Postsynaptic nicotinic acetylcholine receptors facilitate excitation of developing CA1 pyramidal neurons.

The hippocampus plays a key role in learning and memory. The normal development and mature function of hippocampal networks supporting these cognitive functions depends on afferent cholinergic neurotransmission mediated by nicotinic acetylcholine receptors. Whereas it is well-established that nicotinic receptors are present on GABAergic interneurons and on glutamatergic presynaptic terminals within the hippocampus, the ability of these receptors to mediate postsynaptic signaling in pyramidal neurons is not well understood. We use whole cell electrophysiology to show that heteromeric nicotinic receptors mediate direct inward currents, depolarization from rest and enhanced excitability in hippocampus CA1 pyramidal neurons of male mice. Measurements made throughout postnatal development provide a thorough developmental profile for these heteromeric nicotinic responses, which are greatest during the first 2 wk of postnatal life and decrease to low adult levels shortly thereafter. Pharmacological experiments show that responses are blocked by a competitive antagonist of α4ß2* nicotinic receptors and augmented by a positive allosteric modulator of α5 subunit-containing receptors, which is consistent with expression studies suggesting the presence of α4ß2 and α4ß2α5 nicotinic receptors within the developing CA1 pyramidal cell layer. These findings demonstrate that functional heteromeric nicotinic receptors are present on CA1 pyramidal neurons during a period of major hippocampal development, placing these receptors in a prime position to play an important role in the establishment of hippocampal cognitive networks.

The Dynamic Multisensory Engram: Neural Circuitry Underlying Crossmodal Object Recognition in Rats Changes with the Nature of Object Experience.

Rats, humans, and monkeys demonstrate robust crossmodal object recognition (CMOR), identifying objects across sensory modalities. We have shown that rats' performance of a spontaneous tactile-to-visual CMOR task requires functional integration of perirhinal (PRh) and posterior parietal (PPC) cortices, which seemingly provide visual and tactile object feature processing, respectively. However, research with primates has suggested that PRh is sufficient for multisensory object representation. We tested this hypothesis in rats using a modification of the CMOR task in which multimodal preexposure to the to-be-remembered objects significantly facilitates performance. In the original CMOR task, with no preexposure, reversible lesions of PRh or PPC produced patterns of impairment consistent with modality-specific contributions. Conversely, in the CMOR task with preexposure, PPC lesions had no effect, whereas PRh involvement was robust, proving necessary for phases of the task that did not require PRh activity when rats did not have preexposure; this pattern was supported by results from c-fos imaging. We suggest that multimodal preexposure alters the circuitry responsible for object recognition, in this case obviating the need for PPC contributions and expanding PRh involvement, consistent with the polymodal nature of PRh connections and results from primates indicating a key role for PRh in multisensory object representation. These findings have significant implications for our understanding of multisensory information processing, suggesting that the nature of an individual's past experience with an object strongly determines the brain circuitry involved in representing that object's multisensory features in memory. SIGNIFICANCE STATEMENT: The ability to integrate information from multiple sensory modalities is crucial to the survival of organisms living in complex environments. Appropriate responses to behaviorally relevant objects are informed by integration of multisensory object features. We used crossmodal object recognition tasks in rats to study the neurobiological basis of multisensory object representation. When rats had no prior exposure to the to-be-remembered objects, the spontaneous ability to recognize objects across sensory modalities relied on functional interaction between multiple cortical regions. However, prior multisensory exploration of the task-relevant objects remapped cortical contributions, negating the involvement of one region and significantly expanding the role of another. This finding emphasizes the dynamic nature of cortical representation of objects in relation to past experience.

Cholinergic manipulations bidirectionally regulate object memory destabilization.

Consolidated memories can become destabilized and open to modification upon retrieval. Destabilization is most reliably prompted when novel information is present during memory reactivation. We hypothesized that the neurotransmitter acetylcholine (ACh) plays an important role in novelty-induced memory destabilization because of its established involvement in new learning. Accordingly, we investigated the effects of cholinergic manipulations in rats using an object recognition paradigm that requires reactivation novelty to destabilize object memories. The muscarinic receptor antagonist scopolamine, systemically or infused directly into the perirhinal cortex, blocked this novelty-induced memory destabilization. Conversely, systemic oxotremorine or carbachol, muscarinic receptor agonists, administered systemically or intraperirhinally, respectively, mimicked the destabilizing effect of novel information during reactivation. These bidirectional effects suggest a crucial influence of ACh on memory destabilization and the updating functions of reconsolidation. This is a hitherto unappreciated mnemonic role for ACh with implications for its potential involvement in cognitive flexibility and the dynamic process of long-term memory storage.

Intraperirhinal cortex administration of the synthetic cannabinoid, HU210, disrupts object recognition memory in rats.

Cannabinoids disrupt learning and memory in human and nonhuman participants. Object recognition memory, which is particularly susceptible to the impairing effects of cannabinoids, relies critically on the perirhinal cortex (PRh); however, to date, the effects of cannabinoids within PRh have not been assessed. In the present study, we evaluated the effects of localized administration of the synthetic cannabinoid, HU210 (0.01, 1.0 µg/hemisphere), into PRh on spontaneous object recognition in Long-Evans rats. Animals received intra-PRh infusions of HU210 before the sample phase, and object recognition memory was assessed at various delays in a subsequent retention test. We found that presample intra-PRh HU210 dose dependently (1.0 µg but not 0.01 µg) interfered with spontaneous object recognition performance, exerting an apparently more pronounced effect when memory demands were increased. These novel findings show that cannabinoid agonists in PRh disrupt object recognition memory.

The neural bases of crossmodal object recognition in non-human primates and rodents: a review.

The ability to integrate information from different sensory modalities to form unique multisensory object representations is a highly adaptive cognitive function. Surprisingly, non-human animal studies of the neural substrates of this form of multisensory integration have been somewhat sparse until very recently, and this may be due in part to a relative paucity of viable testing methods. Here we review the historical development and use of various "crossmodal" cognition tasks for non-human primates and rodents, focusing on tests of "crossmodal object recognition", the ability to recognize an object across sensory modalities. Such procedures have great potential to elucidate the cognitive and neural bases of object representation as it pertains to perception and memory. Indeed, these studies have revealed roles in crossmodal cognition for various brain regions (e.g., prefrontal and temporal cortices) and neurochemical systems (e.g., acetylcholine). A recent increase in behavioral and physiological studies of crossmodal cognition in rodents augurs well for the future of this research area, which should provide essential information about the basic mechanisms of object representation in the brain, in addition to fostering a better understanding of the causes of, and potential treatments for, cognitive deficits in human diseases characterized by atypical multisensory integration.

Evidence for a specific role for muscarinic receptors in crossmodal object recognition in rats.

Acetylcholine (ACh) has been implicated in numerous cognitive functions, including multisensory feature binding. In the present study, we systematically assessed the involvement of cholinergic muscarinic receptors in several variations of an object recognition task for rats. In the standard spontaneous object recognition (SOR) task, tactile and visual properties of objects were freely available throughout the sample and choice phases. In the tactile- and visual-only unimodal SOR tasks, exploration in both phases was restricted to tactile and visual information, respectively. For the basic crossmodal object recognition (CMOR) task, sample object exploration was limited to tactile features, whereas choice objects were available only in the visual domain. In Experiment 1, pre-sample systemic administration of scopolamine (0.2mg/kg) disrupted performance on standard SOR, both unimodal SOR tasks, and basic CMOR, consistent with a role for muscarinic receptors in memory encoding. Conversely, in Experiment 2, pre-choice systemic scopolamine selectively impaired object recognition on the CMOR task. For Experiment 3, the inclusion of multimodal, but not unimodal pre-exposure to the to-be-remembered objects prevented scopolamine from disrupting performance on the CMOR task when given prior to the choice phase. These results suggest that ACh is necessary during the choice phase of the CMOR task to facilitate the binding of object features across sensory modalities, a function that is not required for the other tasks assessed. Multimodal object pre-exposure might preclude the requisite contribution of ACh in the choice phase by allowing rats to bind important visual and tactile object information prior to testing.

Delineating prefrontal cortex region contributions to crossmodal object recognition in rats.

In the present study, we assessed the involvement of the prefrontal cortex (PFC) in the ability of rats to perform crossmodal (tactile-to-visual) object recognition tasks. We tested rats with 3 different types of bilateral excitotoxic lesions: (1) Large PFC lesions, including the medial PFC (mPFC) and ventral and lateral regions of the orbitofrontal cortex (OFC); (2) selective mPFC lesions; and (3) selective OFC lesions. Rats were tested on 2 versions of crossmodal object recognition (CMOR): (1) The original CMOR task, which uses a tactile-only sample phase and a visual-only choice phase; and (2) a "multimodal pre-exposure" version (PE/CMOR), in which simultaneous pre-exposure to the tactile and visual features of an object facilitates CMOR performance over longer memory delays. Inclusive PFC lesions disrupted performance on both versions of CMOR, whereas selective mPFC damage had no effect. Lesions limited to the OFC caused delay-dependent deficits on the CMOR task, but failed to reverse the enhancement produced by multimodal object pre-exposure. This pattern of functional dissociations suggests complex, multidimensional contributions of the PFC and its subregions to crossmodal cognition.

Crossmodal object recognition in rats with and without multimodal object pre-exposure: no effect of hippocampal lesions.

The neural mechanisms and brain circuitry involved in the formation, storage, and utilization of multisensory object representations are poorly understood. We have recently introduced a crossmodal object recognition (CMOR) task that enables the study of such questions in rats. Our previous research has indicated that the perirhinal and posterior parietal cortices functionally interact to mediate spontaneous (tactile-to-visual) CMOR performance in rats; however, it remains to be seen whether other brain regions, particularly those receiving polymodal sensory inputs, contribute to this cognitive function. In the current study, we assessed the potential contribution of one such polymodal region, the hippocampus (HPC), to crossmodal object recognition memory. Rats with bilateral excitotoxic HPC lesions were tested in two versions of crossmodal object recognition: (1) the original CMOR task, which requires rats to compare between a stored tactile object representation and visually-presented objects to discriminate the novel and familiar stimuli; and (2) a novel 'multimodal pre-exposure' version of the CMOR task (PE/CMOR), in which simultaneous exploration of the tactile and visual sensory features of an object 24 h prior to the sample phase enhances CMOR performance across longer retention delays. Hippocampus-lesioned rats performed normally on both crossmodal object recognition tasks, but were impaired on a radial arm maze test of spatial memory, demonstrating the functional effectiveness of the lesions. These results strongly suggest that the HPC, despite its polymodal anatomical connections, is not critically involved in tactile-to-visual crossmodal object recognition memory.

Severe cross-modal object recognition deficits in rats treated sub-chronically with NMDA receptor antagonists are reversed by systemic nicotine: implications for abnormal multisensory integration in schizophrenia.

Schizophrenia is a complex and debilitating disorder, characterized by positive, negative, and cognitive symptoms. Among the cognitive deficits observed in patients with schizophrenia, recent work has indicated abnormalities in multisensory integration, a process that is important for the formation of comprehensive environmental percepts and for the appropriate guidance of behavior. Very little is known about the neural bases of such multisensory integration deficits, partly because of the lack of viable behavioral tasks to assess this process in animal models. In this study, we used our recently developed rodent cross-modal object recognition (CMOR) task to investigate multisensory integration functions in rats treated sub-chronically with one of two N-methyl-D-aspartate receptor (NMDAR) antagonists, MK-801, or ketamine; such treatment is known to produce schizophrenia-like symptoms. Rats treated with the NMDAR antagonists were impaired on the standard spontaneous object recognition (SOR) task, unimodal (tactile or visual only) versions of SOR, and the CMOR task with intermediate to long retention delays between acquisition and testing phases, but they displayed a selective CMOR task deficit when mnemonic demand was minimized. This selective impairment in multisensory information processing was dose-dependently reversed by acute systemic administration of nicotine. These findings suggest that persistent NMDAR hypofunction may contribute to the multisensory integration deficits observed in patients with schizophrenia and highlight the valuable potential of the CMOR task to facilitate further systematic investigation of the neural bases of, and potential treatments for, this hitherto overlooked aspect of cognitive dysfunction in schizophrenia.

On the dynamic nature of the engram: evidence for circuit-level reorganization of object memory traces following reactivation.

Research has implicated the perirhinal cortex (PRh) in several aspects of object recognition memory. The specific role of the hippocampus (HPC) remains controversial, but its involvement in object recognition may pertain to processing contextual information in relation to objects rather than object representation per se. Here we investigated the roles of the PRh and HPC in object memory reconsolidation using the spontaneous object recognition task for rats. Intra-PRh infusions of the protein synthesis inhibitor anisomycin immediately following memory reactivation prevented object memory reconsolidation. Similar deficits were observed when a novel object or a salient contextual change was introduced during the reactivation phase. Intra-HPC infusions of anisomycin, however, blocked object memory reconsolidation only when a contextual change was introduced during reactivation. Moreover, disrupting functional interaction between the HPC and PRh by infusing anisomycin unilaterally into each structure in opposite hemispheres also impaired reconsolidation when reactivation was done in an altered context. These results show for the first time that the PRh is critical for reconsolidation of object memory traces and provide insight into the dynamic process of object memory storage; the selective requirement for hippocampal involvement following reactivation in an altered context suggests a substantial circuit level object trace reorganization whereby an initially PRh-dependent object memory becomes reliant on both the HPC and PRh and their interaction. Such trace reorganization may play a central role in reconsolidation-mediated memory updating and could represent an important aspect of lingering consolidation processes proposed to underlie long-term memory modulation and stabilization.