Successful Execution of Working Memory Linked to Synchronized High-Frequency Gamma Oscillations

SummaryNeuronal oscillations have been hypothesized to play an important role in cognition and its ensuing behavior, but evidence that links a specific neuronal oscillation to a discrete cognitive event is largely lacking. We measured neuronal activity in the entorhinal-hippocampal circuit while mice performed a reward-based spatial working memory task. During the memory retention period, a transient burst of high gamma synchronization preceded an animal’s correct choice in both prospective planning and retrospective mistake correction, but not an animal’s incorrect choice. Optogenetic inhibition of the circuit targeted to the choice point area resulted in a coordinated reduction in both high gamma synchrony and correct execution of a working-memory-guided behavior. These findings suggest that transient high gamma synchrony contributes to the successful execution of spatial working memory. Furthermore, our data are consistent with an association between transient high gamma synchrony and explicit awareness of the working memory content

Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons

Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.Howard Hughes Medical InstituteRikagaku Kenkyūjo (Japan

Island Cells Control Temporal Association Memory

Episodic memory requires associations of temporally discontiguous events. In the entorhinal-hippocampal network, temporal associations are driven by a direct pathway from layer III of the medial entorhinal cortex (MECIII) to the hippocampal CA1 region. However, the identification of neural circuits that regulate this association has remained unknown. In layer II of entorhinal cortex (ECII), we report clusters of excitatory neurons called island cells, which appear in a curvilinear matrix of bulblike structures, directly project to CA1, and activate interneurons that target the distal dendrites of CA1 pyramidal neurons. Island cells suppress the excitatory MECIII input through the feed-forward inhibition to control the strength and duration of temporal association in trace fear memory. Together, the two EC inputs compose a control circuit for temporal association memory.RIKEN Brain Science Institut

Impaired Hippocampal Ripple-Associated Replay in a Mouse Model of Schizophrenia

The cognitive symptoms of schizophrenia presumably result from impairments of information processing in neural circuits. We recorded neural activity in the hippocampus of freely behaving mice that had a forebrain-specific knockout of the synaptic plasticity- mediating phosphatase calcineurin and were previously shown to exhibit behavioral and cognitive abnormalities, recapitulating the symptoms of schizophrenia. Calcineurin knockout (KO) mice exhibited a 2.5-fold increase in the abundance of sharp-wave ripple (SWR) events during awake resting periods and single units in KO were overactive during SWR events. Pairwise measures of unit activity, however, revealed that the sequential reactivation of place cells during SWR events was completely abolished in KO. Since this relationship during postexperience awake rest periods has been implicated in learning, working memory, and subsequent memory consolidation, our findings provide a mechanism underlying impaired information processing that may contribute to the cognitive impairments in schizophrenia.RIKEN Brain Science InstituteAlfred P. Sloan Foundation (Fellowship)Brain & Behavior Research Foundation (NARSAD Young Investigator Award)National Institutes of Health (U.S.) (NIH grant MH78821)National Institutes of Health (U.S.) (NIH grant MH58880)National Institutes of Health (U.S.) (NIH grant MH086702

Creating a False Memory in the Hippocampus

Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram–bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means.RIKEN Brain Science Institut

Cell type–specific genetic and optogenetic tools reveal hippocampal CA2 circuits

The formation and recall of episodic memory requires precise information processing by the entorhinal-hippocampal network. For several decades, the trisynaptic circuit entorhinal cortex layer II (ECII)right arrowdentate gyrusright arrowCA3right arrowCA1 and the monosynaptic circuit ECIIIright arrowCA1 have been considered the primary substrates of the network responsible for learning and memory. Circuits linked to another hippocampal region, CA2, have only recently come to light. Using highly cell type–specific transgenic mouse lines, optogenetics and patch-clamp recordings, we found that dentate gyrus cells, long believed to not project to CA2, send functional monosynaptic inputs to CA2 pyramidal cells through abundant longitudinal projections. CA2 innervated CA1 to complete an alternate trisynaptic circuit, but, unlike CA3, projected preferentially to the deep, rather than to the superficial, sublayer of CA1. Furthermore, contrary to existing knowledge, ECIII did not project to CA2. Our results allow a deeper understanding of the biology of learning and memory.National Institutes of Health (U.S.) (P50-MH58880)National Institutes of Health (U.S.) (R01-MH078821)McGovern Institute for Brain Research at MIT (McGovern Institute Neurotechnology Program)Japan Society for the Promotion of Scienc