A Novel Mechanism for the Grid-to-Place Cell Transformation Revealed by Transgenic Depolarization of Medial Entorhinal Cortex Layer II.

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.

Prkcz null mice show normal learning and memory.

Protein kinase M-ζ (PKM-ζ) is a constitutively active form of atypical protein kinase C that is exclusively expressed in the brain and implicated in the maintenance of long-term memory. Most studies that support a role for PKM-ζ in memory maintenance have used pharmacological PKM-ζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here we use a genetic approach and target exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-ζ (PKC-ζ) and PKM-ζ (Prkcz(-/-) mice). Prkcz(-/-) mice showed normal behaviour in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behaviour. Notably, Prkcz(-/-) mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz(-/-) mice. In vitro, ZIP and scrambled ZIP inhibited PKM-ζ, PKC-ι and PKC-ζ with similar inhibition constant (K(i)) values. Chelerythrine was a weak inhibitor of PKM-ζ (K(i) = 76 µM). Our findings show that absence of PKM-ζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-ζ is not present.

Prefrontal cortex: role in acquisition of overlapping associations and transitive inference.

"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.

The hippocampus contributes to memory expression during transitive inference in mice.

There is substantial evidence that the hippocampus plays a role in transitive inference, the capacity to link overlapping memories and subsequently make novel judgments between elements of those memories that are only indirectly related. However, it is unclear whether the hippocampus is involved primarily during the original acquisition of the overlapping memories, or additionally during the flexible expression of those memories during transitive judgments. Here, we demonstrated that selective hippocampal damage produced after acquisition of the overlapping memories resulted in a severe impairment in subsequent transitive inference judgments, indicating that the hippocampus does play an important role beyond the initial learning phase. Furthermore, this study extends to mice a role for the hippocampus in transitive inference, as previously observed in other species.