possibilities using a simple Pavlovian approach (Fry et al, 2019). The mice were first given conditioning of an auditory stimulus such as a tone paired with the delivery of sucrose solution for consumption.…”

Probing for Conditioned Hallucinations Through Neural Activation in a Ketamine Mouse Model of Schizophrenia

“…Based on the cognitive perspective described above, we and others have shown that mice used to model schizophrenia were more susceptible to psychosis-like behavior than normal animals as instantiated by a greater tendency to form associations between stimuli or events that were mediated by prior experience [2][3][4]. For example, using a well-established ketamine mouse model that is known to recapitulate many of the symptoms seen in schizophrenia [5,6], we used a representation-mediated learning paradigm to show that, when an odor and a taste are repeatedly paired, ketamine-exposed mice have an increased tendency to use the odor to evoke a putative inner representation of the taste that could enter into an association with illness [3].…”

Neural Substrates of Incidental Associations and Mediated Learning: The Role of Cannabinoid Receptors

“…Interestingly, the reconceptualization of schizophrenia symptoms as aberrant perceptions (hallucinations) (Corlett et al, 2019) and beliefs (delusions) (Feeney et al, 2017), has provided the framework to be studied through associative learning tasks in both humans and animals (Powers et al, 2017;Dwyer, 2018;Koh and Gallagher, 2020). Indeed, impaired "reality testing" was recently demonstrated in several animal models of schizophrenia in a way that mimics psychotic-like percepts (McDannald et al, 2011;Kim and Koh, 2016;Busquets-Garcia et al, 2017;Koh et al, 2018;Fry et al, 2019), with recent evidence suggesting that such phenomena involve dopamine signaling (Schmack et al, 2021).…”