How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMζ maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMζ activity. We then examined, using ZIP, the effect of PKMζ inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMζ inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMζ activity. Similarly, PKMζ inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMζ inhibition in the BLA impaired retention of classical conditioned stimulus–unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMζ inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMζ activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.
38We used the psychotomimetic phencyclidine (PCP) to investigate the relationships between 39 cognitive behavior, coordinated neural network function and information processing within the 40 hippocampus place cell system. We report in rats that PCP (5mg/kg i.p.) impairs a well-learned 41 hippocampus-dependent place avoidance behavior in rats that requires cognitive control, even 42 when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium 43 gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive 44 impairment caused by systemic PCP administration. PCP discoordinates theta-modulated 45 medium and slow gamma oscillations in CA1 local field potentials (LFP) such that medium 46 gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell 47 firing fields are preserved under PCP but the drug discoordinates the sub-second temporal 48 organization of discharge amongst place cells. This discoordination causes place cell ensemble 49 representations of a familiar space to cease resembling pre-PCP representations, despite 50 preserved place fields. These findings point to the cognitive impairments caused by PCP arising 51 from neural discoordination. PCP disrupts the timing of discharge with respect to the sub-second 52 timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from 53 local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as 54 the root of PCP-induced cognitive impairment. 55 56 Kao et al 4 SIGNIFICANCE STATEMENT 57 58Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma 59 oscillations in the local field potential, and the discharge of a subset of pyramidal neurons called 60 "place cells" is spatially organized such that discharge is restricted to locations called a cell's 61 "place field." Because this temporal coordination and spatial discharge organization is thought to 62 represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt 63 cognitive behavior and assess the importance of neural coordination and place fields for spatial 64 cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal 65 discharge, without disrupting firing fields. These findings dissociate place fields from spatial 66 cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial 67 cognition. 69 70 Place cells are hippocampus principal cells that discharge in 'place fields' that map discharge to 71 locations, making place cell studies de facto investigations of what information the hippocampus 72 represents and how that information is represented (Friston
In search for the mechanisms underlying complex forms of human memory, such as episodic recollection, a primary challenge is to develop adequate animal models amenable to neurobiological investigation. Here, we proposed a novel framework and paradigm that provides means to quantitatively evaluate the ability of rats to form and recollect a combined knowledge of what happened, where it happened, and when or in which context it happened (referred to as episodic-like memory) after a few specific episodes in situations as close as possible to a paradigm we recently developed to study episodic memory in humans. In this task, rats have to remember two odor-drink associations (what happened) encountered in distinct locations (where it happened) within two different multisensory enriched environments (in which context/occasion it happened), each characterized by a particular combination of odors and places. By analyzing licking behavior on each drinking port, we characterized quantitatively individual recollection profiles and showed that rats are able to incidentally form and recollect an accurate, long-term integrated episodic-like memory that can last Ն24 d after limited exposure to the episodes. Placing rats in a contextually challenging recollection situation at recall reveals the ability for flexible use of episodic memory as described in humans. We further report that reversible inactivation of the dorsal hippocampus during recall disrupts the animal's capacity to recollect the complete episodic memory. Cellular imaging of c-Fos and Zif268 brain activation reveals that episodic memory recollection recruits a specific, distributed network of hippocampal-prefrontal cortex structures that correlates with the accuracy of the integrated recollection performance.
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