Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability.

Abstract

The authors examined set-shifting abilities in rats injected with antagonists of N-methyl-D-aspartate (NMDA) receptors (MK801) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (LY293558) into the medial prefrontal cortex (mPFC). Set-shifting was assessed with a maze-based task requiring a switch between brightness and texture discrimination strategies. Intra-mPFC injection of MK801 prior to training on the 2nd discrimination impaired discrimination strategy acquisition. The MK801-induced deficit was due to increased perseverative responding. AMPA receptor blockade also impaired acquisition of the 2nd discrimination; these impairments were due to more general cognitive deficits. Results suggest that, within the mPFC, both AMPA and NMDA receptors are necessary for set-shifting, and that NMDA receptor hypofunction impairs the capacity to modify existing knowledge or to inhibit responses that are no longer appropriate.

Multiple Dopamine Receptor Subtypes in the Medial Prefrontal Cortex of the Rat Regulate Set-Shifting

“…These findings suggest that infusions of L-745,870 in the present study may have alleviated a tonic, D4-mediated attenuation of NMDA receptor function, which in turn would be expected to enhance the activity of PFC neural networks, including those engaged during set-shifting (Stefani et al, 2003). In addition, systemic administration of D4 antagonists increases DA extracellular levels within the PFC, without altering the firing properties of midbrain DA neurons (Broderick and Piercey, 1998;Millan et al, 1998;Kawashima et al, 1999).…”

“…Rather, PFC manipulations only disrupt behavior when rats are required to shift from one strategy to another (Ragozzino et al, 1999;Ragozzino, 2002;Stefani et al, 2003). As such, we were not interested in the effects of intra-PFC infusions of DA compounds during initial discrimination learning, and on day 1 rats in all groups received a saline infusion into the PFC.…”

“…Stimulation of D4 receptors with PD-168,077 attenuates NMDA-mediated synaptic transmission in PFC pyramidal neurons by reducing NMDA-mediated currents and increasing the internalization of these receptors (Wang et al, 2003). With respect to the functional role of NMDA receptors in PFC, Stefani et al (2003) have shown that blockade of these receptors via intra-PFC infusion of MK-801 impairs performance on a similar set-shifting task by selectively increasing perseverative errors, in a manner similar to that observed following infusions of PD-168,077 in the present study. Taken together, it is reasonable to propose that excessive stimulation of PFC D4 receptors may attenuate normal NMDA receptor function, and that this in turn may disrupt the patterns of NMDA-mediated activity of PFC neurons that are required for efficient performance of this task.…”

“…Specifically, lesions to the dorsolateral PFC in marmosets cause a selective impairment on extradimensional shifts, while having no effect on reversal learning (Dias et al, 1997). In rats, lesions or blockade of NMDA receptors in the medial PFC impairs setshifting on a number of tasks and causes a selective increase in perseverative errors, whereas the learning and maintenance of a new strategy remains unaffected (Ragozzino et al, 1999;Birrell and Brown, 2000;Stefani et al, 2003). Surprisingly, there have been few studies investigating the importance of PFC DA transmission in attentional setshifting.…”

A mixed filter algorithm for cognitive state estimation from simultaneously recorded continuous and binary measures of performance

“…Learning is typically studied by showing that after a set of trialand-error attempts, a subject is able to execute an unfamiliar task more reliably than chance would predict. The ability of an animal to learn a new task is frequently studied to characterize how attentional modulation (Cook and Maunsell 2002), genetics (Rondi-Reig et al 2001), brain lesions (Roman et al 1993;Whishaw and Tomie 1991;Dusek and Eichenbaum 1997;Fox et al 2003;Wise and Murray 1999), or drug interventions (Stefani et al 2003) affect learning. Accurate characterizations of learning are also important to relate changes in behavior to changes in neural activity in specific brain regions (Jog et al 1999;Law et al 2005;Wirth et al 2003).…”