Roles of the medial prefrontal cortex, mediodorsal thalamus, and their combined circuit for performance of the odor span task in rats: analysis of memory capacity and foraging behavior.

Working memory (WM), the capacity for short-term storage of small quantities of information for immediate use, is thought to depend on activity within the prefrontal cortex. Recent evidence indicates that the prefrontal neuronal activity supporting WM is driven by thalamocortical connections arising in mediodorsal thalamus (mdThal). However, the role of these connections has not been studied using olfactory stimuli leaving open the question of whether this circuit extends to all sensory modalities. Additionally, manipulations of the mdThal in olfactory memory tasks have yielded mixed results. In the present experiment, we investigated the role of connections between the rat medial prefrontal cortex (mPFC) and mdThal in the odor span task (OST) using a pharmacological contralateral disconnection technique. Inactivation of either the mPFC or mdThal alone both significantly impaired memory performance in the OST, replicating previous findings with the mPFC and confirming that the mdThal plays an essential role in intact OST performance. Contralateral disconnection of the two structures impaired OST performance in support of the idea that the OST relies on mPFC-mdThal connections, but ipsilateral control infusions also impaired performance, complicating this interpretation. We also performed a detailed analysis of rats' errors and foraging behavior and found a dissociation between mPFC and mdThal inactivation conditions. Inactivation of the mdThal and mPFC caused a significant reduction in the number of approaches rats made per odor, whereas only mdThal inactivation or mPFC-mdThal disconnection caused significant increases in choice latency. Our results confirm that the mdThal is necessary for performance of the OST and that it may critically interact with the mPFC to mediate OST performance. Additionally, we have provided evidence that the mPFC and mdThal play dissociable roles in mediating foraging behavior.

Task phase-specific involvement of the rat posterior parietal cortex in performance of the TUNL task.

The posterior parietal cortex (PPC) participates in cognitive processes including working memory (WM), sensory evidence accumulation, and perceptually guided decision making. However, surprisingly little work has used temporally precise manipulations to dissect its role in different epochs of behavior taking place over short timespans, such as WM tasks. As a result, a consistent view of the temporally precise role of the PPC in these processes has not been described. In the present study, we investigated the temporally specific role of the PPC in the Trial-Unique, Nonmatching-to-Location (TUNL) task, a touchscreen-based, visuospatial WM task that relies on the PPC. To disrupt PPC activity in a temporally precise manner, we applied mild intracranial electrical stimulation (ICES). We found that intra-PPC ICES (100 µA) significantly impaired accuracy in TUNL without significantly altering response latency. Moreover, we found that the impairment was specific to ICES applied during the delay and test phases of TUNL. Consistent with previous reports showing delay- and choice-specific neuronal activity in the PPC, the results provide evidence that the rat PPC is required for maintaining memory representations of stimuli over a delay period as well as for making successful comparisons and choices between test stimuli. In contrast, the PPC appears not to be critical for initial encoding of sample stimuli. This pattern of results may indicate that early encoding of visual stimuli is independent of the PPC or that the PPC becomes engaged only when visual stimuli are spatially complex or involve memory or decision making.

Acute stress, but not corticosterone, facilitates acquisition of paired associates learning in rats using touchscreen-equipped operant conditioning chambers.

Acute stress influences learning and memory in humans and rodents, enhancing performance in some tasks while impairing it in others. Typically, subjects preferentially employ striatal-mediated stimulus-response strategies in spatial memory tasks following stress, making use of fewer hippocampal-based strategies which may be more cognitively demanding. Previous research demonstrated that the acquisition of rodent paired associates learning (PAL) relies primarily on the striatum, while task performance after extensive training is impaired by hippocampal disruption. Therefore, we sought to explore whether the acquisition of PAL, an operant conditioning task involving spatial stimuli, could be enhanced by acute stress. Male Long-Evans rats were trained to a predefined criterion in PAL and then subjected to either a single session of restraint stress (30 min) or injection of corticosterone (CORT; 3 mg/kg). Subsequent task performance was monitored for one week. We found that rats subjected to restraint stress, but not those rats injected with CORT, performed with higher accuracy and efficiency, when compared to untreated controls. These results suggest that while acute stress enhances the acquisition of PAL, CORT alone does not. This dissociation may be due to differences between these treatments and their ability to produce sufficient catecholamine release in the amygdala, a requirement for stress effects on memory.

Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801.

RATIONALE: Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies. OBJECTIVES: We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis. METHODS: To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms. RESULTS: Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay. CONCLUSIONS: These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects.