Interactions between medial prefrontal cortex and dorsomedial striatum are necessary for odor span capacity in rats: role of GluN2B-containing NMDA receptors

Abstract

Working memory is involved in the maintenance and manipulation of information essential for complex cognition. While the neural substrates underlying working memory capacity have been studied in humans, considerably less is known about the circuitry mediating working memory capacity in rodents. Therefore, the present experiments tested the involvement of medial prefrontal cortex (mPFC) and dorsal striatum (STR) in the odor span task (OST), a task proposed to assay working memory capacity in rodents. Initially, Long Evans rats were trained to dig in scented sand for food following a serial delayed nonmatching-to-sample rule. Temporary inactivation of dorsomedial (dm) STR significantly reduced span in well trained rats. Inactivation of mPFC or contralateral disconnection of the mPFC and dmSTR also reduced span. Infusing the GluN2B-containing NMDA receptor antagonist Ro 25-6981 into mPFC did not affect span; however, span was significantly reduced following bilateral Ro 25-6981 infusions into dmSTR or contralateral disconnection of mPFC (inactivation) and dmSTR (Ro 25-6981). These results suggest that span capacity in rats depends on GluN2B-containing NMDA receptor-dependent interactions between the mPFC and the dmSTR. Therefore, interventions targeting this circuit may improve the working memory capacity impairments in patients with schizophrenia, Alzheimer's disease, and Parkinson's disease.

Figure 1.

(A) Illustration of the OST. See text for details. Odors are indicated with letters. On subsequent trials for a given span, the bowl (black circle) that contains the novel odor is rewarded (+) while previously encountered bowl(s) are not (−). Bowls are added one at a time to the platform until an error occurs. Span is calculated as the number of bowls on the platform for the last error free trial minus 1. Note that all bowls are moved around the platform before each new trial. (B) Mean odor spans during the 7 d of training prior to the first treatment for all rats in the three experiments (n = 24). Rats had significantly higher spans on days 4–7 than day 1 (see Results for details). (C) Infusions sites of florescent muscimol in the right hemisphere of the mPFC (top), left hemisphere of the dmSTR (bottom left), and right hemisphere of the dlSTR (bottom right).

Figure 2.

Effects of dmSTR or dlSTR inactivations on performance of the OST (n = 9). (A) Mean spans of rats following vehicle (Veh) or muscimol and baclofen (Mus/Bac) infusions into dmSTR (left). Mean latency of the rats to begin digging in a bowl for the dmSTR treatments (right). (B) Mean spans of rats following Veh or Mus/Bac infusions into dlSTR (left). Mean latency of the rats to start digging in a bowl for the dlSTR treatments (right). (C) Representative infusions sites in the dmSTR and dlSTR for the experiments that occurred in A and B. Numbers refer to the anterior–posterior location of the plates relative to bregma. * Refers to a significant difference between treatments (P < 0.05).

Figure 3.

Effects of mPFC or dmSTR inactivations on performance of the OST (n = 7). (A) Mean spans of rats following vehicle (Veh) or muscimol and baclofen (Mus/Bac) infusions into the mPFC (left). Mean latency of the rats to begin digging in a bowl for the mPFC treatments (right). (B) Mean spans of rats following Veh or Mus/Bac infusions into the dmSTR (left). Mean latency of rats to start digging in a bowl for the dmSTR treatments. (C) Mean spans of rats following Veh or Mus/Bac for contralateral disconnection of mPFC and dmSTR (left; see text for details). Mean latency of rats to start digging in a bowl for the contralateral disconnection treatments (right). (D) Representative infusions sites in the mPFC (left) for experiments A and C, and dmSTR (right) for experiments B and C. Numbers refer to the anterior–posterior location of the plates relative to bregma. * Refers to a significant difference between treatments (P < 0.05).

Figure 4.

The effects of blocking GluN2B-containing NMDA receptors on performance on the OST (n = 8). (A) Mean spans of rats following vehicle (Veh) or Ro 25-6981 (Ro) infusions into the mPFC (left). Mean spans of rats in the same mPFC treatments with two poorly performing vehicle rats removed (middle). Mean latency of the rats to begin digging in a bowl for the mPFC treatments (right). (B) Mean spans of rats following Veh or Ro infusions into the dmSTR (left). Mean latency of the rats to begin digging in a bowl for the dmSTR treatments (right). (C) Mean spans of rats following Veh or muscimol and baclofen+Ro (M/B+Ro) for contralateral disconnection in mPFC (M/B) and dmSTR (Ro) (left; see text for details). Mean latency of rats to start digging in a bowl for the contralateral disconnection treatments (right). (D) Representative infusions sites in the mPFC (left) for experiments A and C, and dmSTR (right) for experiments B and C. Numbers refer to the anterior–posterior location of the plates relative to bregma. * Refers to a significant difference between treatments (P < 0.05).