Acute NMDA receptor antagonism impairs working memory performance but not attention in rats—Implications for the NMDAr hypofunction theory of schizophrenia.

Abstract

Cognitive deficits in schizophrenia, which include impairments in working memory and attention, represent some of the most disabling symptoms of this complex psychiatric condition, and lack effective treatments. NMDA receptor (NMDAr) hypofunction is a strong candidate mechanism underlying schizophrenia pathophysiology, and has been modeled preclinically using acute administration of NMDAr antagonists to rodents to investigate biological mechanisms underpinning cognitive dysfunction. However, whether and how NMDAr hypofunction specifically influences all affected cognitive domains is unclear. Here we studied the effects of the NMDAr antagonist MK-801 (dizocilpine) on tasks of attention and working memory in rats using automated touchscreen chambers. Adult male Wistar rats were trained to perform the trial-unique nonmatching to location (TUNL) task of spatial working memory, or the 5-choice serial reaction time task (5CSRTT) of attention. Once trained, rats received injection of vehicle (saline) or low-dose MK-801 (0.06 mg/kg sc) 10 min prior to commencing test sessions. MK-801 significantly impaired working memory, as evidenced by reduced performance accuracy on the TUNL task (p < .0001), compared with vehicle. However, we found no significant effects on attentional processing or perseveration on the 5CSRTT. Additional measures indicated that MK-801 impaired behavioral flexibility in the TUNL task, and decreased response inhibition in both tasks. Using the automated touchscreen system to measure different cognitive functions under the same testing environment, we demonstrate that spatial working memory, response inhibition, and behavioral flexibility are more vulnerable to NMDAr hypofunction than attentional processing. This may have implications for the NMDAr hypofunction hypothesis of schizophrenia.

Plasma Kynurenine Level is Associated With Left DLPFC Activity and Can Predict Treatment Response in Major Depressive Disorder

“…Although KYN itself does not directly excite or inhibit neural activity, the downstream metabolites of KYN, quinolinic acid and 3-HK, are known to have N-methyl-D-aspartate (NMDA) receptor agonist effects, while KYNA is known to have NMDA receptor antagonist effects 50 . The balance of both affects neural activity via NMDA receptors 51 , and therefore, it may be related to brain functions, such as attention and working memory, in which NMDA receptors play an important role [52][53][54][55] . In the DLPFC, a brain region important for working memory and attention, NMDA receptors are known to be involved in attention and working memory by activating pyramidal cells to re synapses persistently 56,57 .…”

The Touchscreen‐Based Trial‐Unique, Nonmatching‐To‐Location (TUNL) Task as a Measure of Working Memory and Pattern Separation in Rats and Mice

“…The length of the session has previously been set at a shorter time of 30 min/session, requiring the completion of 60 trials during a session (Oomen et al, 2013). The short session length contrasts with researchers who have doubled the session length but have maintained a relatively low number of required trials, 64 trials in 60 min (Lee et al, 2020). This protocol mirrors the general ratio of 1-2 trials/min by requiring the rats to reach the criterion of 84 trials in 60 min, which has been previously found to be successful (Anderson et al, 2020;Davies et al, 2017;Scott et al, 2019;Scott et al, 2021).…”

“…The approach described in this protocol aligns with substage c, as a reward pellet is only delivered when the correct light stimulus is selected; otherwise, no response is observed. The rats can progress to the next substage when they reach the expressed criterion (Lee et al., 2020; Oomen et al., 2013). The length of the session has previously been set at a shorter time of 30 min/session, requiring the completion of 60 trials during a session (Oomen et al., 2013).…”

“…When a rat makes a correct selection, it receives three reward pellets and initiates a 5‐s ITI for a duration of up to 60 min (Hurtubise et al., 2017; Lee et al., 2020; Oomen et al., 2013; Talpos et al., 2010). This approach reinforces the learned rule that touching a light stimulus is associated with a food reward, and a correct selection is increasingly rewarded (Hurtubise et al., 2017; Lee et al., 2020; Oomen et al., 2013; Talpos et al., 2010). The training period for Initial Touch Training was originally shorter, 30‐min in length, and this was deemed to be enough time to learn the rule (Talpos et al., 2010).…”

“…A 5‐s timeout period is universally applied. Throughout Punish Incorrect, Initial TUNL, and Full TUNL Training, a performance accuracy criterion of around 70%‐80% of stable performance is promoted (Anderson et al., 2020; Davies et al., 2017; Horner et al., 2013; Hurtubise et al., 2017; Lee et al., 2020; Oomen et al., 2013; Scott et al., 2019, 2021). There has, however, been the rare occasion where the required performance was set at a stable performance accuracy of above 50% (McAllister et al., 2013).…”