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

Ketamine facilitates appetitive trace conditioning in mice: Further evidence for abnormal stimulus representation in schizophrenia model animals.

“…In accordance with the long-term changes in cell expression, a recent study by Widman and McMahon (2018) found that in vitro application of low-dose (1 μM) ketamine onto HPC slices increased the synaptic excitability of CA1 pyramidal neurons by decreasing the inhibitory transmission from GABAergic interneurons. While such disinhibition should generally interfere with normal network functions to cause deficits in various learning and memory tasks (e.g., Bast et al, 2017; McGarrity et al, 2017; O’Donnell, 2012), and disinhibition is indeed one of the major system-level accounts of schizophrenia (e.g., Koh & Gallagher, 2020; Lisman et al, 2008; Moghaddam & Javitt, 2012), precisely how circuit disturbance is manifested in behavior should critically depend on the specific task requirement. For example, assuming that normal inhibitory activity of the HPC maintains internal representations of absent stimuli to the secondary or reduced level/state of activation, then its disinhibition might result in stronger activation, consequently leading to supranormal associative learning.…”

“…As previously mentioned, ketamine is a noncompetitive N -methyl-D-aspartate-receptor antagonist that has been widely used as an anesthetic and that, at lower doses, produces psychosis-like states in humans (e.g., Breier et al, 1997; Krystal et al, 1994) and animals (Fleming et al, 2022; Koh et al, 2018; Schmack et al, 2021). Although the precise mechanisms through which the drug produces its various effects are still not fully understood, many recent studies supported the validity of ketamine administration as a model of positive symptoms of schizophrenia (see Corlett et al, 2007, 2016; Frohlich & Van Horn, 2014; Koh & Gallagher, 2020, for reviews). We predicted that ketamine injections would facilitate the acquisition of trace, but not delay conditioning.…”

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

“…This disparity could result in connections being made between seemingly unrelated concepts or ideas, which are then linked together and elaborated upon, a characteristic of creative thinking but also of the development of a delusional system, often present in psychiatric conditions such as schizophrenia and psychosis. 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).…”

Variables influencing conditioning-evoked hallucinations: overview and future applications

“…Although hallucinations across (and within) these different populations likely represent equifinal outcomes – with different etiologies culminating in similar symptoms – establishing a common framework to understand them may prove a powerful means by which to elucidate their mechanisms and what may go awry in more serious clinical manifestations (Corlett & Schoenbaum, 2021 ). Drawing on a classic body of work, recent studies in the field of learning have begun to document how associative links between stimuli can give rise to instances where an evoked representation of a sensory experience is experienced as reality (Corlett & Schoenbaum, 2021 ; Koh & Gallagher, 2020 ; McDannald & Schoenbaum, 2009 ), otherwise known as impaired reality testing. In the context of pre-clinical associative learning studies, impaired reality testing is demonstrated when a stimulus is able to evoke perceptual processing of absent features related to a second stimulus with which it was previously paired (e.g.…”

“…While previous reviews (e.g. Koh and Gallagher, 2020 ) have focused more explicitly on preclinical models of hallucinations, this review seeks to bridge the gap between human conditioned hallucination studies, and impaired reality testing in animals, while highlighting commonalities and diverging features. Toward that end, we will examine both historical and contemporary examples of conditioned hallucinations and discuss the factors that may mediate their strength.…”