Hippocampal Neural Activity Research Articles

Hippocampal synaptic and neural network deficits in young mice carrying the human APOE4 gene

Apolipoprotein E4 (APOE4)is a major genetic risk factor for late-onset sporadic Alzheimer disease. Emerging evidence demonstrates a hippocampus-associated learning and memory deficit in aged APOE4 human carriers and also in aged mice carrying human APOE4 gene. This suggests that either exogenous APOE4 or endogenous APOE4 alters the cognitive profile and hippocampal structure and function. However, little is known regarding how Apoe4 modulates hippocampal dendritic morphology, synaptic function, and neural network activity in young mice. In this study, we compared hippocampal dendritic and spine morphology and synaptic function of young (4months) mice with transgenic expression of the human APOE4 and APOE3 genes. Hippocampal dendritic and spine morphology and synaptic function were assessed by neuronal imaging and electrophysiological approaches. Morphology results showed that shortened dendritic length and reduced spine density occurred at hippocampal CA1 neurons in Apoe4 mice compared to Apoe3 mice. Electrophysiological results demonstrated that in the hippocampal CA3-CA1 synapses of young Apoe4 mice, basic synaptic transmission, and paired-pulse facilitation were enhanced but long-term potentiation and carbachol-induced hippocampal theta oscillations were impaired compared to young Apoe3 mice. However, both Apoe genotypes responded similarly to persistent stimulations (4, 10, and 40Hz for 4seconds). Our results suggest significant alterations in hippocampal dendritic structure and synaptic function in Apoe4 mice, even at an early age.

Predicting the stimulation effectiveness using pre-stimulation neural states via optogenetic activation of the medial septum glutamatergic neurons modulating the hippocampal neural activity.

In this study, we explored the role of pre-stimulation neural states on the effectiveness of optogenetic stimulation. Optogenetic stimulation was applied to the medial septum glutamatergic neurons to modulate the hippocampal neural activity in a rat tetanus toxin seizure model. The hippocampal local field potential was recorded using a multi electrode array in an awake and behaving rat. Optical stimulation with a 465nm light source was applied at 35Hz in a 20 seconds off / 20 seconds on pattern with simultaneous recording from the hippocampus. Both the baseline and the stimulation period recordings were divided into 2 second segments and used for the further analysis. In the first experiment, a support vector machine (SVM) model classified the neural states by using spectral features between 0 and 50Hz. 447 out of 545 segments (82.02%) were correctly labeled as `Baseline' while only 326 out of 544 (59.93%) segments from the stimulation period were correctly labeled as `Stimulation.' As the ratio of mislabels is significantly higher for the stimulation period (chi-squared, p<;0.01), we concluded that the stimulation was not always effective. In the second experiment, an SVM model predicted the stimulation effectiveness using the spectral features of the pre-stimulation segments. The classification result shows that 63.7% of the pre-stimulation segments correctly predicted the stimulation effectiveness. These findings suggest that the prediction of the stimulation effectiveness may improve the stimulation efficacy by implementing a state-based stimulation protocol.

Theta-paced flickering between place-cell maps in the hippocampus: A model based on short-term synaptic plasticity.

Hippocampal place cells represent different environments with distinct neural activity patterns. Following an abrupt switch between two familiar configurations of visual cues defining two environments, the hippocampal neural activity pattern switches almost immediately to the corresponding representation. Surprisingly, during a transient period following the switch to the new environment, occasional fast transitions between the two activity patterns (flickering) were observed (Jezek, Henriksen, Treves, Moser, & Moser, 2011). Here we show that an attractor neural network model of place cells with connections endowed with short‐term synaptic plasticity can account for this phenomenon. A memory trace of the recent history of network activity is maintained in the state of the synapses, allowing the network to temporarily reactivate the representation of the previous environment in the absence of the corresponding sensory cues. The model predicts that the number of flickering events depends on the amplitude of the ongoing theta rhythm and the distance between the current position of the animal and its position at the time of cue switching. We test these predictions with new analysis of experimental data. These results suggest a potential role of short‐term synaptic plasticity in recruiting the activity of different cell assemblies and in shaping hippocampal activity of behaving animals.

Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition.

We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, that is, deficient GABA transmission, within the prefrontal cortex and the hippocampus, for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico-hippocampal neural activity, and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age-related cognitive decline. Regional neural disinhibition, disrupting spatio-temporal control of neural activity and causing aberrant drive of projections, may disrupt processing within the disinhibited region and efferent regions. Recent studies in rats showed that prefrontal and hippocampal neural disinhibition (by local GABA antagonist microinfusion) dysregulates burst firing, which has been associated with important aspects of neural information processing. Using translational tests of clinically relevant cognitive functions, these studies showed that prefrontal and hippocampal neural disinhibition disrupts regional cognitive functions (including prefrontal attention and hippocampal memory function). Moreover, hippocampal neural disinhibition disrupted attentional performance, which does not require the hippocampus but requires prefrontal-striatal circuits modulated by the hippocampus. However, some prefrontal and hippocampal functions (including inhibitory response control) are spared by regional disinhibition. We consider conceptual implications of these findings, regarding the distinct relationships of distinct cognitive functions to prefrontal and hippocampal GABA tone and neural activity. Moreover, the findings support the proposition that prefrontal and hippocampal neural disinhibition contributes to clinically relevant cognitive deficits, and we consider pharmacological strategies for ameliorating cognitive deficits by rebalancing disinhibition-induced aberrant neural activity. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Hippocampal fractional amplitude of low-frequency fluctuation and functional connectivity changes in premenstrual syndrome.

To investigate differences in hippocampal activity between premenstrual syndrome (PMS) patients and healthy controls, to elucidate the neural mechanisms of PMS. Twenty female patients with PMS (PMS group) and 21 healthy controls (HC group) underwent a single-shot gradient-recalled echo planar imaging (EPI) sequence scan during the luteal phase in 3.0 Tesla MRI. Spontaneous neural activity in hippocampus (HIPP) was measured by fractional amplitude of low-frequency fluctuation (fALFF). Functional connectivity (FC) was used to examine the neural networks of PMS patients by selecting the abnormal HIPP as the seed region. All participants completed a daily record of severity of problems (DRSP) questionnaire to measure the severity of clinical symptoms. Results from a two-sample t-test showed increased left HIPP fALFF in the PMS group compared with the HC group (P = 0.042), while there was no between-group difference of fALFF in the right HIPP (P = 0.1011). A secondary analysis using a two-sample t-test with the left HIPP as the seed region, the results revealed that the PMS group exhibited increased FC between the left HIPP and left medial prefrontal cortex (mPFC), left posterior cingulate cortex (PCC), right middle cingulate cortex (MCC), and bilateral precentral cortex (PC), while decreased FC between the left HIPP and right orbitofrontal cortex (OFC). Moreover, the PMS group exhibited higher DRSP scores, which were positively correlated (r = 0.64, P = 0.003) with FC between the left HIPP and mPFC during the luteal phase. Altered spontaneous neural activity and connectivity of left HIPP may be involved in PMS. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:545-553.

Vocal Tract Images Reveal Neural Representations of Sensorimotor Transformation During Speech Imitation.

Imitating speech necessitates the transformation from sensory targets to vocal tract motor output, yet little is known about the representational basis of this process in the human brain. Here, we address this question by using real-time MR imaging (rtMRI) of the vocal tract and functional MRI (fMRI) of the brain in a speech imitation paradigm. Participants trained on imitating a native vowel and a similar nonnative vowel that required lip rounding. Later, participants imitated these vowels and an untrained vowel pair during separate fMRI and rtMRI runs. Univariate fMRI analyses revealed that regions including left inferior frontal gyrus were more active during sensorimotor transformation (ST) and production of nonnative vowels, compared with native vowels; further, ST for nonnative vowels activated somatomotor cortex bilaterally, compared with ST of native vowels. Using test representational similarity analysis (RSA) models constructed from participants’ vocal tract images and from stimulus formant distances, we found that RSA searchlight analyses of fMRI data showed either type of model could be represented in somatomotor, temporal, cerebellar, and hippocampal neural activation patterns during ST. We thus provide the first evidence of widespread and robust cortical and subcortical neural representation of vocal tract and/or formant parameters, during prearticulatory ST.

Hippocampal neural activity reflects the economy of choices during goal-directed navigation.

Distinguishing spatial contexts is likely essential for the well-known role of the hippocampus in episodic memory. We studied whether types of hippocampal neural organization thought to underlie context discrimination are impacted by learned economic considerations of choice behavior. Hippocampal place cells and theta activity were recorded as rats performed a maze-based probability discounting task that involved choosing between a small certain reward or a large probabilistic reward. Different spatial distributions of place fields were observed in response to changes in probability, the outcome of the rats' choice, and whether or not rats were free to make that choice. The degree to which the reward location was represented by place cells scaled with the expected probability of rewards. Theta power increased around the goal location also in proportion to the expected probability of signaled rewards. Furthermore, theta power dynamically varied as specific econometric information was obtained "on the fly" during task performance. Such an economic perspective of memory processing by hippocampal place cells expands our view of the nature of context memories retrieved by hippocampus during adaptive navigation.

The role of the hippocampus in navigation is memory.

There is considerable research on the neurobiological mechanisms within the hippocampal system that support spatial navigation. In this article I review the literature on navigational strategies in humans and animals, observations on hippocampal function in navigation, and studies of hippocampal neural activity in animals and humans performing different navigational tasks and tests of memory. Whereas the hippocampus is essential to spatial navigation via a cognitive map, its role derives from the relational organization and flexibility of cognitive maps and not from a selective role in the spatial domain. Correspondingly, hippocampal networks map multiple navigational strategies, as well as other spatial and nonspatial memories and knowledge domains that share an emphasis on relational organization. These observations suggest that the hippocampal system is not dedicated to spatial cognition and navigation, but organizes experiences in memory, for which spatial mapping and navigation are both a metaphor for and a prominent application of relational memory organization.

Network mechanisms of hippocampal laterality, place coding, and goal-directed navigation.

The hippocampus and associated structures are responsible for episodic memory in humans. In rodents, the most prominent behavioral correlate of hippocampal neural activity is place coding, which is thought to underlie spatial navigation. While episodic memory is considered to be unique to humans in a restricted context, it has been proposed that the same neural circuitry and algorithms that enable spatial coding and navigation also support episodic memory. Here we review the recent progress in neural circuit mechanisms of hippocampal activity by introducing several topics: (1) cooperation and specialization of the bilateral hippocampi, (2) the role of synaptic plasticity in gamma phase-locking of spikes and place cell formation, (3) impaired goal-related activity and oscillations in a mouse model of mental disorders, and (4) a prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation.

Scoring sequences of hippocampal activity using hidden Markov models.

We propose a novel sequence score to determine to what extent neural activity is consistent with trajectories through latent ensemble states - virtual place fields - in an associated environment. In particular, we show how hidden Markov models (HMMs) can be used to model and analyze sequences of neural activity, and how the resulting joint probability of an observation sequence and an underlying sequence of states naturally lead to the development of a two component sequence score in which the sequential and contextual information are decoupled. We also show how this score can discriminate between true and shuffled sequences of hippocampal neural activity.

Effect of Acute Ethanol Administration on the Hippocampal Region Neural Activity Using a Microelectrode Array.

Because acute ethanol (EtOH) administration is known to influence cognitive processes by impairing hippocampal function, electrophysiological responses of the hippocampus following EtOH exposure warrant investigation. To mimic invivo conditions, we recorded and analyzed critical firing characteristics of the neuronal population dynamically, particularly in the hippocampal region, before and after acute EtOH administration. Microelectrodes were inserted in the hippocampus CA1 region of 21 Institute of Cancer Research mice. The mice were divided into 3 groups, including an EtOH injection group (1.5g/kg), a saline injection group (1.5g/kg), and a negative control group that received no injection. A data acquisition system was employed to detect the local field potentials (LFPs) and spike potentials following acute EtOH administration. Various multichannel electrophysiological signals were collected invivo in each group at 60minutes, from which the firing rate and wavelet entropy (WE) were analyzed further. Firing rates began to decline at 20 minutes postinjection and then gradually recovered from 40 to 60 minutes. In contrast, 20minutes post-injection, WE increased maximally and then returned to normal from 40 to 60minutes (p<0.05). Pronounced changes in the relative energy of theta and alpha oscillations were also observed after 20minutes of alcohol exposure and recovery occurred by 60minutes (p<0.05). A major mechanism of EtOH's action on the hippocampus is neurotransmitter blocking in the form of excitatory neuron inhibition invivo. Changes in hippocampal spikes coincided with changes in LFPs during the entire time course of acute EtOH administration. The correlation between spikes and LFPs suggests that they jointly affect encoding in hippocampus.

What Versus Where: Non-spatial Aspects of Memory Representation by the Hippocampus.

Since the discovery of place cells and other findings indicating strong involvement of the hippocampus in spatial information processing, there has been continued controversy about the extent to which the hippocampus also processes non-spatial aspects of experience. In recent years, many experiments studying the effects of hippocampal damage and characterizing hippocampal neural activity in animals and humans have revealed a clear and specific role of the hippocampus in the processing of non-spatial information. Here this evidence is reviewed in support of the notion that the hippocampus organizes the contents of memory in space, in time, and in networks of related memories.

The hippocampus

The hippocampus

Does the hippocampus preplay memories?

Previous studies have reported 'preplay' of hippocampal neural activity patterns associated with events yet to occur. Silva et al. challenge this finding on the basis of large-scale recordings before and after experiences.

Enzymatic Depletion of the Polysialic Acid Moiety Associated with the Neural Cell Adhesion Molecule Inhibits Antidepressant Efficacy.

Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic-pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy.

A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.

BackgroundA converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling.ResultsHere, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.ConclusionsOur study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

Clusterless Decoding of Position from Multiunit Activity Using a Marked Point Process Filter.

Point process filters have been applied successfully to decode neural signals and track neural dynamics. Traditionally these methods assume that multiunit spiking activity has already been correctly spike-sorted. As a result, these methods are not appropriate for situations where sorting cannot be performed with high precision, such as real-time decoding for brain-computer interfaces. Because the unsupervised spike-sorting problem remains unsolved, we took an alternative approach that takes advantage of recent insights into clusterless decoding. Here we present a new point process decoding algorithm that does not require multiunit signals to be sorted into individual units. We use the theory of marked point processes to construct a function that characterizes the relationship between a covariate of interest (in this case, the location of a rat on a track) and features of the spike waveforms. In our example, we use tetrode recordings, and the marks represent a four-dimensional vector of the maximum amplitudes of the spike waveform on each of the four electrodes. In general, the marks may represent any features of the spike waveform. We then use Bayes's rule to estimate spatial location from hippocampal neural activity. We validate our approach with a simulation study and experimental data recorded in the hippocampus of a rat moving through a linear environment. Our decoding algorithm accurately reconstructs the rat's position from unsorted multiunit spiking activity. We then compare the quality of our decoding algorithm to that of a traditional spike-sorting and decoding algorithm. Our analyses show that the proposed decoding algorithm performs equivalent to or better than algorithms based on sorted single-unit activity. These results provide a path toward accurate real-time decoding of spiking patterns that could be used to carry out content-specific manipulations of population activity in hippocampus or elsewhere in the brain.

Enhancement of long-term potentiation via muscarinic modulation in the hippocampus of HCNP precursor transgenic mice

Hippocampal cholinergic neurostimulating peptide (HCNP) regulates acetylcholine synthesis in the septal hippocampus through the quantitative increase of choline acetyltransferase levels in the septal nucleus both in vitro and in vivo. Additionally, HCNP-precursor protein transgenic (HCNP-pp Tg) mice display depressive behavior. To examine the physiological function of HCNP and/or HCNP-pp on hippocampal neural activity, we investigated whether overexpression of HCNP-pp strengthened the efficiency of neural activity in the hippocampus. Long-term potentiation (LTP) of excitatory synaptic transmission was induced by a tetanic stimulation of the Schaffer collateral-commissural fibers (SCs) in mouse hippocampal slices. LTP in HCNP-pp Tg mice was significantly enhanced when compared with wild-type littermate (WT) mice. This facilitation of LTP in HCNP-pp Tg mice was blocked by atropine or pirenzepine, but not by mecamylamine. In contrast, LTP in WT mice was not affected by atropine, but enhanced by carbachol. However, neither difference in the input–output relationship of field excitatory postsynaptic potentials nor in the facilitation ratio in paired-pulse stimulation of the SCs was observed between HCNP-pp Tg and WT mice, indicating that presynaptic glutamate release in HCNP-pp Tg mice is similar to that of WT mice. These results suggest that muscarinic (M1) modulation of glutamatergic postsynaptic function may be involved in strengthening LTP in HCNP-pp Tg mice.

Relationship between hippocampal CA1 neuronal and sympathetic nerve activity during fear conditioning in rats

The hippocampus has been implicated in the emotional responses of sympathetic nerve activity (SNA) to fear. However, there is a lack of direct evidence of the changes in hippocampal neuronal activity and SNA and on the functional relationships between these activities during the fear response. The aim of the present study was to measure the relationship between hippocampal neuronal activity and SNA during fear conditioning. Male Wistar rats were chronically implanted with multiple electrodes to monitor hippocampal CA1 neuronal activity, and bipolar electrodes to monitor renal SNA (RSNA) and lumbar SNA (LSNA). Electroencephalography was performed. Each rat was given a 5‐s tone terminating with a 1‐s, 5‐mA foot shock twice a day over 3 days. Hippocampal CA1 neuronal activity, RSNA, and LSNA were measured simultaneously during the quiet awake state in the rat's own cage. Heart rate decreased during the 3‐day fear conditioning. Hippocampal CA1 neuronal activity and RSNA increased, while LSNA decreased during the 3‐day fear conditioning. These data suggest that there is a positive neuronal coupling between hippocampal neural activity and RSNA during fear conditioning in rats. JSPS Grant.

The electrical activity of hippocampal pyramidal neuron is subjected to descending control by the brain orexin/hypocretin system

The hippocampus receives sparse orexinergic innervation from the lateral hypothalamus and expresses a high level of orexin receptor. The function of orexin receptor in the regulation of hippocampal neural activity has never been investigated. In this study, in vivo single unit recording was performed in urethane-anesthetized rats. After 15min of baseline recording from pyramidal neuron within the CA1 region of the dorsal hippocampus, i.c.v. injection of orexin-A 0.5nmol, SB334867 400nmol, a selective orexin receptor 1 antagonist, saline, or DMSO, or microinjection of carbachol 250nmol or saline into the ipsilateral lateral hypothalamus were performed using a Hamilton microsyringe, and the spontaneous firing activity continued to be recorded for 25min. Results showed that orexin administration into the lateral cerebral ventricle excited 6 out of 8 neurons and inhibited 1 neuron. Chemical stimulation of the lateral hypothalamus by carbachol excited 9 out of 13 hippocampal neurons and inhibited 3 neurons. On the other hand, i.c.v. injection of the SB334867, caused reductions in the firing activity of 6 out of 10 neurons and increases in 4 additional neurons. It seems that orexin neurotransmission in the hippocampus mostly elicits an excitatory response, whereas blockade of orexin receptor has an inhibitory effect. Further studies need to be done to elucidate the underlying mechanism of orexin action on hippocampal neurons.