Delayed-matching-to-position working memory in mice relies on NMDA-receptors in prefrontal pyramidal cells

A hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs) has been implicated in the pathogenesis of schizophrenia by clinical and rodent studies. However, to what extent NMDAR-hypofunction in distinct cell-types across the brain causes different symptoms of this disease is largely unknown. One pharmaco-resistant core symptom of schizophrenia is impaired working memory (WM). NMDARs have been suggested to mediate sustained firing in excitatory neurons of the prefrontal cortex (PFC) that might underlie WM storage. However, if NMDAR-hypofunction in prefrontal excitatory neurons may indeed entail WM impairments is unknown. We here investigated this question in mice, in which NMDARs were genetically-ablated in PFC excitatory cells. This cell type-selective NMDAR-hypofunction caused a specific deficit in a delayed-matching-to-position (DMTP) 5-choice-based operant WM task. In contrast, T-maze rewarded alternation and several psychological functions including attention, spatial short-term habituation, novelty-processing, motivation, sociability, impulsivity, and hedonic valuation remained unimpaired at the level of GluN1-hypofunction caused by our manipulation. Our data suggest that a hypofunction of NMDARs in prefrontal excitatory neurons may indeed cause WM impairments, but are possibly not accounting for most other deficits in schizophrenia.

Episodic-like memory of rats as retrospective retrieval of incidentally encoded locations and involvement of the retrosplenial cortex

To examine episodic memory in rats, we trained rats to perform two tasks and tested them for memory of past self-behavior without making them expect to be asked about the memory later when encoding. One of the trained tasks was a delayed matching-to-position task in which the rats were required to remember the location of a presented lever. The other was a tone discrimination task in which the rats were required to discriminate between two pure tones. After learning both tasks, the rats were unexpectedly asked the location of the pressed lever after responding to the cue tone in probe trials during test sessions. The rats demonstrated a response bias that suggests that they have the ability to retrospectively recollect their self-behavior, i.e., episodic memory. We next made excitotoxic lesions in the retrosplenial cortex (RSC) and investigated the effects of the lesions on the unexpected recollection. In the rats with lesions of the RSC, the response bias disappeared. This suggests that the RSC has a role in retrospectively answering unexpected questions about self-behavior.

Triadimefon Disrupts Working Memory in the Matching-to-Position Task

Triadimefon (TDF) is a fungicide which has psychostimulant properties similar to cocaine and amphetamine. Past studies with psychostimulants suggests that acute exposure leads to disruptions in working memory. In this study, we examined the effects of TDF exposure (relative to corn oil control) on performance in the delayed matching-to-position task in two separate studies using Sprague-Dawley male rats. In both studies, TDF exposure led to significantly poorer performance across delays. TDF shows similar properties to cocaine and amphetamine in terms of disrupting working memory.

Representation of actions and outcomes in medial prefrontal cortex during delayed conditional decision-making: Population analyses of single neuron activity

Background: To respond adaptively in a dynamic environment, it is important for organisms to utilise information about recent events to decide between response options. Methods: To examine the role of medial prefrontal cortex in adaptive decision-making, we recorded single neuron activity in rats performing a dynamic delayed non-matching to position task. Results: We recorded activity from 1335 isolated neurons, 458 (34%) with criterion event-related activity, of which 431 (94%) exhibited 1 of 10 distinct excitatory response types: five at different times relative to delivery (or lack) of reinforcement following sample and choice responses and five correlated with movements or lever press actions that occurred multiple times in each trial. Normalised population averages revealed a precisely timed cascade of population responses representing the temporal organisation behavioural events that constitute delayed non-matching to position trials. Firing field analyses identified a subset of neurons with restricted spatial fields: responding to the conjunction of a behavioural event with a specific location. Anatomical analyses showed considerable overlap in the distribution of different response types in medial prefrontal cortex with a significant trend for dorsal areas to contain more neurons with action-related activity and ventral areas more responses related to action outcomes. Conclusion: These results indicate that medial prefrontal cortex contains discrete populations of neurons that represent the temporal organisation of actions and outcomes during delayed non-matching to position trials. They support the hypothesis that medial prefrontal cortex promotes flexible control of complex behaviours by action–outcome contingencies.