Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

This study reveals extensive non-canonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1, perirhinal cortex and subicular complex, and shows that genetic inactivation of projection from ventral CA1 to dorsal CA3 impairs object-related spatial learning and memory.     

Activity dynamics and behavioral correlates of CA3 and CA1 hippocampal pyramidal neurons

The CA3 and CA1 pyramidal neurons are the major principal cell types of the hippocampus proper. The strongly recurrent collateral system of CA3 cells and the largely parallel-organized CA1 neurons suggest that these regions perform distinct computations. However, a comprehensive comparison between CA1 and CA3 pyramidal cells in terms of firing properties, network dynamics, and behavioral correlations is sparse in the intact animal. We performed large-scale recordings in the dorsal hippocampus of rats to quantify the similarities and differences between CA1 (n > 3,600) and CA3 (n > 2,200) pyramidal cells during sleep and exploration in multiple environments. CA1 and CA3 neurons differed significantly in firing rates, spike burst propensity, spike entrainment by the theta rhythm, and other aspects of spiking dynamics in a brain state-dependent manner. A smaller proportion of CA3 than CA1 cells displayed prominent place fields, but place fields of CA3 neurons were more compact, more stable, and carried more spatial information per spike than those of CA1 pyramidal cells. Several other features of the two cell types were specific to the testing environment. CA3 neurons showed less pronounced phase precession and a weaker position versus spike-phase relationship than CA1 cells. Our findings suggest that these distinct activity dynamics of CA1 and CA3 pyramidal cells support their distinct computational roles.     

Phase precession through acceleration of local theta rhythm: a biophysical model for the interaction between place cells and local inhibitory neurons

Phase precession is one of the most well known examples within the temporal coding hypothesis. Here we present a biophysical spiking model for phase precession in hippocampal CA1 which focuses on the interaction between place cells and local inhibitory interneurons. The model's functional block is composed of a place cell (PC) connected with a local inhibitory cell (IC) which is modulated by the population theta rhythm. Both cells receive excitatory inputs from the entorhinal cortex (EC). These inputs are both theta modulated and space modulated. The dynamics of the two neuron types are described by integrate-and-fire models with conductance synapses, and the EC inputs are described using non-homogeneous Poisson processes. Phase precession in our model is caused by increased drive to specific PC/IC pairs when the animal is in their place field. The excitation increases the IC's firing rate, and this modulates the PC's firing rate such that both cells precess relative to theta. Our model implies that phase coding in place cells may not be independent from rate coding. The absence of restrictive connectivity constraints in this model predicts the generation of phase precession in any network with similar architecture and subject to a clocking rhythm, independently of the involvement in spatial tasks.     

Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice

Hippocampal CA1 and CA3 pyramidal neuron place cells encode the spatial location of an animal through localized firing patterns called "place fields." To explore the mechanisms that control place cell firing and their relationship to spatial memory, we studied mice with enhanced spatial memory resulting from forebrain-specific knockout of the HCN1 hyperpolarization-activated cation channel. HCN1 is strongly expressed in CA1 neurons and in entorhinal cortex grid cells, which provide spatial information to the hippocampus. Both CA1 and CA3 place fields were larger but more stable in the knockout mice, with the effect greater in CA1 than CA3. As HCN1 is only weakly expressed in CA3 place cells, their altered activity likely reflects loss of HCN1 in grid cells. The more pronounced changes in CA1 likely reflect the intrinsic contribution of HCN1. The enhanced place field stability may underlie the effect of HCN1 deletion to facilitate spatial learning and memory.     

Oscillation-coordinated,noise-resistant information distribution via the subiculum

The hippocampus processes information associated with spatial navigation. The subiculum receives input from the hippocampus CA1 and projects to various cortical and subcortical regions. Thus, the subiculum is uniquely positioned to distribute hippocampal information to a range of brain areas. Subicular neurons fire at higher rates than CA1 neurons and exhibit similarly or more accurately decodable representations of place, speed, and trajectory. These representations are more noise-resistant and advantageous for long-range information transfer. Subicular neurons selectively or uniformly distribute information to target areas, depending on the information type. Theta oscillations and sharp-wave ripples control information broadcasting in a pathway-specific manner. Thus, the subiculum routes accurately decodable, noise-resistant, navigation-associated information to downstream regions.     

Theta rhythms coordinate hippocampal-prefrontal interactions in a spatial memory task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

Group II Metabotropic Glutamate Receptors Depress Synaptic Transmission onto Subicular Burst Firing Neurons

The subiculum (SUB) is a pivotal structure positioned between the hippocampus proper and various cortical and subcortical areas. Despite the growing body of anatomical and intrinsic electrophysiological data of subicular neurons, modulation of synaptic transmission in the SUB is not well understood. In the present study we investigated the role of group II metabotropic glutamate receptors (mGluRs), which have been shown to be involved in the regulation of synaptic transmission by suppressing presynaptic cAMP activity. Using field potential and patch-clamp whole cell recordings we demonstrate that glutamatergic transmission at CA1-SUB synapses is depressed by group II mGluRs in a cell-type specific manner. Application of the group II mGluR agonist (2S,1′R,2′R,3′R)-2-(2, 3-dicarboxycyclopropyl)glycine (DCG-IV) led to a significantly higher reduction of excitatory postsynaptic currents in subicular bursting cells than in regular firing cells. We further used low-frequency stimulation protocols and brief high-frequency bursts to test whether synaptically released glutamate is capable of activating presynaptic mGluRs. However, neither frequency facilitation is enhanced in the presence of the group II mGluR antagonist {"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}}LY341495, nor is a test stimulus given after a high-frequency burst. In summary, we present pharmacological evidence for presynaptic group II mGluRs targeting subicular bursting cells, but both low- and high-frequency stimulation protocols failed to activate presynaptically located mGluRs.     

Theta Rhythms Coordinate Hippocampal–Prefrontal Interactions in a Spatial Memory Task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

A Temporal Mechanism for Generating the Phase Precession of Hippocampal Place Cells

The phase relationship between the activity of hippocampal place cells and the hippocampal theta rhythm systematically precesses as the animal runs through the region in an environment called the place field of the cell. We present a minimal biophysical model of the phase precession of place cells in region CA3 of the hippocampus. The model describes the dynamics of two coupled point neurons—namely, a pyramidal cell and an interneuron, the latter of which is driven by a pacemaker input. Outside of the place field, the network displays a stable, background firing pattern that is locked to the theta rhythm. The pacemaker input drives the interneuron, which in turn activates the pyramidal cell. A single stimulus to the pyramidal cell from the dentate gyrus, simulating entrance into the place field, reorganizes the functional roles of the cells in the network for a number of cycles of the theta rhythm. In the reorganized network, the pyramidal cell drives the interneuron at a higher frequency than the theta frequency, thus causing a systematic precession relative to the theta input. The frequency of the pyramidal cell can vary to account for changes in the animal's running speed. The transient dynamics end after up to 360 degrees of phase precession when the pacemaker input to the interneuron occurs at a phase to return the network to the stable background firing pattern, thus signaling the end of the place field. Our model, in contrast to others, reports that phase precession is a temporally, and not spatially, controlled process. We also predict that like pyramidal cells, interneurons phase precess. Our model provides a mechanism for shutting off place cell firing after the animal has crossed the place field, and it explains the observed nearly 360 degrees of phase precession. We also describe how this model is consistent with a proposed autoassociative memory role of the CA3 region.     

Theta phase coding in a network model of the entorhinal cortex layer II with entorhinal-hippocampal loop connections

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).     

Simulation of the hippocampal theta rhythm

Centre of Theoretical and Computational Neuroscience, University of Plymouth, UK Basing on the hypothesis about the mechanisms of the theta rhythm generation, the article presents mathematical and computational models of theta activity in the hippocampus. The problem of the theta rhythm modeling is nontrivial because the slow theta oscillations (about 5 Hz) should be generated by a neural system composed of frequently firing neural populations. We studied a model of neural pacemakers in the septum. In this model, the pacemaker follows the frequency of the external signal if this frequency does not deviate too far from the natural frequency of the pacemaker, otherwise the pacemaker returns to the frequency of its own oscillations. These results are in agreement with the experimental records of medial septum neurons. Our model of the septal pacemaker of the theta rhythm is based on the hypothesis that the hippocampal theta appears as a result of the influence of the assemblies of neurons in the medial septum which are under control of pacemaker neurons. Though the model of the pacemaker satisfies many experimental facts, the synchronization of activity in different neural assemblies of the model is not as strong as it should be. Another model of the theta generation is based on the anatomical data about the existence of the inhibitory GABAergic loop between the medial septum and the hippocampus. This model shows stable oscillations at the frequency of the theta rhythm in a broad range of parameter values. It also provides explanation to the experimental data about the variation of the frequency and the amplitude of the theta rhythm under different external stimulations of the system. The role of the theta rhythm for information processing in the hippocampus is discussed.     

Spatial representation along the proximodistal axis of CA1

CA1 cells receive direct input from space-responsive cells in medial entorhinal cortex (MEC), such as grid cells, as well as more nonspatial cells in lateral entorhinal cortex (LEC). Because MEC projects preferentially to the proximal part of the CA1, bordering CA2, whereas LEC innervates only the distal part, bordering subiculum, we asked if spatial tuning is graded along the transverse axis of CA1. Tetrodes were implanted along the entire proximodistal axis of dorsal CA1 in rats. Data were recorded in cylinders large enough to elicit firing at more than one location in many neurons. Distal CA1 cells showed more dispersed firing and had a larger number of firing fields than proximal cells. Phase-locking of spikes to MEC theta oscillations was weaker in distal CA1 than in proximal CA1. The findings suggest that spatial firing in CA1 is organized transversally, with the strongest spatial modulation occurring in the MEC-associated proximal part.     

Theta Coordinated Error-Driven Learning in the Hippocampus

The learning mechanism in the hippocampus has almost universally been assumed to be Hebbian in nature, where individual neurons in an engram join together with synaptic weight increases to support facilitated recall of memories later. However, it is also widely known that Hebbian learning mechanisms impose significant capacity constraints, and are generally less computationally powerful than learning mechanisms that take advantage of error signals. We show that the differential phase relationships of hippocampal subfields within the overall theta rhythm enable a powerful form of error-driven learning, which results in significantly greater capacity, as shown in computer simulations. In one phase of the theta cycle, the bidirectional connectivity between CA1 and entorhinal cortex can be trained in an error-driven fashion to learn to effectively encode the cortical inputs in a compact and sparse form over CA1. In a subsequent portion of the theta cycle, the system attempts to recall an existing memory, via the pathway from entorhinal cortex to CA3 and CA1. Finally the full theta cycle completes when a strong target encoding representation of the current input is imposed onto the CA1 via direct projections from entorhinal cortex. The difference between this target encoding and the attempted recall of the same representation on CA1 constitutes an error signal that can drive the learning of CA3 to CA1 synapses. This CA3 to CA1 pathway is critical for enabling full reinstatement of recalled hippocampal memories out in cortex. Taken together, these new learning dynamics enable a much more robust, high-capacity model of hippocampal learning than was available previously under the classical Hebbian model.     

Reduced Threshold for Induction of LTP by Activation of Dopamine D1/D5 Receptors at Hippocampal CA1–Subiculum Synapses

The phasic release of dopamine in the hippocampal formation has been shown to facilitate the encoding of novel information. There is evidence that the subiculum operates as a detector and distributor of sensory information, which incorporates the novelty and relevance of signals received from CA1. The subiculum acts as the final hippocampal relay station for outgoing information. Subicular pyramidal cells have been classified as regular- and burst-spiking neurons. The goal of the present study was to study the effect of dopamine D1/D5 receptor activation on synaptic transmission and plasticity in the subicular regular-spiking neurons of 4–6 week old Wistar rats. We demonstrate that prior activation of D1/D5 receptors reduces the threshold for the induction of long-term potentiation (LTP) in subicular regular-spiking neurons. Our results indicate that D1/D5 receptor activation facilitates a postsynaptic form of LTP in subicular regular-spiking cells that is NMDA receptor-dependent, relies on postsynaptic Ca²⁺ signaling, and requires the activation of protein kinase A. The enhanced propensity of subicular regular-spiking cells to express postsynaptic LTP after activation of D1/D5 receptors provides an intriguing mechanism for the encoding of hippocampal output information.     

Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity

Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.     

The hippocampal-VTA loop: controlling the entry of information into long-term memory

In this article we develop the concept that the hippocampus and the midbrain dopaminergic neurons of the ventral tegmental area (VTA) form a functional loop. Activation of the loop begins when the hippocampus detects newly arrived information that is not already stored in its long-term memory. The resulting novelty signal is conveyed through the subiculum, accumbens, and ventral pallidum to the VTA where it contributes (along with salience and goal information) to the novelty-dependent firing of these cells. In the upward arm of the loop, dopamine (DA) is released within the hippocampus; this produces an enhancement of LTP and learning. These findings support a model whereby the hippocampal-VTA loop regulates the entry of information into long-term memory.     

Independence of the unimodal tuning of firing rate from theta phase precession in hippocampal place cells

There are two prominent features for place cells in rat hippocampus. The firing rate remarkably increases when rat enters the cell’s place field and reaches a maximum around the center of place field, and it decreases when the animal approaches the end of the place field. Simultaneously the spikes gradually and monotonically advance to earlier phase relative to hippocampal theta rhythm as the rat traverses along the cell’s place field, known as temporal coding. In this paper, we investigate whether two main characteristics of place cell firing are independent or not by mainly focusing on the generation mechanism of the unimodal tuning of firing rate by using a reduced CA1 two-compartment neuron model. Based on recent evidences, we hypothesize that the coupling of dendritic with the somatic compartment is not constant but dynamically regulated as the animal moves further along the place field, in contrast to previous two-compartment modeling. Simulations show that the regulable coupling is critically responsible for the generation of unimodal firing rate profile in place cells, independent of phase precession. Predictions of our model accord well with recent observations like occurrence of phase precession with very low as well as high firing rate (Huxter et al. Nature 425:828–832, 2003) and persistency of phase precession after transient silence of hippocampus activity (Zugaro et al. Nat Neurosci 8:67–71, 2005.     

Differential but complementary mnemonic functions of the hippocampus and subiculum

In this study we describe how the hippocampus and subiculum act in concert to encode information in a spatial delayed-nonmatch-to-sample (DNMS) task. This encoding was functionally partitioned between neurons within subiculum and hippocampus to uniquely identify trial-specific information accounting for both spatial and temporal constraints on performance within and between trials. Encoding by subicular neurons in the task was normally accurate and specific, but only if delays were shorter than 15 s, whereas trial-specific information encoded by hippocampal neurons was subject to strong biases from prior trial sequences and was accessible only when delays exceeded 15 s. The two structures operated in a complementary manner to encode information correctly on 75% of all trials using the above strategies. The remaining 25% of trials were at risk due to inherent idiosyncrasies by which hippocampal and subicular neurons encoded information and became errors when the random sequence of trials conflicted with these constraints.     

Phase locking of single neuron activity to theta oscillations during working memory in monkey extrastriate visual cortex

Working memory has been linked to elevated single neuron discharge in monkeys and to oscillatory changes in the human EEG, but the relation between these effects has remained largely unexplored. We addressed this question by measuring local field potentials and single unit activity simultaneously from multiple electrodes placed in extrastriate visual cortex while monkeys were performing a working memory task. We describe a significant enhancement in theta band energy during the delay period. Theta oscillations had a systematic effect on single neuron activity, with neurons emitting more action potentials near their preferred angle of each theta cycle. Sample-selective delay activity was enhanced if only action potentials emitted near the preferred theta angle were considered. Our results suggest that extrastriate visual cortex is involved in short-term maintenance of information and that theta oscillations provide a mechanism for structuring the recurrent interaction between neurons in different brain regions that underlie working memory.     

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.