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1.  Fluctuating Inhibitory Inputs Promote Reliable Spiking at Theta Frequencies in Hippocampal Interneurons 
Theta-frequency (4–12 Hz) rhythms in the hippocampus play important roles in learning and memory. CA1 interneurons located at the stratum lacunosum-moleculare and radiatum junction (LM/RAD) are thought to contribute to hippocampal theta population activities by rhythmically pacing pyramidal cells with inhibitory postsynaptic potentials. This implies that LM/RAD cells need to fire reliably at theta frequencies in vivo. To determine whether this could occur, we use biophysically based LM/RAD model cells and apply different cholinergic and synaptic inputs to simulate in vivo-like network environments. We assess spike reliabilities and spiking frequencies, identifying biophysical properties and network conditions that best promote reliable theta spiking. We find that synaptic background activities that feature large inhibitory, but not excitatory, fluctuations are essential. This suggests that strong inhibitory input to these cells is vital for them to be able to contribute to population theta activities. Furthermore, we find that Type I-like oscillator models produced by augmented persistent sodium currents (INaP) or diminished A-type potassium currents (IA) enhance reliable spiking at lower theta frequencies. These Type I-like models are also the most responsive to large inhibitory fluctuations and can fire more reliably under such conditions. In previous work, we showed that INaP and IA are largely responsible for establishing LM/RAD cells’ subthreshold activities. Taken together with this study, we see that while both these currents are important for subthreshold theta fluctuations and reliable theta spiking, they contribute in different ways – INaP to reliable theta spiking and subthreshold activity generation, and IA to subthreshold activities at theta frequencies. This suggests that linking subthreshold and suprathreshold activities should be done with consideration of both in vivo contexts and biophysical specifics.
doi:10.3389/fncom.2012.00030
PMCID: PMC3359426  PMID: 22654751
spike reliability; inhibition; noise; subthreshold oscillations; theta rhythm; interneuron; hippocampus; biophysical model
2.  Entorhinal stellate cells show preferred spike phase-locking to theta inputs that is enhanced by correlations in synaptic activity 
In active networks, excitatory and inhibitory synaptic inputs generate membrane voltage fluctuations that drive spike activity in a probabilistic manner. Despite this, some cells in vivo show a strong propensity to precisely lock to the local field potential and maintain a specific spike-phase relationship relative to other cells. In recordings from rat medial entorhinal cortical stellate cells, we measured spike phase-locking in response to sinusoidal “test” inputs in the presence of different forms of background membrane voltage fluctuations, generated via dynamic clamp. We find that stellate cells show strong and robust spike phase-locking to theta (4–12 Hz) inputs. This response occurs under a wide variety of background membrane voltage fluctuation conditions that include a substantial increase in overall membrane conductance. Furthermore, the IH current present in stellate cells is critical to the enhanced spike phase-locking response at theta. Finally, we show that correlations between inhibitory and excitatory conductance fluctuations, which can arise through feed-back and feed-forward inhibition, can substantially enhance the spike phase-locking response. The enhancement in locking is a result of a selective reduction in the size of low frequency membrane voltage fluctuations due to cancelation of inhibitory and excitatory current fluctuations with correlations. Hence, our results demonstrate that stellate cells have a strong preference for spike phase-locking to theta band inputs and that the absolute magnitude of locking to theta can be modulated by the properties of background membrane voltage fluctuations.
doi:10.1523/JNEUROSCI.3892-12.2013
PMCID: PMC3680114  PMID: 23554484
synaptic correlations; high conductance; theta; IH; voltage fluctuations; balanced excitation and inhibition; spike phase-locking
3.  Hippocampal Theta Modulation of Neocortical Spike Times and Gamma Rhythm: A Biophysical Model Study 
PLoS ONE  2012;7(10):e45688.
The hippocampal theta and neocortical gamma rhythms are two prominent examples of oscillatory neuronal activity. The hippocampus has often been hypothesized to influence neocortical networks by its theta rhythm, and, recently, evidence for such a direct influence has been found. We examined a possible mechanism for this influence by means of a biophysical model study using conductance-based model neurons. We found, in agreement with previous studies, that networks of fast-spiking GABA -ergic interneurons, coupled with shunting inhibition, synchronize their spike activity at a gamma frequency and are able to impose this rhythm on a network of pyramidal cells to which they are coupled. When our model was supplied with hippocampal theta-modulated input fibres, the theta rhythm biased the spike timings of both the fast-spiking and pyramidal cells. Furthermore, both the amplitude and frequency of local field potential gamma oscillations were influenced by the phase of the theta rhythm. We show that the fast-spiking cells, not pyramidal cells, are essential for this latter phenomenon, thus highlighting their crucial role in the interplay between hippocampus and neocortex.
doi:10.1371/journal.pone.0045688
PMCID: PMC3462809  PMID: 23056213
4.  Theta-Gamma-Modulated Synaptic Currents in Hippocampal Granule Cells In Vivo Define a Mechanism for Network Oscillations 
Neuron  2014;81(1):140-152.
Summary
Theta-gamma network oscillations are thought to represent key reference signals for information processing in neuronal ensembles, but the underlying synaptic mechanisms remain unclear. To address this question, we performed whole-cell (WC) patch-clamp recordings from mature hippocampal granule cells (GCs) in vivo in the dentate gyrus of anesthetized and awake rats. GCs in vivo fired action potentials at low frequency, consistent with sparse coding in the dentate gyrus. GCs were exposed to barrages of fast AMPAR-mediated excitatory postsynaptic currents (EPSCs), primarily relayed from the entorhinal cortex, and inhibitory postsynaptic currents (IPSCs), presumably generated by local interneurons. EPSCs exhibited coherence with the field potential predominantly in the theta frequency band, whereas IPSCs showed coherence primarily in the gamma range. Action potentials in GCs were phase locked to network oscillations. Thus, theta-gamma-modulated synaptic currents may provide a framework for sparse temporal coding of information in the dentate gyrus.
Highlights
•Granule cells in vivo fire action potentials sparsely but often in bursts•Granule cells are exposed to barrages of fast excitatory postsynaptic currents•Granule cells receive theta-coherent excitation but gamma-coherent inhibition
Pernía-Andrade and Jonas characterize the synaptic mechanisms underlying network oscillations and temporal coding in the dorsal hippocampus in awake rats. Theta-gamma-modulated synaptic currents may provide a framework for sparse temporal coding of information in the dentate gyrus.
doi:10.1016/j.neuron.2013.09.046
PMCID: PMC3909463  PMID: 24333053
5.  Ketamine disrupts theta modulation of gamma in a computer model of hippocampus 
Abnormalities in oscillations have been suggested to play a role in schizophrenia. We studied theta-modulated gamma oscillations in a computer model of hippocampal CA3 in vivo with and without simulated application of ketamine, an NMDA receptor antagonist and psychotomimetic. Networks of 1200 multi-compartment neurons (pyramidal, basket and oriens-lacunosum moleculare, OLM, cells) generated theta and gamma oscillations from intrinsic network dynamics: basket cells primarily generated gamma and amplified theta, while OLM cells strongly contributed to theta. Extrinsic medial septal inputs paced theta and amplified both theta and gamma oscillations. Exploration of NMDA receptor reduction across all location combinations demonstrated that the experimentally-observed ketamine effect occurred only with isolated reduction of NMDA receptors on OLMs. In the ketamine simulations, lower OLM activity reduced theta power and disinhibited pyramidal cells, resulting in increased basket cell activation and gamma power. Our simulations predict:
ketamine increases firing rates;oscillations can be generated by intrinsic hippocampal circuits;medial septum inputs pace and augment oscillations;pyramidal cells lead basket cells at the gamma peak but lag at trough;basket cells amplify theta rhythms;ketamine alters oscillations due to primary blockade at OLM NMDA receptors;ketamine alters phase relationships of cell firing;ketamine reduces network responsivity to the environmentketamine effect could be reversed by providing a continuous inward current to OLM cells.
We suggest that this last prediction has implications for a possible novel treatment for cognitive deficits of schizophrenia by targeting OLM cells.
doi:10.1523/JNEUROSCI.0501-11.2011
PMCID: PMC3177405  PMID: 21832203
6.  Long-Term Plasticity Is Proportional to Theta-Activity 
PLoS ONE  2009;4(6):e5850.
Background
Theta rhythm in the hippocampal formation is a main feature of exploratory behaviour and is believed to enable the encoding of new spatial information and the modification of synaptic weights. Cyclic changes of dentate gyrus excitability during theta rhythm are related to its function, but whether theta epochs per se are able to alter network properties of dentate gyrus for long time-periods is still poorly understood.
Methodology/Principal Findings
We used low-frequency stimulation protocols that amplify the power of endogenous theta oscillations, in order to estimate the plasticity effect of endogenous theta oscillations on a population level. We found that stimulation-induced augmentation of the theta rhythm is linked to a subsequent increase of neuronal excitability and decrease of the synaptic response. This EPSP-to-Spike uncoupling is related to an increased postsynaptic spiking on the positive phases of theta frequency oscillations. Parallel increase of the field EPSP slope and the population spike occurs only after concurrent pre- and postsynaptic activation. Furthermore, we observed that long-term potentiation (>24 h) occurs in the dentate gyrus of freely behaving adult rats after phasic activity of entorhinal afferents in the theta-frequency range. This plasticity is proportional to the field bursting activity of granule cells during the stimulation, and may comprise a key step in spatial information transfer. Long-term potentiation of the synaptic component occurs only when the afferent stimulus precedes the evoked population burst, and is input-specific.
Conclusions/Significance
Our data confirm the role of the dentate gyrus in filtering information to the subsequent network during the activated state of the hippocampus.
doi:10.1371/journal.pone.0005850
PMCID: PMC2688745  PMID: 19513114
7.  Ih Tunes Theta/Gamma Oscillations and Cross-Frequency Coupling In an In Silico CA3 Model 
PLoS ONE  2013;8(10):e76285.
channels are uniquely positioned to act as neuromodulatory control points for tuning hippocampal theta (4–12 Hz) and gamma (25 Hz) oscillations, oscillations which are thought to have importance for organization of information flow. contributes to neuronal membrane resonance and resting membrane potential, and is modulated by second messengers. We investigated oscillatory control using a multiscale computer model of hippocampal CA3, where each cell class (pyramidal, basket, and oriens-lacunosum moleculare cells), contained type-appropriate isoforms of . Our model demonstrated that modulation of pyramidal and basket allows tuning theta and gamma oscillation frequency and amplitude. Pyramidal also controlled cross-frequency coupling (CFC) and allowed shifting gamma generation towards particular phases of the theta cycle, effected via 's ability to set pyramidal excitability. Our model predicts that in vivo neuromodulatory control of allows flexibly controlling CFC and the timing of gamma discharges at particular theta phases.
doi:10.1371/journal.pone.0076285
PMCID: PMC3799898  PMID: 24204609
8.  Spike-Timing Precision and Neuronal Synchrony Are Enhanced by an Interaction between Synaptic Inhibition and Membrane Oscillations in the Amygdala 
PLoS ONE  2012;7(4):e35320.
The basolateral complex of the amygdala (BLA) is a critical component of the neural circuit regulating fear learning. During fear learning and recall, the amygdala and other brain regions, including the hippocampus and prefrontal cortex, exhibit phase-locked oscillations in the high delta/low theta frequency band (∼2–6 Hz) that have been shown to contribute to the learning process. Network oscillations are commonly generated by inhibitory synaptic input that coordinates action potentials in groups of neurons. In the rat BLA, principal neurons spontaneously receive synchronized, inhibitory input in the form of compound, rhythmic, inhibitory postsynaptic potentials (IPSPs), likely originating from burst-firing parvalbumin interneurons. Here we investigated the role of compound IPSPs in the rat and rhesus macaque BLA in regulating action potential synchrony and spike-timing precision. Furthermore, because principal neurons exhibit intrinsic oscillatory properties and resonance between 4 and 5 Hz, in the same frequency band observed during fear, we investigated whether compound IPSPs and intrinsic oscillations interact to promote rhythmic activity in the BLA at this frequency. Using whole-cell patch clamp in brain slices, we demonstrate that compound IPSPs, which occur spontaneously and are synchronized across principal neurons in both the rat and primate BLA, significantly improve spike-timing precision in BLA principal neurons for a window of ∼300 ms following each IPSP. We also show that compound IPSPs coordinate the firing of pairs of BLA principal neurons, and significantly improve spike synchrony for a window of ∼130 ms. Compound IPSPs enhance a 5 Hz calcium-dependent membrane potential oscillation (MPO) in these neurons, likely contributing to the improvement in spike-timing precision and synchronization of spiking. Activation of the cAMP-PKA signaling cascade enhanced the MPO, and inhibition of this cascade blocked the MPO. We discuss these results in the context of spike-timing dependent plasticity and modulation by neurotransmitters important for fear learning, such as dopamine.
doi:10.1371/journal.pone.0035320
PMCID: PMC3338510  PMID: 22563382
9.  Parvalbumin-containing fast-spiking basket cells generate the field potential oscillations induced by cholinergic receptor activation in the hippocampus 
Gamma frequency oscillations in cortical regions can be recorded during cognitive processes, including attention or memory tasks. These oscillations are generated locally as a result of reciprocal interactions between excitatory pyramidal cells and perisomatic inhibitory interneurons. Here, we examined the contribution of the three perisomatic interneuron types – the parvalbumin-containing fast-spiking basket (FSBC) and axo-axonic (AAC) cells, as well as the cholecystokinin-containing regular-spiking basket cells (RSBC) to cholinergically induced oscillations in hippocampal slices, a rhythmic activity that captures several features of the gamma oscillations recorded in vivo. By analyzing the spiking activities of single neurons recorded in parallel with local field potentials, we found that all three cell types fired phase-locked to the carbachol-induced oscillations, although with different frequencies and precision. During these oscillations FSBCs fired the most with the highest accuracy compared to the discharge of AACs and RSBCs. In further experiments we showed that activation of μ-opioid receptors by DAMGO, which significantly reduced the inhibitory, but not excitatory transmission, suppressed or even blocked network oscillations both in vitro and in vivo, leading to the desynchronization of pyramidal cell firing. Using paired recordings we demonstrated that carbachol application blocked GABA release from RSBCs and reduced it from FSBCs and AACs, whereas DAMGO further suppressed the GABA release only from FSBCs, but not from AACs.
These results collectively suggest that the rhythmic perisomatic inhibition, generating oscillatory fluctuation in local field potentials after carbachol treatment of hippocampal slices, is the result of periodic GABA release from FSBCs.
doi:10.1523/JNEUROSCI.4104-10.2010
PMCID: PMC3044880  PMID: 21068319
inhibition; rhythm; μ-opioid receptor; gamma oscillations; in vivo; in vitro
10.  Inhibitory control of hippocampal inhibitory neurons 
Information processing within neuronal networks is determined by a dynamic partnership between principal neurons and local circuit inhibitory interneurons. The population of GABAergic interneurons is extremely heterogeneous and comprises, in many brain regions, cells with divergent morphological and physiological properties, distinct molecular expression profiles, and highly specialized functions. GABAergic interneurons have been studied extensively during the past two decades, especially in the hippocampus, which is a relatively simple cortical structure. Different types of hippocampal inhibitory interneurons control spike initiation [e.g., axo-axonic and basket cells (BCs)] and synaptic integration (e.g., bistratified and oriens–lacunosum moleculare interneurons) within pyramidal neurons and synchronize local network activity, providing a means for functional segregation of neuronal ensembles and proper routing of hippocampal information. Thus, it is thought that, at least in the hippocampus, GABAergic inhibitory interneurons represent critical regulating elements at all stages of information processing, from synaptic integration and spike generation to large-scale network activity. However, this raises an important question: if inhibitory interneurons are fundamental for network computations, what are the mechanisms that control the activity of the interneurons themselves? Given the essential role of synaptic inhibition in the regulation of neuronal activity, it would be logical to expect that specific inhibitory mechanisms have evolved to control the operation of interneurons. Here, we review the mechanisms of synaptic inhibition of interneurons and discuss their role in the operation of hippocampal inhibitory circuits.
doi:10.3389/fnins.2012.00165
PMCID: PMC3496901  PMID: 23162426
hippocampus; inhibition; interneuron-specific interneuron; GABA; synapse
11.  A Computational Predictor of Human Episodic Memory Based on a Theta Phase Precession Network 
PLoS ONE  2009;4(10):e7536.
In the rodent hippocampus, a phase precession phenomena of place cell firing with the local field potential (LFP) theta is called “theta phase precession” and is considered to contribute to memory formation with spike time dependent plasticity (STDP). On the other hand, in the primate hippocampus, the existence of theta phase precession is unclear. Our computational studies have demonstrated that theta phase precession dynamics could contribute to primate–hippocampal dependent memory formation, such as object–place association memory. In this paper, we evaluate human theta phase precession by using a theory–experiment combined analysis. Human memory recall of object–place associations was analyzed by an individual hippocampal network simulated by theta phase precession dynamics of human eye movement and EEG data during memory encoding. It was found that the computational recall of the resultant network is significantly correlated with human memory recall performance, while other computational predictors without theta phase precession are not significantly correlated with subsequent memory recall. Moreover the correlation is larger than the correlation between human recall and traditional experimental predictors. These results indicate that theta phase precession dynamics are necessary for the better prediction of human recall performance with eye movement and EEG data. In this analysis, theta phase precession dynamics appear useful for the extraction of memory-dependent components from the spatio–temporal pattern of eye movement and EEG data as an associative network. Theta phase precession may be a common neural dynamic between rodents and humans for the formation of environmental memories.
doi:10.1371/journal.pone.0007536
PMCID: PMC2762313  PMID: 19851508
12.  Theta phase precession of grid and place cell firing in open environments 
Place and grid cells in the rodent hippocampal formation tend to fire spikes at successively earlier phases relative to the local field potential theta rhythm as the animal runs through the cell's firing field on a linear track. However, this ‘phase precession’ effect is less well characterized during foraging in two-dimensional open field environments. Here, we mapped runs through the firing fields onto a unit circle to pool data from multiple runs. We asked which of seven behavioural and physiological variables show the best circular–linear correlation with the theta phase of spikes from place cells in hippocampal area CA1 and from grid cells from superficial layers of medial entorhinal cortex. The best correlate was the distance to the firing field peak projected onto the animal's current running direction. This was significantly stronger than other correlates, such as instantaneous firing rate and time-in-field, but similar in strength to correlates with other measures of distance travelled through the firing field. Phase precession was stronger in place cells than grid cells overall, and robust phase precession was seen in traversals through firing field peripheries (although somewhat less than in traversals through the centre), consistent with phase coding of displacement along the current direction. This type of phase coding, of place field distance ahead of or behind the animal, may be useful for allowing calculation of goal directions during navigation.
doi:10.1098/rstb.2012.0532
PMCID: PMC3866450  PMID: 24366140
temporal coding; theta rhythm; hippocampus; entorhinal cortex; space; oscillation
13.  Chronic stimulation of cultured neuronal networks boosts low frequency oscillatory activity at theta and gamma with spikes phase-locked to gamma frequencies 
Journal of Neural Engineering  2012;9(2):026015.
Slow wave oscillations in the brain are essential for coordinated network activity but have not been shown to self-organize in vitro. Here, the development of dissociated hippocampal neurons into an active network with oscillations on multi-electrode arrays was evaluated in the absence and presence of chronic external stimulation. Significant changes in signal power were observed in the range of 1-400 Hz with an increase in amplitude during bursts. Stimulation increased oscillatory activity primarily in the theta (4-11 Hz) and slow gamma (30-55 Hz) bands. Spikes were most prominently phase-locked to the slow gamma waves. Notably, the dissociated network self-organized to exhibit sustained delta, theta, beta and gamma oscillations without input from cortex, thalamus or organized pyramidal cell layers.
doi:10.1088/1741-2560/9/2/026015
PMCID: PMC3376752  PMID: 22361724
14.  Theta oscillations provide temporal windows for local circuit computation in the entorhinal-hippocampal loop 
Neuron  2009;64(2):267-280.
Summary
Theta oscillations are believed to play an important role in the coordination of neuronal firing in the entorhinal (EC)-hippocampal system but the underlying mechanisms are not known. We simultaneously recorded from neurons in multiple regions of the EC-hippocampal loop and examined their temporal relationships. Theta coordinated synchronous spiking of EC neuronal populations predicted the timing of current sinks in target layers in the hippocampus. However, the temporal delays between population activities in successive anatomical stages were longer (typically by a half theta cycle) than expected from axon conduction velocities and passive synaptic integration of feed-forward excitatory inputs. We hypothesize that the temporal windows set by the theta cycles allow for local circuit interactions and thus a considerable degree of computational independence in subdivisions of the EC-hippocampal loop.
doi:10.1016/j.neuron.2009.08.037
PMCID: PMC2771122  PMID: 19874793
15.  Intracellular Dynamics of Virtual Place Cells 
Neural computation  2010;10.1162/NECO_a_00087.
The pattern of spikes recorded from place cells in the rodent hippocampus is strongly modulated by both the spatial location in the environment and the theta rhythm. The phases of the spikes in the theta cycle advance during movement through the place field. Recently intracellular recordings from hippocampal neurons (Harvey, Collman, Dombeck, & Tank, 2009) showed an increase in the amplitude of membrane potential oscillations inside the place field, which was interpreted as evidence that an intracellular mechanism caused phase precession. Here we show that an existing network model of the hippocampus (Tsodyks, Skaggs, Sejnowski, & McNaughton, 1996) can equally reproduce this and other aspects of the intracellular recordings, which suggests that new experiments are needed to distinguish the contributions of intracellular and network mechanisms to phase precession.
doi:10.1162/NECO_a_00087
PMCID: PMC3161172  PMID: 21162664
16.  A Computational Study on Altered Theta-Gamma Coupling during Learning and Phase Coding 
PLoS ONE  2012;7(6):e36472.
There is considerable interest in the role of coupling between theta and gamma oscillations in the brain in the context of learning and memory. Here we have used a neural network model which is capable of producing coupling of theta phase to gamma amplitude firstly to explore its ability to reproduce reported learning changes and secondly to memory-span and phase coding effects. The spiking neural network incorporates two kinetically different GABAA receptor-mediated currents to generate both theta and gamma rhythms and we have found that by selective alteration of both NMDA receptors and GABAA,slow receptors it can reproduce learning-related changes in the strength of coupling between theta and gamma either with or without coincident changes in theta amplitude. When the model was used to explore the relationship between theta and gamma oscillations, working memory capacity and phase coding it showed that the potential storage capacity of short term memories, in terms of nested gamma-subcycles, coincides with the maximal theta power. Increasing theta power is also related to the precision of theta phase which functions as a potential timing clock for neuronal firing in the cortex or hippocampus.
doi:10.1371/journal.pone.0036472
PMCID: PMC3380897  PMID: 22737207
17.  Switching between gamma and theta: Dynamic network control using subthreshold electric fields 
Neurocomputing  2007;70(10-12):2091-2095.
We implemented an experimentally observed orthogonal arrangement of theta and gamma generation circuitry in septotemporal and lamellar dimensions is a two-dimensional model of hippocampus. The model includes three types of cells: pyramidal, basket, and oriens lacunosum-moleculare (OLM) neurons. In this reduced model, application of continuous electric fields allowed us to switch between theta, gamma and mixed theta–gamma regimes without additional pharmacological manipulation. Electric field effects on individual neurons were modeled based on experimental data. Network simulation results predict a flexible experimental technique, which would employ adaptive subthreshold electric fields to continuously modulate neuronal ensemble activity, and can be used for testing cognitive correlates of oscillatory rhythms as well as for suppressing epileptiform activity.
doi:10.1016/j.neucom.2006.10.124
PMCID: PMC2186062  PMID: 18185843
18.  Speed Controls the Amplitude and Timing of the Hippocampal Gamma Rhythm 
PLoS ONE  2011;6(6):e21408.
Cortical and hippocampal gamma oscillations have been implicated in many behavioral tasks. The hippocampus is required for spatial navigation where animals run at varying speeds. Hence we tested the hypothesis that the gamma rhythm could encode the running speed of mice. We found that the amplitude of slow (20–45 Hz) and fast (45–120 Hz) gamma rhythms in the hippocampal local field potential (LFP) increased with running speed. The speed-dependence of gamma amplitude was restricted to a narrow range of theta phases where gamma amplitude was maximal, called the preferred theta phase of gamma. The preferred phase of slow gamma precessed to lower values with increasing running speed. While maximal fast and slow gamma occurred at coincident phases of theta at low speeds, they became progressively more theta-phase separated with increasing speed. These results demonstrate a novel influence of speed on the amplitude and timing of the hippocampal gamma rhythm which could contribute to learning of temporal sequences and navigation.
doi:10.1371/journal.pone.0021408
PMCID: PMC3123337  PMID: 21731735
19.  Theta Phase Precession in Rat Ventral Striatum Links Place and Reward Information 
The Journal of Neuroscience  2011;31(8):2843-2854.
A functional interaction between the hippocampal formation and the ventral striatum is thought to contribute to the learning and expression of associations between places and rewards. However, the mechanism of how such associations may be learned and used is currently unknown. We recorded neural ensembles and local field potentials from the ventral striatum and CA1 simultaneously as rats ran a modified T-maze. Theta-modulated cells in ventral striatum almost invariably showed firing phase precession relative to the hippocampal theta rhythm. Across the population of ventral striatal cells, phase precession was preferentially associated with an anticipatory ramping of activity up to the reward sites. In contrast, CA1 population activity and phase precession were distributed more uniformly. Ventral striatal phase precession was stronger to hippocampal than ventral striatal theta and was accompanied by increased theta coherence with hippocampus, suggesting that this effect is hippocampally derived. These results suggest that the firing phase of ventral striatal neurons contains motivationally relevant information and that phase precession serves to bind hippocampal place representations to ventral striatal representations of reward.
doi:10.1523/JNEUROSCI.4869-10.2011
PMCID: PMC3758553  PMID: 21414906
20.  Theta phase precession emerges from a hybrid computational model of a CA3 place cell 
Cognitive Neurodynamics  2007;1(3):237-248.
The origins and functional significance of theta phase precession in the hippocampus remain obscure, in part, because of the difficulty of reproducing hippocampal place cell firing in experimental settings where the biophysical underpinnings can be examined in detail. The present study concerns a neurobiologically based computational model of the emergence of theta phase precession in which the responses of a single model CA3 pyramidal cell are examined in the context of stimulation by realistic afferent spike trains including those of place cells in entorhinal cortex, dentate gyrus, and other CA3 pyramidal cells. Spike-timing dependent plasticity in the model CA3 pyramidal cell leads to a spatially correlated associational synaptic drive that subsequently creates a spatially asymmetric expansion of the model cell’s place field. Following an initial training period, theta phase precession can be seen in the firing patterns of the model CA3 pyramidal cell. Through selective manipulations of the model it is possible to decompose theta phase precession in CA3 into the separate contributing factors of inheritance from upstream afferents in the dentate gyrus and entorhinal cortex, the interaction of synaptically controlled increasing afferent drive with phasic inhibition, and the theta phase difference between dentate gyrus granule cell and CA3 pyramidal cell activity. In the context of a single CA3 pyramidal cell, the model shows that each of these factors plays a role in theta phase precession within CA3 and suggests that no one single factor offers a complete explanation of the phenomenon. The model also shows parallels between theta phase encoding and pattern completion within the CA3 autoassociative network.
Electronic supplementary material
The online version of this article (doi:10.1007/s11571-007-9018-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11571-007-9018-9
PMCID: PMC2267674  PMID: 19003516
Theta rhythm; Hippocampus; Pyramidal cell; Computer simulation; Learning and memory
21.  Theta Frequency Background Tunes Transmission but Not Summation of Spiking Responses 
PLoS ONE  2013;8(1):e55607.
Hippocampal neurons are known to fire as a function of frequency and phase of spontaneous network rhythms, associated with the animal's behaviour. This dependence is believed to give rise to precise rate and temporal codes. However, it is not well understood how these periodic membrane potential fluctuations affect the integration of synaptic inputs. Here we used sinusoidal current injection to the soma of CA1 pyramidal neurons in the rat brain slice to simulate background oscillations in the physiologically relevant theta and gamma frequency range. We used a detailed compartmental model to show that somatic current injection gave comparable results to more physiological synaptically driven theta rhythms incorporating excitatory input in the dendrites, and inhibitory input near the soma. We systematically varied the phase of synaptic inputs with respect to this background, and recorded changes in response and summation properties of CA1 neurons using whole-cell patch recordings. The response of the cell was dependent on both the phase of synaptic inputs and frequency of the background input. The probability of the cell spiking for a given synaptic input was up to 40% greater during the depolarized phases between 30–135 degrees of theta frequency current injection. Summation gain on the other hand, was not affected either by the background frequency or the phasic afferent inputs. This flat summation gain, coupled with the enhanced spiking probability during depolarized phases of the theta cycle, resulted in enhanced transmission of summed inputs during the same phase window of 30–135 degrees. Overall, our study suggests that although oscillations provide windows of opportunity to selectively boost transmission and EPSP size, summation of synaptic inputs remains unaffected during membrane oscillations.
doi:10.1371/journal.pone.0055607
PMCID: PMC3561309  PMID: 23383242
22.  Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus 
The behaviour-contingent rhythmic synchronization of neuronal activity is reported by local field potential oscillations in the theta, gamma and sharp wave-related ripple (SWR) frequency ranges. In the hippocampus, pyramidal cell assemblies representing temporal sequences are coordinated by GABAergic interneurons selectively innervating specific postsynaptic domains, and discharging phase locked to network oscillations. We compare the cellular network dynamics in the CA1 and CA3 areas recorded with or without anaesthesia. All parts of pyramidal cells, except the axon initial segment, receive GABA from multiple interneuron types, each with distinct firing dynamics. The axon initial segment is exclusively innervated by axo-axonic cells, preferentially firing after the peak of the pyramidal layer theta cycle, when pyramidal cells are least active. Axo-axonic cells are inhibited during SWRs, when many pyramidal cells fire synchronously. This dual inverse correlation demonstrates the key inhibitory role of axo-axonic cells. Parvalbumin-expressing basket cells fire phase locked to field gamma activity in both CA1 and CA3, and also strongly increase firing during SWRs, together with dendrite-innervating bistratified cells, phasing pyramidal cell discharge. Subcellular domain-specific GABAergic innervation probably developed for the coordination of multiple glutamatergic inputs on different parts of pyramidal cells through the temporally distinct activity of GABAergic interneurons, which differentially change their firing during different network states.
doi:10.1098/rstb.2012.0518
PMCID: PMC3866441  PMID: 24366131
oscillation; interneuron; inhibition; synapse; GABA
23.  Theta phase coding in a network model of the entorhinal cortex layer II with entorhinal-hippocampal loop connections 
Cognitive Neurodynamics  2006;1(2):169-184.
We investigated successive firing of the stellate cells within a theta cycle, which replicates the phase coding of place information, using a network model of the entorhinal cortex layer II with loop connections. Layer II of the entorhinal cortex (ECII) sends signals to the hippocampus, and the hippocampus sends signals back to layer V of the entorhinal cortex (ECV). In addition to this major pathway, projection from ECV to ECII also exists. It is, therefore, inferred that reverberation activity readily appears if projections from ECV to ECII are potentiated. The frequency of the reverberation would be in a gamma range because it takes signals 20–30 ms to go around the entorhinal-hippocampal loop circuits. On the other hand, it has been suggested that ECII is a theta rhythm generator. If the reverberation activity appears in the entorhinal-hippocampal loop circuits, gamma oscillation would be superimposed on a theta rhythm in ECII like a gamma-theta oscillation. This is a reminiscence of the theta phase coding of place information. In this paper, first, a network model of ECII will be developed in order to reproduce a theta rhythm. Secondly, we will show that loop connections from one stellate cell to the other one are selectively potentiated by afferent signals to ECII. Frequencies of those afferent signals are different, and transmission delay of the loop connections is 20 ms. As a result, stellate cells fire successively within one cycle of the theta rhythm. This resembles gamma-theta oscillation underlying the phase coding. Our model also replicates the phase precession of stellate cell firing within a cycle of subthreshold oscillation (theta rhythm).
doi:10.1007/s11571-006-9003-8
PMCID: PMC2267667  PMID: 19003510
Network model; Entorhinal cortex layer II; Loop connections; Stellate cell; Theta rhythm; Phase coding; Spike-timing dependent plasticity
24.  Intracellular dynamics of hippocampal place cells during virtual navigation 
Nature  2009;461(7266):941-946.
Hippocampal place cells encode spatial information in rate and temporal codes. To examine the mechanisms underlying hippocampal coding, we measured the intracellular dynamics of place cells by combining in vivo whole cell recordings with a virtual reality system. Head-restrained mice, running on a spherical treadmill, interacted with a computer-generated visual environment to perform spatial behaviors. Robust place cell activity was present during movement along a virtual linear track. From whole cell recordings, we identified three subthreshold signatures of place fields: (1) an asymmetric ramp-like depolarization of the baseline membrane potential; (2) an increase in the amplitude of intracellular theta oscillations; and, (3) a phase precession of the intracellular theta oscillation relative to the extracellularly-recorded theta rhythm. These intracellular dynamics underlie the primary features of place cell rate and temporal codes. The virtual reality system developed here will enable new experimental approaches to study the neural circuits underlying navigation.
doi:10.1038/nature08499
PMCID: PMC2771429  PMID: 19829374
25.  Mu opioid receptor activation normalizes temporo-ammonic pathway driven inhibition in hippocampal CA1 
Neuropharmacology  2010;60(2-3):472-479.
The hippocampus of the mammalian brain is important for the formation of long term memories. Hippocampal-dependent learning can be affected by a number of neurotransmitters including the activation of μ-opioid receptors (MOR). It has been shown that MOR activation can alter synaptic plasticity and network oscillations in the hippocampus, both of which are thought to be important for the encoding of information and formation of memories. One hippocampal oscillation that has been correlated with learning and memory formation is the 4-10 Hz theta rhythm. During theta rhythms, inputs to hippocampal CA1 from CA3 (Schaffer collaterals, SC) and the entorhinal cortex (perforant path) can integrate at different times within an individual theta cycle. Consequently, when excitatory inputs in the stratum lacunosum-moleculare (the temporo-ammonic pathway (TA), which includes the perforant path) are stimulated approximately one theta period before SC inputs, the TA can indirectly inhibit SC inputs. This inhibition is due to the activation of postsynaptic GABAB receptors on CA1 pyramidal neurons. Importantly, MOR activation has been shown to suppress GABAB inhibitory postsynaptic potentials in CA1 pyramidal neurons. Therefore, we examined how MOR activation affects the integration between TA inputs and SC inputs in hippocampal CA1. To do this we used voltage-sensitive dye imaging and whole cell patch clamping from acute hippocampal slices taken from young adult rats. Here we show that MOR activation has no effect on the integration between TA and SC inputs when activation of the TA precedes SC by less than one half of a theta cycle (< 75 ms). However, MOR activation completely blocked the inhibitory action of TA on SC inputs when TA stimulation occurred approximately one theta cycle before SC activation (> 150 ms). This MOR suppression of TA driven inhibition occurred in both the SC input layer of hippocampal CA1 (stratum radiatum) and the output layer of CA1 pyramidal neurons (stratum pyramidale). Thus MOR activation can have profound effects on the temporal integration between two primary excitatory pathways to hippocampal CA1 and subsequently the resultant output from CA1 pyramidal neurons. These data provide important information for understanding how acute or chronic MOR activation may affect the integration of activity within hippocampal CA1 during theta rhythm.
doi:10.1016/j.neuropharm.2010.10.029
PMCID: PMC3014450  PMID: 21056047
voltage-sensitive dye; integration; interneuron; feed forward; theta

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