Publications by authors named "Stefan Leutgeb"

46 Publications

Multimodal neural recordings with Neuro-FITM uncover diverse patterns of cortical-hippocampal interactions.

Nat Neurosci 2021 06 19;24(6):886-896. Epub 2021 Apr 19.

Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, USA.

Many cognitive processes require communication between the neocortex and the hippocampus. However, coordination between large-scale cortical dynamics and hippocampal activity is not well understood, partially due to the difficulty in simultaneously recording from those regions. In the present study, we developed a flexible, insertable and transparent microelectrode array (Neuro-FITM) that enables investigation of cortical-hippocampal coordinations during hippocampal sharp-wave ripples (SWRs). Flexibility and transparency of Neuro-FITM allow simultaneous recordings of local field potentials and neural spiking from the hippocampus during wide-field calcium imaging. These experiments revealed that diverse cortical activity patterns accompanied SWRs and, in most cases, cortical activation preceded hippocampal SWRs. We demonstrated that, during SWRs, different hippocampal neural population activity was associated with distinct cortical activity patterns. These results suggest that hippocampus and large-scale cortical activity interact in a selective and diverse manner during SWRs underlying various cognitive functions. Our technology can be broadly applied to comprehensive investigations of interactions between the cortex and other subcortical structures.
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http://dx.doi.org/10.1038/s41593-021-00841-5DOI Listing
June 2021

A role for medial entorhinal cortex in spatial and nonspatial forms of memory in rats.

Behav Brain Res 2021 06 26;407:113259. Epub 2021 Mar 26.

Department of Psychiatry 0603, University of California, San Diego, La Jolla, CA, 92093, USA. Electronic address:

Many studies have focused on the role of the medial entorhinal cortex (MEC) in spatial memory and spatial processing. However, more recently, studies have suggested that the functions of the MEC may extend beyond the spatial domain and into the temporal aspects of memory processing. The current study examined the effect of MEC lesions on spatial and nonspatial tasks that require rats to learn and remember information about location or stimulus-stimulus associations across short temporal gaps. MEC- and sham-lesioned male rats were tested on a watermaze delayed match to position (DMP) task and trace fear conditioning (TFC). Rats with MEC lesions were impaired at remembering the platform location after both the shortest (1 min) and the longest (6 h) delays on the DMP task, never performing as precisely as sham rats under the easiest condition and performing poorly at the longest delay. On the TFC task, although MEC-lesioned rats were not impaired at remembering the conditioning context, they showed reduced freezing in response to the previously associated tone. These findings suggest that the MEC plays a role in bridging temporal delays during learning and memory that extend beyond its established role in spatial memory processing.
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http://dx.doi.org/10.1016/j.bbr.2021.113259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143915PMC
June 2021

Concordant neurophysiological signatures of cognitive control in humans and rats.

Neuropsychopharmacology 2021 06 21;46(7):1252-1262. Epub 2021 Mar 21.

McLean Hospital & Harvard Medical School, Belmont, MA, USA.

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals. To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials. Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.
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http://dx.doi.org/10.1038/s41386-021-00998-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134486PMC
June 2021

Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes.

Neuron 2020 12 25;108(5):937-952.e7. Epub 2020 Sep 25.

Departments of Neurosciences and Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address:

The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. We sought to understand whether neuronal activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neuronal activity. In particular, neuronal activity regulates BBB efflux transporter expression and function, which is critical for excluding many small lipophilic molecules from the brain parenchyma. Furthermore, we found that neuronal activity regulates the expression of circadian clock genes within brain endothelial cells, which in turn mediate the activity-dependent control of BBB efflux transport. These results have important clinical implications for CNS drug delivery and clearance of CNS waste products, including Aβ, and for understanding how neuronal activity can modulate diurnal processes.
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http://dx.doi.org/10.1016/j.neuron.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736535PMC
December 2020

Hippocampal firing rates count.

Nat Neurosci 2020 05;23(5):597-599

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, San Diego, CA, USA.

Standfirst: Sun et al. discover that neuronal firing rates of hippocampal place cells code for periodically repeating events and that the rate code can flexibly transfer to new situations. These findings suggest that abstract neural representations of regularly occurring events may be foundational for performing complex cognitive tasks.
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http://dx.doi.org/10.1038/s41593-020-0631-9DOI Listing
May 2020

Time Cells in the Hippocampus Are Neither Dependent on Medial Entorhinal Cortex Inputs nor Necessary for Spatial Working Memory.

Neuron 2019 06 2;102(6):1235-1248.e5. Epub 2019 May 2.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

A key function of the hippocampus and entorhinal cortex is to bridge events that are discontinuous in time, and it has been proposed that medial entorhinal cortex (mEC) supports memory retention by sustaining the sequential activity of hippocampal time cells. Therefore, we recorded hippocampal neuronal activity during spatial working memory and asked whether time cells depend on mEC inputs. Working memory was impaired in rats with mEC lesions, but the occurrence of time cells and of trajectory-coding cells in the stem did not differ from controls. Rather, the main effect of mEC lesions was an extensive spatial coding deficit of CA1 cells, which included inconsistency over time and reduced firing differences between positions on the maze. Therefore, mEC is critical for providing stable and distinct spatial information to hippocampus, while working memory (WM) maintenance is likely supported either by local synaptic plasticity in hippocampus or by activity patterns elsewhere in the brain.
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http://dx.doi.org/10.1016/j.neuron.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602601PMC
June 2019

Hippocampal CA1 replay becomes less prominent but more rigid without inputs from medial entorhinal cortex.

Nat Commun 2019 03 22;10(1):1341. Epub 2019 Mar 22.

Department Biology II, Ludwig-Maximilians-Universität München, Martinsried, 82152, Germany.

The hippocampus is an essential brain area for learning and memory. However, the network mechanisms underlying memory storage, consolidation and retrieval remain incompletely understood. Place cell sequences during theta oscillations are thought to be replayed during non-theta states to support consolidation and route planning. In animals with medial entorhinal cortex (MEC) lesions, the temporal organization of theta-related hippocampal activity is disrupted, which allows us to test whether replay is also compromised. Two different analyses-comparison of co-activation patterns between running and rest epochs and analysis of the recurrence of place cell sequences-reveal that the enhancement of replay by behavior is reduced in MEC-lesioned versus control rats. In contrast, the degree of intrinsic network structure prior and subsequent to behavior remains unaffected by MEC lesions. The MEC-dependent temporal coordination during theta states therefore appears to facilitate behavior-related plasticity, but does not disrupt pre-existing functional connectivity.
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http://dx.doi.org/10.1038/s41467-019-09280-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430812PMC
March 2019

Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation.

Proc Natl Acad Sci U S A 2019 04 15;116(17):8576-8581. Epub 2019 Mar 15.

Psychiatry Department, University of California, San Diego, La Jolla, CA 92093;

The neural circuits underlying memory change over prolonged periods after learning, in a process known as systems consolidation. Postlearning spontaneous reactivation of memory-related neural ensembles is thought to mediate this process, although a causal link has not been established. Here we test this hypothesis in mice by using optogenetics to selectively reactivate neural ensembles representing a contextual fear memory (sometimes referred to as engram neurons). High-frequency stimulation of these ensembles in the retrosplenial cortex 1 day after learning produced a recent memory with features normally observed in consolidated remote memories, including higher engagement of neocortical areas during retrieval, contextual generalization, and decreased hippocampal dependence. Moreover, this effect was only present if memory ensembles were reactivated during sleep or light anesthesia. These results provide direct support for postlearning memory ensemble reactivation as a mechanism of systems consolidation, and show that this process can be accelerated by ensemble reactivation in an unconscious state.
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http://dx.doi.org/10.1073/pnas.1818432116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486739PMC
April 2019

The impact of pathological high-frequency oscillations on hippocampal network activity in rats with chronic epilepsy.

Elife 2019 02 22;8. Epub 2019 Feb 22.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.

In epilepsy, brain networks generate pathological high-frequency oscillations (pHFOs) during interictal periods. To understand how pHFOs differ from normal oscillations in overlapping frequency bands and potentially perturb hippocampal processing, we performed high-density single unit and local field potential recordings from hippocampi of behaving rats with and without chronic epilepsy. In epileptic animals, we observed two types of co-occurring fast oscillations, which by comparison to control animals we could classify as 'ripple-like' or 'pHFO'. We compared their spectral characteristics, brain state dependence, and cellular participants. Strikingly, pHFO occurred irrespective of brain state, were associated with interictal spikes, engaged distinct subnetworks of principal neurons compared to ripple-like events, increased the sparsity of network activity, and initiated both general and immediate disruptions in spatial information coding. Taken together, our findings suggest that events that result in pHFOs have an immediate impact on memory processes, corroborating the need for proper classification of pHFOs to facilitate therapeutic interventions that selectively target pathological activity.
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http://dx.doi.org/10.7554/eLife.42148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386518PMC
February 2019

The hippocampal code for space in Mongolian gerbils.

Hippocampus 2019 09 12;29(9):787-801. Epub 2019 Feb 12.

Department Biologie II, Ludwig-Maximilians-Universität München, Martinsried, Germany.

Large parts of our knowledge about the physiology of the hippocampus in the intact brain are derived from studies in rats and mice. While many of those findings fit well to the limited data available from humans and primates, there are also marked differences, for example, in hippocampal oscillation frequencies and in the persistence of theta oscillations. To test whether the distinct sensory specializations of the visual and auditory system of primates play a key role in explaining these differences, we recorded basic hippocampal physiological properties in Mongolian gerbils, a rodent species with high visual acuity, and good low-frequency hearing, similar to humans. We found that gerbils show only minor differences to rats regarding hippocampal place field activity, theta properties (frequency, persistence, phase precession, theta compression), and sharp wave ripple events. The only major difference between rats and gerbils was a considerably higher degree of head direction selectivity of gerbil place fields, which may be explained by their visual system being able to better resolve distant cues. Thus, differences in sensory specializations between rodent species only affect hippocampal circuit dynamics to a minor extent, which implies that differences to other mammalian lineages, such as bats and primates, cannot be solely explained by specialization in the auditory or visual system.
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http://dx.doi.org/10.1002/hipo.23075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690818PMC
September 2019

Recurrent circuits within medial entorhinal cortex superficial layers support grid cell firing.

Nat Commun 2018 09 12;9(1):3701. Epub 2018 Sep 12.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, 92093, USA.

Specialized cells in the medial entorhinal cortex (mEC), such as speed cells, head direction (HD) cells, and grid cells, are thought to support spatial navigation. To determine whether these computations are dependent on local circuits, we record neuronal activity in mEC layers II and III and optogenetically perturb locally projecting layer II pyramidal cells. We find that sharply tuned HD cells are only weakly responsive while speed, broadly tuned HD cells, and grid cells show pronounced transient excitatory and inhibitory responses. During the brief period of feedback inhibition, there is a reduction in specifically grid accuracy, which is corrected as firing rates return to baseline. These results suggest that sharp HD cells are embedded in a separate mEC sub-network from broad HD cells, speed cells, and grid cells. Furthermore, grid tuning is not only dependent on local processing but also rapidly updated by HD, speed, or other afferent inputs to mEC.
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http://dx.doi.org/10.1038/s41467-018-06104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135799PMC
September 2018

Stability of medial entorhinal cortex representations over time.

Hippocampus 2019 03 2;29(3):284-302. Epub 2018 Sep 2.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, La Jolla, California.

Distinct functional cell types in the medial entorhinal cortex (mEC) have been shown to represent different aspects of experiences. To further characterize mEC cell populations, we examined whether spatial representations of neurons in mEC superficial layers depended on the scale of the environment and changed over extended time periods. Accordingly, mEC cells were recorded while rats repeatedly foraged in a small or a large environment in sessions that were separated by time intervals from minutes to hours. Comparing between large and small environments, we found that the overall precision of grid and non-grid cell spatial maps was higher in smaller environments. When examining the stability of spatial firing patterns over time, differences and similarities were observed across cell types. Within-session stability was higher for grid cells than for non-grid cell populations. Despite differences in baseline stability between cell types, stability levels remained consistent over time between sessions, up to 1 hr. Even for sessions separated by 6 hrs, activity patterns of grid cells and of most non-grid cells lacked any systematic decrease in spatial similarity over time. However, a subset of ~15% of mEC non-grid cells recorded preferentially from layer III exhibited dramatic, time dependent changes in firing patterns across 6 hrs, reminiscent of previous characterizations of the hippocampal CA2 subregion. Collectively, our data suggest that mEC grid cell input to hippocampus in conjunction with many time invariant non-grid cells may aid in stabilizing hippocampal spatial maps, while a subset of time varying non-grid cells could provide complementary temporal information.
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http://dx.doi.org/10.1002/hipo.23017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377822PMC
March 2019

Recent and remote retrograde memory deficit in rats with medial entorhinal cortex lesions.

Neurobiol Learn Mem 2018 11 31;155:157-163. Epub 2018 Jul 31.

Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The hippocampus is critically involved in the acquisition and retrieval of spatial memories. Even though some memories become independent of the hippocampus over time, expression of spatial memories have consistently been found to permanently depend on the hippocampus. Recent studies have focused on the adjacent medial entorhinal cortex (MEC), as it provides major projections to the hippocampus. These studies have shown that lesions of the MEC disrupt spatial processing in the hippocampus and impair spatial memory acquisition on the watermaze task. MEC lesions acquired after learning the watermaze task also disrupt recently acquired spatial memories. However, the effect of MEC lesions on remotely acquired memories is unknown. The current study examined the effect of MEC lesions on recent and remote memory retrieval using three hippocampus-dependent tasks: the watermaze, trace fear conditioning, and novel object recognition. MEC lesions caused impaired retrieval of recently and remotely acquired memory for the watermaze. Rats with MEC lesions also showed impaired fear memory when exposed to the previously conditioned context or the associated tone, and this reduction was seen both when the lesion occurred soon after trace fear condition and when it occurred a month after conditioning. In contrast, MEC lesions did not disrupt novel object recognition. These findings indicate that even with an intact hippocampus, rats with MEC lesions cannot retrieve recent or remote spatial memories. In addition, the involvement of the MEC in memory extends beyond is role in navigation and place memory.
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http://dx.doi.org/10.1016/j.nlm.2018.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544028PMC
November 2018

Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress.

Proc Natl Acad Sci U S A 2018 05 23;115(20):5064-5071. Epub 2018 Apr 23.

Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093-0357;

Neurotransmitter switching in the adult mammalian brain occurs following photoperiod-induced stress, but the mechanism of regulation is unknown. Here, we demonstrate that elevated activity of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PaVN) in the adult rat is required for the loss of dopamine expression after long-day photoperiod exposure. The transmitter switch occurs exclusively in PaVN dopaminergic neurons that coexpress vesicular glutamate transporter 2 (VGLUT2), is accompanied by a loss of dopamine type 2 receptors (D2Rs) on corticotrophin-releasing factor (CRF) neurons, and can lead to increased release of CRF. Suppressing activity of all PaVN glutamatergic neurons decreases the number of inhibitory PaVN dopaminergic neurons, indicating homeostatic regulation of transmitter expression in the PaVN.
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http://dx.doi.org/10.1073/pnas.1801598115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960321PMC
May 2018

Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies.

Curr Biol 2018 04 5;28(8):1179-1188.e3. Epub 2018 Apr 5.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA; Kavli Institute for Brain and Mind, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA. Electronic address:

Biological oscillations can be controlled by a small population of rhythmic pacemaker cells, or in the brain, they also can emerge from complex cellular and circuit-level interactions. Whether and how these mechanisms are combined to give rise to oscillatory patterns that govern cognitive function are not well understood. For example, the activity of hippocampal networks is temporally coordinated by a 7- to 9-Hz local field potential (LFP) theta rhythm, yet many individual cells decouple from the LFP frequency to oscillate at frequencies ∼1 Hz higher. To better understand the network interactions that produce these complex oscillatory patterns, we asked whether the relative frequency difference between LFP and individual cells is retained when the LFP frequency is perturbed experimentally. We found that rhythmic optogenetic stimulation of medial septal GABAergic neurons controlled the hippocampal LFP frequency outside of the endogenous theta range, even during behavioral states when endogenous mechanisms would otherwise have generated 7- to 9-Hz theta oscillations. While the LFP frequency matched the optogenetically induced stimulation frequency, the oscillation frequency of individual hippocampal cells remained broadly distributed, and in a subset of cells including interneurons, it was accelerated beyond the new base LFP frequency. The inputs from septal GABAergic neurons to the hippocampus, therefore, do not appear to directly control the cellular oscillation frequency but rather engage cellular and circuit mechanisms that accelerate the rhythmicity of individual cells. Thus, theta oscillations are an example of cortical oscillations that combine inputs from a subcortical pacemaker with local computations to generate complex oscillatory patterns that support cognitive functions.
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http://dx.doi.org/10.1016/j.cub.2018.02.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488523PMC
April 2018

Hippocampal Global Remapping Can Occur without Input from the Medial Entorhinal Cortex.

Cell Rep 2018 03;22(12):3152-3159

Neurobiology Section and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093, USA; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The high storage capacity of the episodic memory system relies on distinct representations for events that are separated in time and space. The spatial component of these computations includes the formation of independent maps by hippocampal place cells across environments, referred to as global remapping. Such remapping is thought to emerge by the switching of input patterns from specialized spatially selective cells in medial entorhinal cortex (mEC), such as grid and border cells. Although it has been shown that acute manipulations of mEC firing patterns are sufficient for inducing hippocampal remapping, it remains unknown whether specialized spatial mEC inputs are necessary for the reorganization of hippocampal spatial representations. Here, we examined remapping in rats without mEC input to the hippocampus and found that highly distinct spatial maps emerged rapidly in every individual rat. Our data suggest that hippocampal spatial computations do not depend on inputs from specialized cell types in mEC.
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http://dx.doi.org/10.1016/j.celrep.2018.02.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929481PMC
March 2018

Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons.

Nat Neurosci 2018 02 15;21(2):258-269. Epub 2018 Jan 15.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.

Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.
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http://dx.doi.org/10.1038/s41593-017-0061-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800997PMC
February 2018

Theta sequences of grid cell populations can provide a movement-direction signal.

Curr Opin Behav Sci 2017 Oct 1;17:147-154. Epub 2017 Sep 1.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

It has been proposed that path integration in mammals is performed by the convergence of internally generated speed and directional inputs onto grid cells. Although this hypothesis has been supported by the discovery that head direction, speed, and grid cells are intermixed within entorhinal cortex and by the recent finding that head-direction inputs are necessary for grid firing, many details on how grid cells are generated have remained elusive. For example, analysis of recording data suggests that substituting head direction for movement direction accrues errors that preclude the formation of grid patterns. To address this discrepancy, we propose that the organization of grid networks makes it plausible that movement-direction signals are an output from grid cells and that temporally precise grid cell sequences provide a robust directional signal to other spatial and directional cell types.
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http://dx.doi.org/10.1016/j.cobeha.2017.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761317PMC
October 2017

Grid and Nongrid Cells in Medial Entorhinal Cortex Represent Spatial Location and Environmental Features with Complementary Coding Schemes.

Neuron 2017 Apr 23;94(1):83-92.e6. Epub 2017 Mar 23.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The medial entorhinal cortex (mEC) has been identified as a hub for spatial information processing by the discovery of grid, border, and head-direction cells. Here we find that in addition to these well-characterized classes, nearly all of the remaining two-thirds of mEC cells can be categorized as spatially selective. We refer to these cells as nongrid spatial cells and confirmed that their spatial firing patterns were unrelated to running speed and highly reproducible within the same environment. However, in response to manipulations of environmental features, such as box shape or box color, nongrid spatial cells completely reorganized their spatial firing patterns. At the same time, grid cells retained their spatial alignment and predominantly responded with redistributed firing rates across their grid fields. Thus, mEC contains a joint representation of both spatial and environmental feature content, with specialized cell types showing different types of integrated coding of multimodal information.
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http://dx.doi.org/10.1016/j.neuron.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444540PMC
April 2017

Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention.

J Neurosci 2015 Nov;35(47):15635-48

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, and

Unlabelled: Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention.

Significance Statement: Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.
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http://dx.doi.org/10.1523/JNEUROSCI.5112-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659826PMC
November 2015

Memory and Space: Towards an Understanding of the Cognitive Map.

J Neurosci 2015 Oct;35(41):13904-11

Department of Psychology and Center for Neuroscience, University of California at Davis, Davis, California 95616.

Unlabelled: More than 50 years of research have led to the general agreement that the hippocampus contributes to memory, but there has been a major schism among theories of hippocampal function over this time. Some researchers argue that the hippocampus plays a broad role in episodic and declarative memory, whereas others argue for a specific role in the creation of spatial cognitive maps and navigation. Although both views have merit, neither provides a complete account of hippocampal function. Guided by recent reviews that attempt to bridge between these views, here we suggest that reconciliation can be accomplished by exploring hippocampal function from the perspective of Tolman's (1948) original conception of a cognitive map as organizing experience and guiding behavior across all domains of cognition. We emphasize recent studies in animals and humans showing that hippocampal networks support a broad range of domains of cognitive maps, that these networks organize specific experiences within the contextually relevant map, and that network activity patterns reflect behavior guided through cognitive maps. These results are consistent with a framework that bridges theories of hippocampal function by conceptualizing the hippocampus as organizing incoming information within the context of a multidimensional cognitive map of spatial, temporal, and associational context.

Significance Statement: Research of hippocampal function is dominated by two major views. The spatial view argues that the hippocampus tracks routes through space, whereas the memory view suggests a broad role in declarative memory. Both views rely on considerable evidence, but neither provides a complete account of hippocampal function. Here we review evidence that, in addition to spatial context, the hippocampus encodes a wide variety of information about temporal and situational context, about the systematic organization of events in abstract space, and about routes through maps of cognition and space. We argue that these findings cross the boundaries of the memory and spatial views and offer new insights into hippocampal function as a system supporting a broad range of cognitive maps.
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http://dx.doi.org/10.1523/JNEUROSCI.2618-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608181PMC
October 2015

The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity.

Nat Neurosci 2015 Aug 29;18(8):1123-32. Epub 2015 Jun 29.

1] Neurobiology Section and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, California, USA. [2] Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, California, USA.

The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC.
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http://dx.doi.org/10.1038/nn.4056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711275PMC
August 2015

Hippocampal CA2 activity patterns change over time to a larger extent than between spatial contexts.

Neuron 2015 Jan;85(1):190-201

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The hippocampal CA2 subregion has a different anatomical connectivity pattern within the entorhino-hippocampal circuit than either the CA1 or CA3 subregion. Yet major differences in the neuronal activity patterns of CA2 compared with the other CA subregions have not been reported. We show that standard spatial and temporal firing patterns of individual hippocampal principal neurons in behaving rats, such as place fields, theta modulation, and phase precession, are also present in CA2, but that the CA2 subregion differs substantially from the other CA subregions in its population coding. CA2 ensembles do not show a persistent code for space or for differences in context. Rather, CA2 activity patterns become progressively dissimilar over time periods of hours to days. The weak coding for a particular context is consistent with recent behavioral evidence that CA2 circuits preferentially support social, emotional, and temporal rather than spatial aspects of memory.
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http://dx.doi.org/10.1016/j.neuron.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392894PMC
January 2015

Spatial and memory circuits in the medial entorhinal cortex.

Curr Opin Neurobiol 2015 Jun 30;32:16-23. Epub 2014 Oct 30.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA. Electronic address:

The large capacity of episodic memory is thought to be supported by the emergence of distinct hippocampal cell assemblies for unrelated memories, such that interference is minimized. In large-scale population recordings, the orthogonal nature of hippocampal representations across environments is evident in the complete reorganization of the firing locations of hippocampal place cells. Entorhinal grid cells provide inputs to the hippocampus, and their firing patterns shift relative to each other across different environments. Although this suggests that altered grid cell firing could generate distinct hippocampal population codes, it has recently been shown that new and distinct hippocampal place fields emerge while grid cell firing is compromised. We therefore propose that separate circuits within the medial entorhinal cortex are specialized for performing either spatial or memory-related computations.
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http://dx.doi.org/10.1016/j.conb.2014.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416067PMC
June 2015

Medial entorhinal cortex lesions only partially disrupt hippocampal place cells and hippocampus-dependent place memory.

Cell Rep 2014 Nov 30;9(3):893-901. Epub 2014 Oct 30.

Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The entorhinal cortex provides the primary cortical projections to the hippocampus, a brain structure critical for memory. However, it remains unclear how the precise firing patterns of medial entorhinal cortex (MEC) cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of the MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields, but with decreased spatial precision and decreased long-term spatial stability. In addition, MEC rats were as impaired in the water maze as hippocampus rats, while rats with combined MEC and hippocampal lesions had an even greater deficit. However, MEC rats were not impaired on other hippocampus-dependent tasks, including those in which an object location or context was remembered. Thus, the MEC is not necessary for all types of spatial coding or for all types of hippocampus-dependent memory, but it is necessary for the normal acquisition of place memory.
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http://dx.doi.org/10.1016/j.celrep.2014.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294707PMC
November 2014

Replay to remember: a boost from dopamine.

Nat Neurosci 2014 Dec;17(12):1629-31

1] Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA [2] Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, California, USA.

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http://dx.doi.org/10.1038/nn.3875DOI Listing
December 2014

New and distinct hippocampal place codes are generated in a new environment during septal inactivation.

Neuron 2014 May;82(4):789-96

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The hippocampus generates distinct neural codes to disambiguate similar experiences, a process thought to underlie episodic memory function. Entorhinal grid cells provide a prominent spatial signal to hippocampus, and changes in their firing pattern could thus generate a distinct spatial code in each context. We examined whether we would preclude the emergence of new spatial representations in a novel environment during muscimol inactivation of the medial septal area, a manipulation known to disrupt theta oscillations and grid cell firing. We found that new, highly distinct configurations of place fields emerged immediately and remained stable during the septal inactivation. The new place code persisted when theta oscillations had recovered. Theta rhythmicity and feedforward input from grid cell networks were thus not required to generate new spatial representations in the hippocampus.
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http://dx.doi.org/10.1016/j.neuron.2014.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294702PMC
May 2014

Parallel and convergent processing in grid cell, head-direction cell, boundary cell, and place cell networks.

Wiley Interdiscip Rev Cogn Sci 2014 Mar 23;5(2):207-219. Epub 2013 Dec 23.

Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.

The brain is able to construct internal representations that correspond to external spatial coordinates. Such brain maps of the external spatial topography may support a number of cognitive functions, including navigation and memory. The neuronal building block of brain maps are place cells, which are found throughout the hippocampus of rodents and, in a lower proportion, primates. Place cells typically fire in one or few restricted areas of space, and each area where a cell fires can range, along the dorsoventral axis of the hippocampus, from 30 cm to at least several meters. The sensory processing streams that give rise to hippocampal place cells are not fully understood, but substantial progress has been made in characterizing the entorhinal cortex, which is the gateway between neocortical areas and the hippocampus. Entorhinal neurons have diverse spatial firing characteristics, and the different entorhinal cell types converge in the hippocampus to give rise to a single, spatially modulated cell type-the place cell. We therefore suggest that parallel information processing in different classes of cells-as is typically observed at lower levels of sensory processing-continues up into higher level association cortices, including those that provide the inputs to hippocampus. WIREs Cogn Sci 2014, 5:207-219. doi: 10.1002/wcs.1272 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.
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http://dx.doi.org/10.1002/wcs.1272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935336PMC
March 2014

Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex.

Nat Neurosci 2013 Aug 14;16(8):1085-93. Epub 2013 Jul 14.

Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway.

In the hippocampus, spatial and non-spatial parameters may be represented by a dual coding scheme, in which coordinates in space are expressed by the collective firing locations of place cells and the diversity of experience at these locations is encoded by orthogonal variations in firing rates. Although the spatial signal may reflect input from medial entorhinal cortex, the sources of the variations in firing rate have not been identified. We found that rate variations in rat CA3 place cells depended on inputs from the lateral entorhinal cortex (LEC). Hippocampal rate remapping, induced by changing the shape or the color configuration of the environment, was impaired by lesions in those parts of the ipsilateral LEC that provided the densest input to the hippocampal recording position. Rate remapping was not observed in LEC itself. The findings suggest that LEC inputs are important for efficient rate coding in the hippocampus.
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http://dx.doi.org/10.1038/nn.3462DOI Listing
August 2013

Hippocampal activation during the recall of remote spatial memories in radial maze tasks.

Neurobiol Learn Mem 2013 Nov 4;106:324-33. Epub 2013 Jun 4.

Neurobiology Section and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093, USA; Division of Neurobiology, Department Biology II, Ludwig-Maximilians-Universität, Munich, Germany.

Temporally graded retrograde amnesia is observed in human patients with medial temporal lobe lesions as well as in animal models of medial temporal lobe lesions. A time-limited role for these structures in memory recall has also been suggested by the observation that the rodent hippocampus and entorhinal cortex are activated during the retrieval of recent but not of remote memories. One notable exception is the recall of remote memories for platform locations in the water maze, which requires an intact hippocampus and results in hippocampal activation irrespective of the age of the memory. These findings raise the question whether the hippocampus is always involved in the recall of spatial memories or, alternatively, whether it might be required for procedural computations in the water maze task, such as for calculating a path to a hidden platform. We performed spatial memory testing in radial maze tasks to distinguish between these possibilities. Radial maze tasks require a choice between spatial locations on a center platform and thus have a lesser requirement for navigation than the water maze. However, we used a behavioral design in the radial maze that retained other aspects of the standard water maze task, such as the use of multiple start locations and retention testing in a single trial. Using the immediate early gene c-fos as a marker for neuronal activation, we found that all hippocampal subregions were more activated during the recall of remote compared to recent spatial memories. In areas CA3 and CA1, activation during remote memory testing was higher than in rats that were merely reexposed to the testing environment after the same time interval. Conversely, Fos levels in the dentate gyrus were increased after retention testing to the extent that was also observed in the corresponding exposure control group. This pattern of hippocampal activation was also obtained in a second version of the task that only used a single start arm instead of multiple start arms. The CA3 and CA1 activation during remote memory recall is consistent with the interpretation that an older memory might require increased pattern completion and/or relearning after longer time intervals. Irrespective of whether the hippocampus is required for remote memory recall, the hippocampus might engage in computations that either support recall of remote memories or that update remote memories.
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http://dx.doi.org/10.1016/j.nlm.2013.05.007DOI Listing
November 2013
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