Learning history and cholinergic modulation in the dorsal hippocampus are necessary for rats to infer the status of a hidden event

Abstract

Identifying statistical patterns between environmental stimuli enables organisms to respond adaptively when cues are later observed. However, stimuli are often obscured from detection, necessitating behavior under conditions of ambiguity. Considerable evidence indicates decisions under ambiguity rely on inference processes that draw on past experiences to generate predictions under novel conditions. Despite the high demand for this process and the observation that it deteriorates disproportionately with age, the underlying mechanisms remain unknown. We developed a rodent model of decision-making during ambiguity to examine features of experience that contribute to inference. Rats learned either a simple (positive patterning) or complex (negative patterning) instrumental discrimination between the illumination of one or two lights. During test, only one light was lit while the other relevant light was blocked from physical detection (covered by an opaque shield, rendering its status ambiguous). We found experience with the complex negative patterning discrimination was necessary for rats to behave sensitively to the ambiguous test situation. These rats behaved as if they inferred the presence of the hidden light, responding differently than when the light was explicitly absent (uncovered and unlit). Differential expression profiles of the immediate early gene cFos indicated hippocampal involvement in the inference process while localized microinfusions of the muscarinic antagonist, scopolamine, into the dorsal hippocampus caused rats to behave as if only one light was present. That is, blocking cholinergic modulation prevented the rat from inferring the presence of the hidden light. Collectively, these results suggest cholinergic modulation mediates recruitment of hippocampal processes related to past experiences and transfer of these processes to make decisions during ambiguous situations. Our results correspond with correlations observed between human brain function and inference abilities, suggesting our experiments may inform interventions to alleviate or prevent cognitive dysfunction.

Mental imagery in animals: Learning, memory, and decision-making in the face of missing information

“…These results suggest that something about the negative patterning discrimination was necessary for rats to retrieve images of associated visual cues. We have more recently shown that the effect of concurrent training on positive and negative patterning discriminations on use of an image in the positive patterning discrimination was not due to simple alternative aspects of the task, such as concurrent training per se, or to the amount of reinforcement during training or the amount of training (Fast, Flesher, Nocera, Fanselow, & Blaisdell, 2016).…”

“…The finding that an image of an ambiguously absent visual cue can guide instrumental responding in rats depends on learning a non-linear discrimination such as negative patterning discrimination (Fast & Blaisdell, 2011;Fast, Flesher, et al, 2016) provides a clue to the neural basis of reasoning about ambiguously absent events. Negative patterning discriminations (and configural learning tasks in general) have been shown to depend on a functioning hippocampus, while positive patterning discriminations (which can be solved by linear computational processes) do not (Alvarado & Rudy, 1995;Rudy & Sutherland, 1989;Sakimoto, Hattori, Takeda, Okada, & Sakata, 2013;; but see Davidson, McKernan, & Jarrard, 1993).…”

“…In collaboration with Michael Fanselow, we investigated the role of the hippocampus in processing of an ambiguously covered event (Fast, Flesher, et al, 2016). We replicated the concurrent patterning procedure of Experiment 2 of Fast and Blaisdell (2011).…”

“…Additional evidence highlighting the role of dorsal hippocampus in processing an image of an ambiguously absent visual cue comes from imaging of immediate early gene (IEG) c-Fos (Fast, Flesher, et al, 2016). We replicated the instrumental patterning discrimination procedure of Experiment 1 of Fast and Blaisdell (2011), whereby some rats were trained on only the positive patterning discrimination and others were trained on only the negative patterning discrimination.…”

“…Figure 8 shows representative examples of IEG expression in the dentate gyrus within the dorsal hippocampus (left panels), and the quantified levels of IEG Fig. 7 Mean lever presses occurring during 30-s A-alone tests minus baseline responses in the experiment reported by Fast, Flesher, et al (2016). White bars reflect tests with B uncovered and gray bars illustrate tests with B covered.…”