648 research outputs found

    Theta-band phase locking during encoding leads to coordinated entorhinal-hippocampal replay

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    Precisely timed interactions between hippocampal and cortical neurons during replay epochs are thought to support learning. Indeed, research has shown that replay is associated with heightened hippocampal-cortical synchrony. Yet many caveats remain in our understanding. Namely, it remains unclear how this offline synchrony comes about, whether it is specific to particular behavioral states, and how-if at all-it relates to learning. In this study, we sought to address these questions by analyzing coordination between CA1 cells and neurons of the deep layers of the medial entorhinal cortex (dMEC) while rats learned a novel spatial task. During movement, we found a subset of dMEC cells that were particularly locked to hippocampal LFP theta-band oscillations and that were preferentially coordinated with hippocampal replay during offline periods. Further, dMEC synchrony with CA1 replay peaked ∼10 ms after replay initiation in CA1, suggesting that the distributed replay reflects extra-hippocampal information propagation and is specific to "offline" periods. Finally, theta-modulated dMEC cells showed a striking experience-dependent increase in synchronization with hippocampal replay trajectories, mirroring the animals' acquisition of the novel task and coupling to the hippocampal local field. Together, these findings provide strong support for the hypothesis that synergistic hippocampal-cortical replay supports learning and highlights phase locking to hippocampal theta oscillations as a potential mechanism by which such cross-structural synchrony comes about

    Acetylcholine neuromodulation in normal and abnormal learning and memory: vigilance control in waking, sleep, autism, amnesia, and Alzheimer's disease

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    This article provides a unified mechanistic neural explanation of how learning, recognition, and cognition break down during Alzheimer's disease, medial temporal amnesia, and autism. It also clarifies whey there are often sleep disturbances during these disorders. A key mechanism is how acetylcholine modules vigilance control in cortical layer

    Segregation of cortical head direction cell assemblies on alternating theta cycles

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    High-level cortical systems for spatial navigation, including entorhinal grid cells, critically depend on input from the head direction system. We examined spiking rhythms and modes of synchrony between neurons participating in head direction networks for evidence of internal processing, independent of direct sensory drive, which may be important for grid cell function. We found that head direction networks of rats were segregated into at least two populations of neurons firing on alternate theta cycles (theta cycle skipping) with fixed synchronous or anti-synchronous relationships. Pairs of anti-synchronous theta cycle skipping neurons exhibited larger differences in head direction tuning, with a minimum difference of 40 degrees of head direction. Septal inactivation preserved the head direction signal, but eliminated theta cycle skipping of head direction cells and grid cell spatial periodicity. We propose that internal mechanisms underlying cycle skipping in head direction networks may be critical for downstream spatial computation by grid cells.We kindly thank S. Gillet, J. Hinman, E. Newman and L. Ewell for their invaluable consultations and comments on previous versions of this manuscript, as well as M. Connerney, S. Eriksson, C. Libby and T. Ware for technical assistance and behavioral training. This work was supported by grants from the National Institute of Mental Health (R01 MH60013 and MH61492) and the Office of Naval Research Multidisciplinary University Research Initiative (N00014-10-1-0936). (R01 MH60013 - National Institute of Mental Health; MH61492 - National Institute of Mental Health; N00014-10-1-0936 - Office of Naval Research Multidisciplinary University Research Initiative)Accepted manuscrip

    Replay in minds and machines

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    Cortical-hippocampal processing: prefrontal-hippocampal contributions to the spatiotemporal relationship of events

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    The hippocampus and prefrontal cortex play distinct roles in the generation and retrieval of episodic memory. The hippocampus is crucial for binding inputs across behavioral timescales, whereas the prefrontal cortex is found to influence retrieval. Spiking of hippocampal principal neurons contains environmental information, including information about the presence of specific objects and their spatial or temporal position relative to environmental and behavioral cues. Neural activity in the prefrontal cortex is found to map behavioral sequences that share commonalities in sensory input, movement, and reward valence. Here I conducted a series of four experiments to test the hypothesis that external inputs from cortex update cell assemblies that are organized within the hippocampus. I propose that cortical inputs coordinate with CA3 to rapidly integrate information at fine timescales. Extracellular tetrode recordings of neurons in the orbitofrontal cortex were performed in rats during a task where object valences were dictated by the spatial context in which they were located. Orbitofrontal ensembles, during object sampling, were found to organize all measured task elements in inverse rank relative to the rank previously observed in the hippocampus, whereby orbitofrontal ensembles displayed greater differentiation for object valence and its contextual identity than spatial position. Using the same task, a follow-up experiment assessed coordination between prefrontal and hippocampal networks by simultaneously recording medial prefrontal and hippocampal activity. The circuit was found to coordinate at theta frequencies, whereby hippocampal theta engaged prefrontal signals during contextual sampling, and the order of engagement reversed during object sampling. Two additional experiments investigated hippocampal temporal representations. First, hippocampal patterns were found to represent conjunctions of time and odor during a head-fixed delayed match-to-sample task. Lastly, I assessed the dependence of hippocampal firing patterns on intrinsic connectivity during the delay period versus active navigation of spatial routes, as rats performed a delayed-alternation T-maze. Stimulation of the ventral hippocampal commissure induced remapping of hippocampal activity during the delay period selectively. Despite temporal reorganization, different hippocampal populations emerged to predict temporal position. These results show hippocampal representations are guided by stable cortical signals, but also, coordination between cortical and intrinsic circuitry stabilizes flexible CA1 temporal representations

    The role of medial entorhinal cortex activity in hippocampal CA1 spatiotemporally correlated sequence generation and object selectivity for memory function

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    The hippocampus is crucial for episodic memory and certain forms of spatial navigation. Firing activity of hippocampal principal neurons contains environmental information, including the presence of specific objects, as well as the animal’s spatial and temporal position relative to environmental and behavioral cues. The organization of these firing correlates may allow the formation of memory traces through the integration of object and event information onto a spatiotemporal framework of cell assemblies. Characterizing how external inputs guide internal dynamics in the hippocampus to enable this process across different experiences is crucial to understanding hippocampal function. A body of literature implicates the medial entorhinal cortex (MEC) in supplying spatial and temporal information to the hippocampus. Here we develop a protocol utilizing bilaterally implanted custom designed triple fiber optic arrays and the red-shifted inhibitory opsin JAWS to transiently inactivate large volumes of MEC in freely behaving rats. This was coupled with extracellular tetrode recording of ensembles in CA1 of the hippocampus during a novel memory task involving temporal, spatial and object related epochs, in order to assess the importance of MEC activity for hippocampal feature selectivity during a rich and familiar experience. We report that inactivation of MEC during a mnemonic temporal delay disrupts the existing temporal firing field sequence in CA1 both during and following the inactivation period. Neurons with firing fields prior to the inactivation on each trial remained relatively stable. The disruption of CA1 temporal firing field sequences was accompanied by a behavioral deficit implicating MEC activity and hippocampal temporal field sequences in effective memory across time. Inactivating MEC during the object or spatial epochs of the task did not significantly alter CA1 object selective or spatial firing fields and behavioral performance remained stable. Our findings suggest that MEC is crucial specifically for temporal field organization and expression during a familiar and rich experience. These results support a role for MEC in guiding hippocampal cell assembly sequences in the absence of salient changing stimuli, which may extend to the navigation of cognitive organization in humans and support memory formation and retrieval

    Functional interactions between the hippocampus, medial entorhinal cortex and medial prefrontal cortex for spatial and nonspatial processing

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    Memory formation and recall depend on a complex circuit that includes the hippocampus and associated cortical regions. The goal of this thesis was to understand how two of the cortical connections, the medial entorhinal cortex (MEC) and medial prefrontal cortex (mPFC), influence spatial and nonspatial activity in the hippocampus. Cells in the MEC exhibit prominent spatially selective activity and have been hypothesized to drive place representation in the hippocampus. In Experiment 1 the MEC was transiently inactivated using the inhibitory opsin ArchaerhodopsinT (ArchT), and simultaneous recordings from CA1 were made as rats ran on an elliptical track. In response to MEC disruption some cells in the hippocampus shifted the preferred location of activity, some changed firing rate and others were unaffected. The new representation that developed following MEC disruption remained stable despite the fact that inhibition was transient. If the MEC is the source of spatial activity in the hippocampus the activity would be either time-locked to periods of inhibition or unstable throughout the period of inconsistent input. These results show that the MEC guides spatial representation in the hippocampus but does not directly drive spatial firing. The mPFC is generally thought to guide behavior in response to contextual elements. Experiment 2 examined the interaction between the mPFC and the hippocampus as rats performed a contextual discrimination task. Recordings were made in CA1, and the mPFC was disrupted using ArchT during the odor sampling phase of the discrimination. As animals perform this task neurons in the hippocampus respond to a conjunction of odor and location which indicates an association of what and where information in the hippocampus. Optogenetic disruption of the mPFC led to a decrease in nonspatial representation. Individual cells showed lower levels of odor selectivity, but there was no change in the level of spatial representation. This indicates that the mPFC is important for determining how the hippocampus represents nonspatial information but does not alter the spatial representation. The results are discussed within a model of memory formation that includes binding spatial and nonspatial information in the hippocampus

    Mammalian Brain As a Network of Networks

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    Acknowledgements AZ, SG and AL acknowledge support from the Russian Science Foundation (16-12-00077). Authors thank T. Kuznetsova for Fig. 6.Peer reviewedPublisher PD
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