Using rat operant delayed match-to-sample task to identify neural substrates recruited with increased working memory load

Abstract

The delayed match-to-sample task (DMS) is used to probe working memory (WM) across species. While the involvement of the PFC in this task has been established, limited information exists regarding the recruitment of broader circuitry, especially under the low-versus high-WM load. We sought to address this question by using a variable-delay operant DMS task. Male Sprague-Dawley rats were trained and tested to determine their baseline WM performance across all (0-to 24-sec) delays. Next, rats were tested in a single DMS test with either 0-or 24-sec fixed delay, to assess low-/high-load WM performance. c-Fos mRNA expression was quantified within cortical and subcortical regions and correlated with WM performance. High WM load up-regulated overall c-Fos mRNA expression within the PrL, as well as within a subset of mGlu5+ cells, with load-dependent, local activation of protein kinase C (PKC) as the proposed underlying molecular mechanism. The PrL activity negatively correlated with choice accuracy during high load WM performance. A broader circuitry, including several subcortical regions, was found to be activated under low and/or high load conditions. These findings highlight the role of mGlu5-and/or PKC-dependent signaling within the PrL, and corresponding recruitment of subcortical regions during high-load WM performance.

Evidence for Phosphorylation-Dependent, Dynamic, Regulation of mGlu5 and Homer2 in Expression of Cocaine Aversion in Mice

“…Despite this, the knowledge gap regarding the neurobiological substrates underlying cocaine use disorder impedes therapeutic progress. Cocaine impacts glutamate transmission in brain, producing region-selective changes in the expression and function of the Group1 metabotropic glutamate receptor subtype mGlu5 (c.f., Niedzielska-Andres et al, 2021), which contribute to cocaine-seeking behavior in animal models (e.g., Gass and Olive, 2008;Ben-Shahar et al, 2013;Knackstedt and Schwendt, 2016;Gobin and Schwendt, 2020;). mGlu5 receptors act primarily via Gq/11 proteins to initiate the PLC/IP3/Ca2+ cascade (Niswender and Conn, 2010;Iacovelli et al, 2013), as well as signaling to mitogen-activated protein kinase pathways , and PI3K/Akt/mTOR signaling (Rong et al, 2003;Ronesi and Huber, 2008).…”

Retrospective memory trace sustained by the human hippocampus during working memory task

“…Based on the time span of information retention, working memory is classified as a subcategory of short‐term memory which holds information in mind for seconds to minutes (Milner, 1959; Naya, 2016b). To hold behaviourally relevant information as working memory, persistent neural activity is considered a vehicle to bridge the temporal gap between perceptual input and response output (Funahashi, 2017; Fuster & Alexander, 1971; Kamigaki & Dan, 2017), although other neural mechanisms, including intracellular signalling via chemical modulation of existing proteins (Dash et al, 2007; Gobin et al, 2020), may also serve this purpose. Previous single‐unit studies examining the lateral prefrontal cortex (PFC) of nonhuman primates have shown sustained delay activities during the delayed matching‐to‐sample (DMS) task or delayed response task in the absence of external stimuli (Funahashi et al, 1993; Miller et al, 1996; Sakurai et al, 2004).…”