Hippocampal Network Dynamics Research Articles

Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry

Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider.

Quantitative assessment of hippocampal network dynamics by combining Voltage Sensitive Dye Imaging and Optimal Transportation Theory

Quantitative assessment of hippocampal network dynamics by combining Voltage Sensitive Dye Imaging and Optimal Transportation Theory

Cortical and thalamic inputs drive distinct hippocampal microcircuits to modulate synchronized activity during development

Synchronized activity, a hallmark of hippocampal network dynamics, appears early during development. Whether extrinsic inputs drive such activity remains unknown. In this issue of Neuron, Leprince etal.1 show that synchronized activity, while modulated by both cortical and thalamic inputs exvivo, depends solely on cortical inputs invivo.

CA2 orchestrates hippocampal network dynamics.

The hippocampus is composed of various subregions: CA1, CA2, CA3, and the dentate gyrus (DG). Despite the abundant hippocampal research literature, until recently, CA2 received little attention. The development of new genetic and physiological tools allowed recent studies characterizing the unique properties and functional roles of this hippocampal subregion. Despite its small size, the cellular content of CA2 is heterogeneous at the molecular and physiological levels. CA2 has been heavily implicated in social behaviors, including social memory. More generally, the mechanisms by which the hippocampus is involved in memory include the reactivation of neuronal ensembles following experience. This process is coordinated by synchronous network events known as sharp-wave ripples (SWRs). Recent evidence suggests that CA2 plays an important role in the generation of SWRs. The unique connectivity and physiological properties of CA2 pyramidal cells make this region a computational hub at the core of hippocampal information processing. Here, we review recent findings that support the role of CA2 in coordinating hippocampal network dynamics from a systems neuroscience perspective.

Preconfigured dynamics in the hippocampus are guided by embryonic birthdate and rate of neurogenesis.

The incorporation of new information into the hippocampal network is likely to be constrained by its innate architecture and internally generated activity patterns. However, the origin, organization and consequences of such patterns remain poorly understood. In the present study we show that hippocampal network dynamics are affected by sequential neurogenesis. We birthdated CA1 pyramidal neurons with in utero electroporation over 4 embryonic days, encompassing the peak of hippocampal neurogenesis, and compared their functional features in freely moving adult mice. Neurons of the same birthdate displayed distinct connectivity, coactivity across brain states and assembly dynamics. Same-birthdate neurons exhibited overlapping spatial representations, which were maintained across different environments. Overall, the wiring and functional features of CA1 pyramidal neurons reflected a combination of birthdate and the rate of neurogenesis. These observations demonstrate that sequential neurogenesis during embryonic development shapes the preconfigured forms of adult network dynamics.

Common network effect-patterns after monoamine reuptake inhibition in dissociated hippocampus cultures

The pharmacological treatment of major depressive disorder with currently available antidepressant drugs is still unsatisfying as response to medication is delayed and in some patients even non-existent. To understand complex psychiatric diseases such as major depressive disorder and their treatment, research focus is shifting from investigating single neurons towards a view of the entire functional and effective neuronal network, because alterations on single synapses through antidepressant drugs may translate to alterations in the entire network. Here, we examined the effects of monoamine reuptake inhibitors on in vitro hippocampal network dynamics using calcium fluorescence imaging and analyzing the data with means of graph theoretical parameters. Hypothesizing that monoamine reuptake inhibitors operate through changes of effective connectivity on micro-scale neuronal networks, we measured the effects of the selective monoamine reuptake inhibitors GBR-12783, Sertraline, Venlafaxine, and Amitriptyline on neuronal networks. We identified a common pattern of effects of the different tested monoamine reuptake inhibitors. After treatment with GBR-12783, Sertraline, and Venlafaxine, the connectivity degree, measuring the number of existing connections in the network, was significantly decreased. All tested substances led to networks with more submodules and a reduced global efficiency. No monoamine reuptake inhibitor did affect network-wide firing rate, the characteristic path length, or the network strength. In our study, we found that monoamine reuptake inhibition in neuronal networks in vitro results in a sharpening of the network structure. These alterations could be the basis for the reorganization of a large-scale miswired network in major depressive disorder.

Ablation of p75NTR signaling strengthens gamma\u2013theta rhythm interaction and counteracts A\u03b2-induced degradation of neuronal dynamics in mouse hippocampus in vitro

Gamma and theta brain rhythms play important roles in cognition and their interaction can affect gamma oscillation features. Hippocampal theta oscillations depend on cholinergic and GABAergic input from the medial septum-diagonal band of Broca. These projecting neurons undergo degeneration during aging and maintain high levels of neurotrophin receptor p75 (p75NTR). p75NTR mediates both apoptosis and survival and its expression is increased in Alzheimer’s disease (AD) patients. Here, we investigate the importance of p75NTR for the cholinergic input to the hippocampus. Performing extracellular recordings in brain slices from p75NTR knockout mice (p75−/−) in presence of the muscarinic agonist carbachol, we find that gamma oscillation power and rhythmicity are increased compared to wild-type (WT) mice. Furthermore, gamma activity is more phase-locked to the underlying theta rhythm, which renders a stronger coupling of both rhythms. On the cellular level, we find that fast-spiking interneurons (FSNs) fire more synchronized to a preferred gamma phase in p75−/− mice. The excitatory input onto FSN is more rhythmic displaying a higher similarity with the concomitant gamma rhythm. Notably, the ablation of p75NTR counteracts the Aβ-induced degradation of gamma oscillations and its nesting within the underlying theta rhythm. Our results show that the lack of p75NTR signaling could promote stronger cholinergic modulation of the hippocampal gamma rhythm, suggesting an involvement of p75NTR in the downregulation of cognition-relevant hippocampal network dynamics in pathologies. Moreover, functional data provided here suggest p75NTR as a suitable target in the search for efficacious treatments to counteract the loss of cognitive function observed in amyloid-driven pathologies such as AD.

Anesthetics fragment hippocampal network activity, alter spine dynamics, and affect memory consolidation.

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging, and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all 3 anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

A limited role of NKCC1 in telencephalic glutamatergic neurons for developing hippocampal network dynamics and behavior

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical, and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in vitro excitatory actions of γ-aminobutyric acid (GABA) and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics, and behavioral performance are subtle. Our data reveal a neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

Preexisting hippocampal network dynamics constrain optogenetically induced place fields

Memory models often emphasize the need to encode novel patterns of neural activity imposed by sensory drive. Prior learning and innate architecture likely restrict neural plasticity, however. Here, we test how the incorporation of synthetic hippocampal signals is constrained by preexisting circuit dynamics. We optogenetically stimulated small groups of CA1 neurons as mice traversed a chosen segment of a linear track, mimicking the emergence of place fields. Stimulation induced persistent place field remapping in stimulated and non-stimulated neurons. The emergence of place fields could be predicted from sporadic firing in the new place field location and the temporal relationship to peer neurons before the optogenetic perturbation. Circuit modification was reflected by altered spike transmission between connected pyramidal cells and inhibitory interneurons, which persisted during post-experience sleep. We hypothesize that optogenetic perturbation unmasked sub-threshold place fields. Plasticity in recurrent/lateral inhibition may drive learning through the rapid association of existing states.

Amygdala Stimulation Leads to Functional Network Connectivity State Transitions in the Hippocampus.

Several studies have shown that direct brain stimulation can enhance memory in humans and animal models. Investigating the neurophysiological changes induced by brain stimulation is an important step towards understanding the neural processes underlying memory function. Furthermore, it paves the way for developing more efficient neuromodulation approaches for memory enhancement. In this study, we utilized a combination of unsupervised and supervised machine learning approaches to investigate how amygdala stimulation modulated hippocampal network activities during the encoding phase. Using a sliding window in time, we estimated the hippocampal dynamic functional network connectivity (dFNC) after stimulation and during sham trials, based on the covariance of local field potential recordings in 4 subregions of the hippocampus. We extracted different network states by combining the dFNC samples from 5 subjects and applying k-means clustering. Next, we used the between-state transition numbers as the latent features to classify between amygdala stimulation and sham trials across all subjects. By training a logistic regression model, we could differentiate stimulated from sham trials with 67% accuracy across all subjects. Using elastic net regularization as a feature selection method, we identified specific patterns of hippocampal network state transition in response to amygdala stimulation. These results offer a new approach to better understanding of the causal relationship between hippocampal network dynamics and memory-enhancing amygdala stimulation.

Hippocampal Network Dynamics during Rearing Episodes

SummaryAnimals build a model of their surroundings on the basis of information gathered during exploration. Rearing on the hindlimbs changes the vantage point of the animal, increasing the sampled area of the environment. This environmental knowledge is suggested to be integrated into a cognitive map stored by the hippocampus. Previous studies have found that damage to the hippocampus impairs rearing. Here, we characterize the operational state of the hippocampus during rearing episodes. We observe an increase of theta frequency paralleled by a sink in the dentate gyrus and a prominent theta-modulated fast gamma transient in the middle molecular layer. On the descending phase of rearing, a decrease of theta power is detected. Place cells stop firing during rearing, while a different subset of putative pyramidal cells is activated. Our results suggest that the hippocampus switches to a different operational state during rearing, possibly to update spatial representation with information from distant sources.

Recent Advancements in Understanding Hippocampal Functions

The hippocampal formation located in the medial temporal lobe of the brain has been studied extensively for several decades, both in in vitro slice preparations and in vivo living animals. Recent advancements in large-scale recording techniques, such as multisite silicon probes and tetrodes, enable us to examine the detailed characteristics of temporal spiking patterns of tens or hundreds of neurons in the hippocampal circuit. Here, we introduce how such tools contribute to our understanding of the hippocampal network dynamics and review several hippocampal functions for information processing in the brain, including pattern separation and completion, spatial representation, and encoding of positive and negative valence.

Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice

Amyloid-β (Aβ) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of α7 nicotinic acetylcholine receptors (α7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that α7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between Aβ and α7 nAChRs have been observed, implying that high levels of Aβ may modify the effects of α7 nAChR agonists. Therefore, we tested the α7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old Aβ overproducing 5xFAD mice in an in vivo neurophysiological assay with a high construct and predictive validity for testing procognitive drugs. By recording changes in brainstem-stimulation–elicited hippocampal oscillations, we identified previously undescribed neurophysiological impairments in 5xFAD mice, including significantly decreased power of theta and gamma oscillations and theta-phase–gamma-amplitude coupling. Compared with their saline controls, systemically administered FRM-17874 significantly increased stimulation-induced theta power by 30% in both 5xFAD and wild-type mice. However, FRM-17874 did not impact gamma oscillation or theta-phase–gamma-amplitude coupling in either wild type or 5xFAD mice, and it did not eliminate the significant differences in these parameters between the 2 groups.

Microelectrode array analysis of hippocampal network dynamics following theta-burst stimulation via current source density reconstruction by Gaussian interpolation

BackgroundMultielectrode arrays (MEAs) have been used to understand electrophysiological network dynamics by recording real-time activity in groups of cells. The extent to which the collection of such data enables hypothesis testing on the level of circuits and networks depends largely on the sophistication of the analyses applied. New methodWe studied the systemic temporal variations of endogenous signaling within an organotypic hippocampal network following theta-burst stimulation (TBS) to the Schaffer collateral-commissural pathways. The recovered current source density (CSD) information from the raw grid of extracellular potentials by using a Gaussian interpolation method increases spatial resolution and avoids border artifacts by numerical differentials. ResultsWe compared total sink and source currents in DG, CA3, and CA1; calculated accumulated correlation coefficients to compare pre- with post-stimulation CSD dynamics in each region; and reconstructed functional connectivity maps for regional cross-correlations with respect to temporal CSD variations. The functional connectivity maps for potential correlations pre- and post-TBS were compared to investigate the neural network as a whole, revealing differences post-TBS. Comparison with existing method(s)Previous MEA work on plasticity in hippocampal evoked potentials has focused on synchronicity across the hippocampus within isolated subregions. Such analyses ignore the complex relationships among diverse components of the hippocampal circuitry, thus failing to capture network-level behaviors integral to understanding hippocampal function. ConclusionsThe proposed method of recovering current source density to examine whole-hippocampal function is sensitive to experimental manipulation and is worth further examination in the context of network-level analyses of neural signaling.

Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence

Here we found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain neurons in mice exploring novel environments enhanced the reactivation of pyramidal cell assemblies during subsequent sleep/rest. When applied during spatial learning of new goal locations, dopaminergic photostimulation improved the later recall of neural representations of space and stabilized memory performance. These findings reveal that midbrain dopaminergic neurons promote hippocampal network dynamics associated with memory persistence.

Optogenetically Induced Seizure and the Longitudinal Hippocampal Network Dynamics

Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons. However, our current understanding of seizure dynamics is still limited. Here we propose a novel in vivo model of seizure-like afterdischarges using optogenetics, and report on investigation of directional network dynamics during seizure along the septo-temporal (ST) axis of hippocampus. Repetitive pulse photostimulation was applied to the rodent hippocampus, in which channelrhodopsin-2 (ChR2) was expressed, under simultaneous recording of local field potentials (LFPs). Seizure-like afterdischarges were successfully induced after the stimulation in both W-TChR2V4 transgenic (ChR2V-TG) rats and in wild type rats transfected with adeno-associated virus (AAV) vectors carrying ChR2. Pulse frequency at 10 and 20 Hz, and a 0.05 duty ratio were optimal for afterdischarge induction. Immunohistochemical c-Fos staining after a single induced afterdischarge confirmed neuronal activation of the entire hippocampus. LFPs were recorded during seizure-like afterdischarges with a multi-contact array electrode inserted along the ST axis of hippocampus. Granger causality analysis of the LFPs showed a bidirectional but asymmetric increase in signal flow along the ST direction. State space presentation of the causality and coherence revealed three discrete states of the seizure-like afterdischarge phenomenon: 1) resting state; 2) afterdischarge initiation with moderate coherence and dominant septal-to-temporal causality; and 3) afterdischarge termination with increased coherence and dominant temporal-to-septal causality. A novel in vivo model of seizure-like afterdischarge was developed using optogenetics, which was advantageous in its reproducibility and artifact-free electrophysiological observations. Our results provide additional evidence for the potential role of hippocampal septo-temporal interactions in seizure dynamics in vivo. Bidirectional networks work hierarchically along the ST hippocampus in the genesis and termination of epileptic seizures.

Hippocampal Network Dynamics Constrain the Time Lag between Pyramidal Cells across Modified Environments

The hippocampus provides a spatial map of the environment. Changes in the environment alter the firing patterns of hippocampal neurons, but are presumably constrained by elements of the network dynamics. We compared the neural activity in CA1 and CA3 regions of the hippocampus in rats running for water reward on a linear track, before and after the track length was shortened. A fraction of cells lost their place fields and new sets of cells with fields emerged, indicating distinct representation of the two tracks. Cells active in both environments shifted their place fields in a location-dependent manner, most notably at the beginning and the end of the track. Furthermore, peak firing rates and place-field sizes decreased, whereas place-field overlap and coactivity increased. Power in the theta-frequency band of the local field potentials also decreased in both CA1 and CA3, along with the coherence between the two structures. In contrast, the theta-scale (0-150 ms) time lags between cell pairs, representing distances on the tracks, were conserved, and the activity of the inhibitory neuron population was maintained across environments. We interpret these observations as reflecting the freedoms and constraints of the hippocampal network dynamics. The freedoms permit the necessary flexibility for the network to distinctly represent unique patterns, whereas the dynamics constrain the speed at which activity propagates between the cell assemblies representing the patterns.

Cholinergic suppression of glutamatergic synaptic transmission in hippocampal region CA3 exhibits laminar selectivity: Implication for hippocampal network dynamics

Acetylcholine may help set the dynamics within neural systems to facilitate the learning of new information. Neural models have shown that if new information is encoded at the same time as retrieval of existing information that is already stored, the memories will interfere with each other. Structures such as the hippocampus have a distinct laminar organization of inputs that allows this hypothesis to be tested. In region CA1 of the rat (Sprague Dawley) hippocampus, the cholinergic agonist carbachol (CCh) suppresses transmission in stratum radiatum (SR), at synapses of the Schaffer collateral projection from CA3, while having lesser effects in stratum lacunosum-moleculare (SLM), the perforant path projection from entorhinal cortex ( Hasselmo and Schnell, 1994). The current research extends support of this selectivity by demonstrating laminar effects in region CA3. CCh caused significantly greater suppression in SR than in SLM at low concentrations, while the difference in suppression was not significant at higher concentrations. Differences in paired-pulse facilitation suggest presynaptic inhibition substantially contributes to the suppression and is highly concentration and stratum dependent. This selective suppression of the recurrent excitation would be appropriate to set CA3 dynamics to prevent runaway modification of the synapses of excitatory recurrent collaterals by reducing the influence of previously stored associations and allowing incoming information from the perforant path to have a predominant influence on neural activity.