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PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we examined the amount and distribution of PKMζ in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKMζ increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. During the initial expression of the memory, we tagged principal cells with immediate-early gene Arc promoterdriven transcription of fluorescent proteins. The subset of memory-tagged CA1 cells selectively increases expression of PKMζ during memory storage, and the increase persists in dendritic compartments within stratum radiatum for 1 month, indicating long-term storage of information in the CA3-to-CA1 pathway. We conclude that persistent increases in PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

SUMMARYThe neurobiology of psychological concepts like schema, and psychotherapeutic strategies of cognitive behavioral therapy (CBT) is poorly understood, partly because learning to process information confounds, and is rarely distinguished from acquiring content-specific memory. Learning to learn changes one’s overall information-processing ability, whereas neurobiological investigations typically focus on memory for content from particular experiences. We investigated entorhinal cortex-to-dentate gyrus neural circuit changes while mice learn to learn during cognitive control training (CCT) to judiciously use and ignore information. CCT changes synaptic circuit function by persistently modifying an excitatory-inhibitory interneuron subcircuit lasting weeks. CCT increases dentate gyrus expression of PKMζ that maintains long-term potentiation, particularly in somatostatin-expressing inhibitory interneurons that mediate both widespread inhibition, and through disinhibition, also local excitation of dentate gyrus. These findings that CCT modifies excitation-inhibition circuit coordination provide direct neurobiological evidence for a CBT-neuroplasticity hypothesis that, beyond particular item/event associations, learning to learn persistently changes neural circuit function.

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PKMz-immunohistochemistry reveals persistent increased PKMz in the hippocampus during (A) LTP maintenance, and (B) spatial long-term memory storage.PKMz is an autonomously active, atypical PKC isoform crucial for maintaining synaptic longterm potentiation (LTP) and long-term memory. Unlike other PKCs that are transiently activated by short-lived second messengers, PKMz is persistently activated by long-lasting increases in the amount of the autonomously active kinase during LTP and long-term memory maintenance. Thus, localizing persistent increases in PKMz might reveal traces of physiological LTP maintenance in the circuitry of the brain during long-term memory storage. Using quantitative immunohistochemistry validated by the lack of staining in PKMz-null mice, we visualized the amount and distribution of PKMz during LTP maintenance and spatial long-term memory storage in the hippocampal formation of wild-type mice. Strong afferent stimulation of Schaffer collateral/commissural fibers inducing LTP maintenance increases PKMz in CA1 pyramidal cells for 2 hours in hippocampal slices. Active place avoidance spatial conditioning increases PKMz in CA1 pyramidal cells of the hippocampal formation from 1 day to at least 1 month. The increases in PKMz coincide with the location of cells marked during long-term memory training by Arc promoter-mediated expression of a fluorescent protein, including at dendritic spines. We conclude that increased PKMz forms persistent traces in CA1 pyramidal cells that are sites of molecular information storage during LTP maintenance and spatial long-term memory.

Rodents exhibit neophobia for novel tastes, demonstrated by an initial reluctance to drink novel-tasting, potentially-aversive solutions. Taste neophobia attenuates across days if the solution is not aversive, demonstrated by increased consumption as the solution becomes familiar. This attenuation of taste neophobia is context dependent, which has been demonstrated by maintained reluctance to drink the novel tasting solution if the subject has to drink it after being brought to a novel environment. This spatial context-dependent attenuation of taste neophobia has been described and likely depends on the integrity of the dorsal hippocampus because this brain area is crucial for representing space and spatial context associations, but is unnecessary for processing taste memories per se. Whether changing the non-spatial auditory context causes a similar effect on attenuation of taste neophobia and the potential role of the dorsal hippocampus in processing this decidedly non-spatial information has not been determined. Here we demonstrate that changing the non-spatial auditory context affects the attenuation of taste neophobia in mice, and investigate the consequence of hippocampal lesion. The results demonstrate that the non-spatial auditory context-dependent attenuation of taste neophobia in mice is lost following NMDA excitotoxic lesions of the CA1 region of the dorsal hippocampus. These findings demonstrate that the dorsal hippocampus is crucial for the modulation non-associative taste learning by auditory context, neither of which provide information about space.