Mice lacking a functional vasopressin 1b receptor (Avpr1b) display decreased levels of aggression and social memory. Here, we used Avpr1b-knock-out (Avpr1b Ϫ/Ϫ ) mice to examine whether an abnormality of this receptor results in specific cognitive deficits in the domain of hippocampal function. Avpr1b Ϫ/Ϫ mice were deficient in sociability and in detecting social novelty, extending previous findings of impairment in social recognition in these mutants. Avpr1bϪ/Ϫ mice could recognize previously explored objects and remember where they were experienced, but they were impaired in remembering the temporal order of presentation of those objects. Consistent with this finding, Avpr1bϪ/Ϫ mice were also impaired on an object-odor paired associate task that involved a temporal discontiguity between the associated elements. Finally, Avpr1b Ϫ/Ϫ mice performed normally in learning a set of overlapping odor discriminations and could infer relationships among odors that were only indirectly associated (i.e., transitive inference), indicating intact relational memory. The Avpr1b is expressed at much higher levels than any other part of the brain in the pyramidal cells of hippocampal CA2 area, a subfield of the hippocampus that has physiological and genetic properties that distinguish it from subfields CA1 and CA3. The combined results suggest that the Avpr1b, perhaps in CA2, may play a highly specific role in social behavior and episodic memory. Because schizophrenia and bipolar disorder are associated with a unique pathology in CA2 and impairments in both social behavior and episodic memory, this animal model could provide insights into the etiology of these disorders.

The spatial receptive fields of neurons in medial entorhinal cortex layer II (MECII) and in the hippocampus suggest general and environment-specific maps of space, respectively. However, the relationship between these receptive fields remains unclear. We reversibly manipulated the activity of MECII neurons via chemogenetic receptors and compared the changes in downstream hippocampal place cells to those of neurons in MEC. Depolarization of MECII impaired spatial memory and elicited drastic changes in CA1 place cells in a familiar environment, similar to those seen during remapping between distinct environments, while hyperpolarization did not. In contrast, both manipulations altered the firing rate of MEC neurons without changing their firing locations. Interestingly, only depolarization caused significant changes in the relative firing rates of individual grid fields, reconfiguring the spatial input from MEC. This suggests a novel mechanism of hippocampal remapping whereby rate changes in MEC neurons lead to locational changes of hippocampal place fields.

There is substantial evidence implicating N-methyl-d-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia since morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR−/−) mouse in which the first coding exon of the mouse serine racemase gene has been deleted, to explore the role of d-serine in regulating cognitive functions as well as dendritic architecture. SR −/− mice exhibited a significantly disrupted representation of the order of events in distinct experiences as revealed by object recognition and odor sequence tests; however, SR −/− animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR −/− mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR−/− mice displayed reductions in the complexity, total length, and spine density of apical dendrites. These findings demonstrate that d-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the mPFC. Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.

Animals display an innate preference for novelty, spending more time exploring both novel objects and familiar objects in novel locations. This increase in exploration is thought to allow the animal to gather the information necessary to encode new experiences. Despite extensive evidence that increased exploration following spatial change requires the hippocampus, the patterns of hippocampal activity that support this behavior remain unknown. We examined activity in hippocampal output area CA1 and one synapse upstream in area CA3 while freely behaving rats performed an object-place recognition task. We found that the presence of novelty substantially altered activity in CA1, but not in CA3. During exploration of displaced familiar objects and novel objects in unexpected locations, CA1 place cells showed robust increases in firing rate. These firing rate increases persisted during sharp wave ripples, when place cell representations of previous experiences are replayed. Unexpectedly, increases in CA1 activity were not spatially restricted to regions of the environment that underwent change, indicating a generalized novelty signal. We suggest that hippocampal area CA1 broadcasts the presence of novelty, rather than signaling what is novel, and simultaneously becomes more plastic, allowing the integration of new information into previously stored memories.

“Transitive inference” refers to the ability to judge from memory the relationships between indirectly related items that compose a hierarchically organized series, and this capacity is considered a fundamental feature of relational memory. Here we explored the role of the prefrontal cortex in transitive inference by examining the performance of mice with selective damage to the medial prefrontal cortex. Damage to the infralimbic and prelimbic regions resulted in significant impairment in the acquisition of a series of overlapping odor discrimination problems, such that animals with prefrontal lesions required twice as many trials to learn compared to sham-operated controls. Following eventually successful acquisition, animals with medial prefrontal lesions were severely impaired on a transitive inference probe test, whereas they performed as well as controls on a test that involved a nontransitive judgment from a novel odor pairing. These results suggest that the prefrontal cortex is part of an integral hippocampal–cortical network essential for relational memory organization.

Understanding the neural mechanisms underlying learning and memory in the entorhinal-hippocampal circuit is a central challenge of systems neuroscience. For more than 40 years, electrophysiological recordings in awake, behaving animals have been used to relate the receptive fields of neurons in this circuit to learning and memory. However, the vast majority of such studies are purely observational, as electrical, surgical, and pharmacological circuit manipulations are both challenging and relatively coarse, being unable to distinguish between specific classes of neurons. Recent advances in molecular genetic tools can overcome many of these limitations, enabling unprecedented control over neural activity in behaving animals. Expression of pharmaco-or optogenetic transgenes in cell-type-specific "driver" lines provides unparalleled anatomical and cell-type specificity, especially when delivered by viral complementation. Pharmacogenetic transgenes are specially designed neurotransmitter receptors exclusively activated by otherwise inactive synthetic ligands and have kinetics similar to traditional pharmacology. Optogenetic transgenes use light to control the membrane potential, and thereby operate at the millisecond timescale. Thus, activation of pharmacogenetic transgenes in specific neuronal cell types while recording from other parts of the circuit allows investigation of the role of those neurons in the steady state, whereas optogenetic transgenes allow one to determine the immediate network response.Electrophysiological recordings have been used to study "receptive fields" (RFs) (Table 1) throughout the brain for more than 50 years. Hubel and Wiesel (1959) were among the first to characterize RFs in the brain by recording in the cat striate cortex from neurons that fired specifically in response to bars or edges of specific orientations. This led them to propose that the orientationselective RFs of striate neurons originate via linear summation of aligned RFs of lateral geniculate neurons (Hubel and Wiesel 1962). Unfortunately, the predictions of this model were largely untestable because electrophysiological recordings are purely observational. Although Chapman et al. (1991) were able to provide evidence consistent with Hubel and Wiesel's model by using clever electrophysiological techniques, they were even unable to directly confirm the model. Therefore, determining how the RFs of upstream neurons generate the RFs of downstream neurons remains a central goal of systems neuroscience. Excitingly, recent advances in molecular genetic techniques potentially enable empirical testing of purely theoretical models.Given the centrality of the entorhinal cortex and hippocampal formation to memory (Scoville and Milner 1957), this review focuses on the RFs of neurons in this circuit. More than 10 years after the seminal work of Hubel and Wiesel, O'Keefe and Dostrov-

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