NMDA Receptors in Visual and Olfactory Sensory Integration in Male Long Evans Rats: A Role for the Orbitofrontal Cortex.

Sensory integration (SI) is a cognitive process whereby the brain uses unimodal or multimodal sensory features to create a comprehensive representation of the environment. Integration of sensory input is necessary to achieve a coherent perception of the environment, and to subsequently plan and coordinate action. The neural mechanisms mediating SI are poorly understood; however, recent studies suggest that the regulation of SI involves N-methyl-d-aspartate receptors (NMDARs) in orbitofrontal cortex (OFC). Thus, we tested this hypothesis directly in two experiments using object oddity tests that require SI for visual and olfactory stimuli. First, we blocked NMDARs with acute CPP treatment (i.p., 10 mg/kg) and tested rats in unimodal visual and olfactory SI tests, and respective control unimodal oddity tests that do not require SI. Second, we used intra-OFC infusions of AP5 (30 mM) to examine the role of NMDARs in the OFC in the oddity tests requiring SI. Systemic blockade of NMDARs impaired performance on the visual tests regardless of whether SI was required for determining oddity. In the olfactory tests, systemic treatment with CPP impaired the test requiring SI while sparing olfactory oddity, demonstrating a selective impairment in the olfactory SI. Intra-OFC blockade of NMDARs impaired olfactory SI, without effect on visual SI, demonstrating that intra-OFC NMDARs are essential for olfactory, but not visual SI. The present results are discussed in the context of the function of the OFC and its associated circuitry.

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.

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.