DREADD-inactivation of dorsal CA1 pyramidal neurons in mice impairs retrieval of object and spatial memories.

The hippocampus, a medial temporal lobe brain region, is critical for the consolidation of information from short-term memory into long-term episodic memory and for spatial memory that enables navigation. Hippocampal damage in humans has been linked to amnesia and memory loss, characteristic of Alzheimer's disease and other dementias. Numerous studies indicate that the rodent hippocampus contributes significantly to long-term memory for spatial and nonspatial information. For example, muscimol-induced depression of CA1 neuronal activity in the dorsal hippocampus impairs the encoding, consolidation, and retrieval of nonspatial object memory in mice. Here, a chemogenetic designer receptor exclusively activated by designer drugs (DREADDs) approach was used to test the selective involvement of CA1 pyramidal neurons in memory retrieval for objects and for spatial location in a cohort of male C57BL/6J mice. Activation of the inhibitory (hM4Di) DREADDs receptor expressed in CA1 neurons significantly impaired the retrieval of object memory in the spontaneous object recognition task and of spatial memory in the Morris water maze. Silencing of CA1 neuronal activity in hM4Di-expressing mice was confirmed by comparing Fos expression in vehicle- and clozapine-N-oxide-treated mice after exploration of a novel environment. Histological analyses revealed that expression of the hM4Di receptor was limited to CA1 neurons of the dorsal hippocampus. These results suggest that a common subset of CA1 neurons (i.e., those expressing hM4Di receptors) in mouse hippocampus contributed to the retrieval of long-term memory for nonspatial and spatial information. Our findings support the view that the contribution of the rodent hippocampus is like that of the primate hippocampus, specifically essential for global memory. Our results further validate mice as a suitable model system to study the neurobiological mechanisms of human episodic memory, but also in developing treatments and understanding the underlying causes of diseases affecting long-term memory, such as Alzheimer's disease.

Effect of a hallucinogenic serotonin 5-HT2A receptor agonist on visually guided, hippocampal-dependent spatial cognition in C57BL/6J mice.

By acting on serotonin 5-HT2A receptors (5-HT2A Rs), serotonergic psychedelic drugs induce perceptual and visual hallucinations by increasing neuronal excitability and altering visual-evoked neuronal responses. The present study was designed to examine whether the perceptual alterations induced by a serotonergic psychedelic drug would affect the integrity of hippocampal-dependent, visually guided spatial cognition. phenylalkylamine hallucinogen TCB-2 is a selective agonist of 5-HT2A Rs. Mice received TCB-2 (1.0 mg kg-1 , i.p.), and spatial behaviors and hippocampal electrophysiological responses were measured with water maze tasks and in vivo single-unit recording, respectively. TCB-2 did not affect visual cue approach behavior in the visible platform water maze, but increased the latency of trained mice to initiate goal-directed swimming during a probe test in the hidden platform Morris water maze, which could be prevented by 5-HT2A R antagonist MDL 11,939. Interestingly, TCB-2 did not affect the efficiency of the swim path or the proper use of distal visual cues during the probe test. Hippocampal place cell activity is considered to represent spatial and context-specific episodic memory. Systemic TCB-2 did not affect previously established place fields of CA1 neurons in mice exploring a familiar environment, or the remapping of place cells when the mice explored a novel environment. However, TCB-2 impaired the long-term stability of place fields for the novel environment initially encoded under the influence of TCB-2, which could be prevented by 5-HT2A R antagonist MDL 11,939. Our data indicate that hallucinogenic 5-HT2A R agonist delays the initiation of spatial search behavior, but does not impair the use of visual cues to guide goal-directed spatial behavior. Moreover, activation of 5-HT2A Rs does not impair the coding and retrieval of spatial information, but impairs the long-term stability of new formed place fields of CA1 neurons. © 2017 Wiley Periodicals, Inc.

Mice recognize 3D objects from recalled 2D pictures, support for picture-object equivalence.

Picture-object equivalence or recognizing a three-dimensional (3D) object after viewing a two-dimensional (2D) photograph of that object, is a higher-order form of visual cognition that may be beyond the perceptual ability of rodents. Behavioral and neurobiological mechanisms supporting picture-object equivalence are not well understood. We used a modified visual recognition memory task, reminiscent of those used for primates, to test whether picture-object equivalence extends to mice. Mice explored photographs of an object during a sample session, and 24 h later were presented with the actual 3D object from the photograph and a novel 3D object, or the stimuli were once again presented in 2D form. Mice preferentially explored the novel stimulus, indicating recognition of the "familiar" stimulus, regardless of whether the sample photographs depicted radially symmetric or asymmetric, similar, rotated, or abstract objects. Discrimination did not appear to be guided by individual object features or low-level visual stimuli. Inhibition of CA1 neuronal activity in dorsal hippocampus impaired discrimination, reflecting impaired memory of the 2D sample object. Collectively, results from a series of experiments provide strong evidence that picture-object equivalence extends to mice and is hippocampus-dependent, offering important support for the appropriateness of mice for investigating mechanisms of human cognition.

Object Recognition Memory: Distinct Yet Complementary Roles of the Mouse CA1 and Perirhinal Cortex.

While the essential contribution of the hippocampus to spatial memory is well established, object recognition memory has been traditionally attributed to the perirhinal cortex (PRh). However, the results of several studies indicate that under specific procedural conditions, temporary or permanent lesions of the hippocampus affect object memory processes as measured in the Spontaneous Object Recognition (SOR) task. The PRh and hippocampus are considered to contribute distinctly to object recognition memory based on memory strength. Allowing mice more, or less, exploration of novel objects during the encoding phase of the task (i.e., sample session), yields stronger, or weaker, object memory, respectively. The current studies employed temporary local inactivation and immunohistochemistry to determine the differential contributions of neuronal activity in PRh and the CA1 region of the hippocampus to strong and weak object memory. Temporary inactivation of the CA1 immediately after the SOR sample session impaired strong object memory but spared weak object memory; while temporary inactivation of PRh post-sample impaired weak object memory but spared strong object memory. Furthermore, mRNA transcription and de novo protein synthesis are required for the consolidation of episodic memory, and activation patterns of immediate early genes (IEGs), such as c-Fos and Arc, are linked to behaviorally triggered neuronal activation and synaptic plasticity. Analyses of c-Fos and Arc protein expression in PRh and CA1 neurons by immunohistochemistry, and of Arc mRNA by qPCR after distinct stages of SOR, provide additional support that strong object memory is dependent on CA1 neuronal activity, while weak object memory is dependent on PRh neuronal activity. Taken together, the results support the view that both PRh and CA1 are required for object memory under distinct conditions. Specifically, our results are consistent with a model that as the mouse begins to explore a novel object, information about it accumulates within PRh, and a weak memory of the object is encoded. If object exploration continues beyond some threshold, strong memory for the event of object exploration is encoded; the consolidation of which is CA1-dependent. These data serve to reconcile the dissension in the literature by demonstrating functional and complementary roles for CA1 and PRh neurons in rodent object memory.

Examination of the hippocampal contribution to serotonin 5-HT2A receptor-mediated facilitation of object memory in C57BL/6J mice.

The rodent hippocampus supports non-spatial object memory. Serotonin 5-HT2A receptors (5-HT2AR) are widely expressed throughout the hippocampus. We previously demonstrated that the activation of 5-HT2ARs enhanced the strength of object memory assessed 24 h after a limited (i.e., weak memory) training procedure. Here, we examined the subcellular distribution of 5-HT2ARs in the hippocampal CA1 region and underlying mechanisms of 5-HT2AR-mediated object memory consolidation. Analyses with immuno-electron microscopy revealed the presence of 5-HT2ARs on the dendritic spines and shafts of hippocampal CA1 neurons, and presynaptic terminals in the CA1 region. In an object recognition memory procedure that places higher demand on the hippocampus, only post-training systemic or intrahippocampal administration of the 5-HT2AR agonist TCB-2 enhanced object memory. Object memory enhancement by TCB-2 was blocked by the 5-HT2AR antagonist, MDL 11,937. The memory-enhancing dose of systemic TCB-2 increased extracellular glutamate levels in hippocampal dialysate samples, and increased the mean in vivo firing rate of hippocampal CA1 neurons. In summary, these data indicate a pre- and post-synaptic distribution of 5-HT2ARs, and activation of 5-HT2ARs selectively enhanced the consolidation of object memory, without affecting encoding or retrieval. The 5-HT2AR-mediated facilitation of hippocampal memory may be associated with an increase in hippocampal neuronal firing and glutamate efflux during a post-training time window in which recently encoded memories undergo consolidation.