Hippocampal Local Field Potentials Research Articles

Cholinergic modulation of hippocampal calcium activity across the sleep-wake cycle.

Calcium is a critical second messenger in neurons that contributes to learning and memory, but how the coordination of action potentials of neuronal ensembles with the hippocampal local field potential (LFP) is reflected in dynamic calcium activity remains unclear. Here, we recorded hippocampal calcium activity with endoscopic imaging of the genetically encoded fluorophore GCaMP6 with concomitant LFP in freely behaving mice. Dynamic calcium activity was greater in exploratory behavior and REM sleep than in quiet wakefulness and slow wave sleep, behavioral states that differ with respect to theta and septal cholinergic activity, and modulated at sharp wave ripples (SWRs). Chemogenetic activation of septal cholinergic neurons expressing the excitatory hM3Dq DREADD increased calcium activity and reduced SWRs. Furthermore, inhibition of muscarinic acetylcholine receptors (mAChRs) reduced calcium activity while increasing SWRs. These results demonstrate that hippocampal dynamic calcium activity depends on behavioral and theta state as well as endogenous mAChR activation.

Discrete Structure of the Brain Rhythms

Neuronal activity in the brain generates synchronous oscillations of the Local Field Potential (LFP). The traditional analyses of the LFPs are based on decomposing the signal into simpler components, such as sinusoidal harmonics. However, a common drawback of such methods is that the decomposition primitives are usually presumed from the onset, which may bias our understanding of the signal’s structure. Here, we introduce an alternative approach that allows an impartial, high resolution, hands-off decomposition of the brain waves into a small number of discrete, frequency-modulated oscillatory processes, which we call oscillons. In particular, we demonstrate that mouse hippocampal LFP contain a single oscillon that occupies the θ-frequency band and a couple of γ-oscillons that correspond, respectively, to slow and fast γ-waves. Since the oscillons were identified empirically, they may represent the actual, physical structure of synchronous oscillations in neuronal ensembles, whereas Fourier-defined “brain waves” are nothing but poorly resolved oscillons.

Wave Turbulence and Energy Cascade in the Hippocampus.

Mesoscale cortical activity can be defined as the organization of activity of large neuron populations into collective action, forming time-dependent patterns such as traveling waves. Although collective action may play an important role in the cross-scale integration of brain activity and in the emergence of cognitive behavior, a comprehensive formulation of the laws governing its dynamics is still lacking. Because collective action processes are macroscopic with respect to neuronal activity, these processes cannot be described directly with methods and models developed for the microscale (individual neurons).To identify the characteristic features of mesoscopic dynamics, and to lay the foundations for a theoretical description of mesoscopic activity in the hippocampus, we conduct a comprehensive examination of observational data of hippocampal local field potential (LFP) recordings. We use the strong correlation between rat running-speed and the LFP power to parameterize the energy input into the hippocampus, and show that both the power and non-linearity of collective action (e.g., theta and gamma rhythms) increase with increased speed. Our results show that collective-action dynamics are stochastic (the precise state of a single neuron is irrelevant), weakly non-linear, and weakly dissipative. These are the principles of the theory of weak turbulence. Therefore, we propose weak turbulence a theoretical framework for the description of mesoscopic activity in the hippocampus. The weak turbulence framework provides a complete description of the cross-scale energy exchange (the energy cascade). It uncovers the mechanism governing major features of LFP spectra and bispectra, such as the physical meaning of the exponent α of power-law LFP spectra (e.g., f−α, where f is the frequency), the strengthening of theta-gamma coupling with energy input into the hippocampus, as well as specific phase lags associated with their interaction. Remarkably, the weak turbulence framework is consistent with the theory of self organized criticality, which provides a simple explanation for the existence of the power-law background spectrum. Together with self-organized criticality, weak turbulence could provide a unifying approach to modeling the dynamics of mesoscopic activity.

Theta-gamma cascades and running speed.

Oscillations in the hippocampal local field potential at theta and gamma frequencies are prominent during awake behavior and have demonstrated several behavioral correlates. Both oscillations have been observed to increase in amplitude and frequency as a function of running speed. Previous investigations, however, have examined the relationship between speed and each of these oscillation bands separately. Based on energy cascade models where "…perturbations of slow frequencies cause a cascade of energy dissipation at all frequency scales" (Buzsaki G. Rhythms of the Brain, 2006), we hypothesized that cross-frequency interactions between theta and gamma should increase as a function of speed. We examined these relationships across multiple layers of the CA1 subregion, which correspond to synaptic zones receiving different afferents. Across layers, we found a reliable correlation between the power of theta and the power of gamma, indicative of an amplitude-amplitude relationship. Moreover, there was an increase in the coherence between the power of gamma and the phase of theta, demonstrating increased phase-amplitude coupling with speed. Finally, at higher velocities, phase entrainment between theta and gamma increases. These results have important implications and provide new insights regarding how theta and gamma are integrated for neuronal circuit dynamics, with coupling strength determined by the excitatory drive within the hippocampus. Specifically, rather than arguing that different frequencies can be attributed to different psychological processes, we contend that cognitive processes occur across multiple frequency bands simultaneously with organization occurring as a function of the amount of energy iteratively propagated through the brain. NEW & NOTEWORTHY Often, the theta and gamma oscillations in the hippocampus have been believed to be a consequence of two marginally overlapping phenomena. This perspective, however, runs counter to an alternative hypothesis in which a slow-frequency, high-amplitude oscillation provides energy that cascades into higher frequency, lower amplitude oscillations. We found that as running speed increases, all measures of cross-frequency theta-gamma coupling intensify, providing evidence in favor of the energy cascade hypothesis.

Sharp-wave ripple features in macaques depend on behavioral state and cell-type specific firing.

Sharp‐wave ripples (SWRs) are spontaneous, synchronized neural population events in the hippocampus widely thought to play a role in memory consolidation and retrieval. They occur predominantly in sleep and quiet immobility, and in primates, they also appear during active visual exploration. Typical measures of SWRs in behaving rats include changes in the rate of occurrence, or in the incidence of specific neural ensemble activity contained within the categorical SWR event. Much less is known about the relevance of spatiotemporal SWR features, though they may index underlying activity of specific cell types including ensemble‐specific internally generated sequences. Furthermore, changes in SWR features during active exploratory states are unknown. In this study, we recorded hippocampal local‐field potentials and single‐units during periods of quiescence and as macaques performed a memory‐guided visual search task. We observed that (a) ripples during quiescence have greater amplitudes and larger postripple waves (PRW) compared to those in task epochs, and (b) during “remembered” trials, ripples have larger amplitudes than during “forgotten” trials, with no change in duration or PRWs. We further found that spiking activity influences SWR features as a function of cell type and ripple timing. As expected, larger ripple amplitudes were associated with putative pyramidal or putative basket interneuron (IN) activity, even when the spikes in question exceed the duration of the ripple. In contrast, the PRW was attenuated with activity from low firing rate cells and enhanced with activity from high firing rate cells, with putative IN spikes during ripples leading to the most prominent PRW peaks. The selective changes in SWR features as a function of time window, cell type, and cognitive/vigilance states suggest that this mesoscopic field event can offer additional information about the local network and animal's state than would be appreciated from SWR event rates alone.

ONEIROS, a new miniature standalone device for recording sleep electrophysiology, physiology, temperatures and behavior in the lab and field

BackgroundSleep is an inactive state of reduced environmental awareness shared by all animals. When compared to wakefulness, sleep behavior is associated with changes in physiology and brain activity. The nature of these changes varies considerably across species, and therefore is a rich resource for gaining insight into the evolution and functions of sleep. A major obstacle to capitalizing on this resource is the lack of a small device capable of recording multiple biological parameters for extended periods of time both in the laboratory and the field. New methodONEIROS is a new tool designed for conducting sleep research on small, freely moving animals. The miniature, standalone system is capable of recording up to 26 electrophysiological signals (electroencephalogram, electromyogram, electrooculogram, electrocardiogram), metabolic (3 temperature channels) and behavior via an accelerometer for several days. In addition, the device is equipped with a vibrating motor which can be used to assess arousal thresholds and to disrupt sleep. The system is available in telemetric or data-logger configuration useable in the field. ResultsTo demonstrate the efficacy of this tool, we simultaneously recorded for the first time, electroencephalogram, hippocampal local field potential, electromyogram, electrooculogram, brain, body and ambient temperature, and 3D accelerometry. We also deprived rats of paradoxical sleep by triggering the vibrating motor after online recognition of the state. Finally, by successfully recording a pigeon in an 8 m3 aviary in a social context with the device in the logger configuration, we demonstrate the feasibility of using the device in the field.

High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans.

Epilepsy has been classically seen as a brain disorder resulting from abnormally enhanced neuronal excitability and synchronization. Although it has been described since antiquity, there are still significant challenges achieving the therapeutic goal of seizure freedom. Deep brain stimulation of the anterior nucleus of the thalamus has emerged as a promising therapy for focal drug-resistant epilepsy; the basic mechanism of action, however, remains unclear. Here, we show that desynchronization is a potential mechanism of deep brain stimulation of the anterior nucleus of the thalamus by studying local field potentials recordings from the cortex during high-frequency stimulation (130 Hz) of the anterior nucleus of the thalamus in nine patients with drug-resistant focal epilepsy. We demonstrate that high-frequency stimulation applied to the anterior nucleus of the thalamus desynchronizes ipsilateral hippocampal background electrical activity over a broad frequency range, and reduces pathological epileptic discharges including interictal spikes and high-frequency oscillations. Furthermore, high-frequency stimulation of the anterior nucleus of the thalamus is capable of decoupling large-scale neural activity involving the hippocampus and distributed cortical areas. We found that stimulation frequencies ranging from 15 to 45 Hz were associated with synchronization of hippocampal local field potentials, whereas higher frequencies (>45 Hz) promoted desynchronization of ipsilateral hippocampal activity. Moreover, reciprocal effective connectivity between the anterior nucleus of the thalamus and the hippocampus was demonstrated by hippocampal-thalamic evoked potentials and thalamic-hippocampal evoked potentials. In summary, high-frequency stimulation of the anterior nucleus of the thalamus is shown to desynchronize focal and large-scale epileptic networks, and here is proposed as the mechanism for reducing seizure generation and propagation. Our data also demonstrate position-specific correlation between deep brain stimulation applied to the anterior nucleus of the thalamus and patients with temporal lobe epilepsy and seizure onset zone within the Papaz circuit or limbic system. Our observation may prove useful for guiding electrode implantation to increase clinical efficacy.

Sleep stage dynamics in neocortex and hippocampus.

Mammalian sleep comprises the stages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Additionally, a transition state is often discriminated which in rodents is termed intermediate stage (IS). Although these sleep stages are thought of as unitary phenomena affecting the whole brain in a congruent fashion, recent findings have suggested that sleep stages can also appear locally restricted to specific networks and regions. Here, we compared in rats sleep stages and their transitions between neocortex and hippocampus. We simultaneously recorded the electroencephalogram (EEG) from skull electrodes over frontal and parietal cortex and the local field potential (LFP) from the medial prefrontal cortex and dorsal hippocampus. Results indicate a high congruence in the occurrence of sleep and SWS (>96.5%) at the different recording sites. Congruence was lower for REM sleep (>87%) and lowest for IS (<36.5%). Incongruences occurring at sleep stage transitions were most pronounced for REM sleep which in 36.6 per cent of all epochs started earlier in hippocampal LFP recordings than in the other recordings, with an average interval of 17.2 ± 1.1 s between REM onset in the hippocampal LFP and the parietal EEG (p < 0.001). Earlier REM onset in the hippocampus was paralleled by a decrease in muscle tone, another hallmark of REM sleep. These findings indicate a region-specific regulation of REM sleep which has clear implications not only for our understanding of the organization of sleep, but possibly also for the functions, e.g. in memory formation, that have been associated with REM sleep.

A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice

Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study’s in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1–11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA-treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice.

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

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

Severe and protracted sleep disruptions in mouse model of post-traumatic stress disorder.

Increasing evidences suggest that the predator threat model is a valid animal model of post-traumatic stress disorder (PTSD). However, sleep has never been examined in this model. Since sleep disturbances, including insomnia and excessive daytime sleepiness, are severe and protracted symptoms of PTSD, we hypothesized that mice exposed to predator odor trauma (POT) will display contextual fear conditioning along with severe and protracted sleep disruptions. Adult male C57BL/6J mice, instrumented with wire electrodes (to record hippocampal local field potentials [LFP] and nuchal muscle [electromyogram, EMG] activity), were exposed to contextual conditioning using soiled cat litter as unconditional stimulus (US). On day 1, fear memory acquisition (FMA) training was performed by exposing mice to contextual cage (conditional stimulus; CS) for 30 min followed by exposure to CS + US for 90 min. On day 5, fear memory recall (FMR) testing was performed by exposing mice to CS (without US) for 120 min. LFP and EMG were recorded continuously for 5 days. Mice exposed to POT displayed as follows: (1) hyperarousal coupled with electrophysiological indicators of memory acquisition and retrieval (increased hippocampal θ and γ power) during FMA and FMR; (2) increased nonrapid eye movement (NREM) δ and rapid eye movement θ power during sleep post FMA, indicating memory consolidation; (3) protracted sleep disturbances as evident by increased wakefulness, reduced NREM sleep and NREM δ power, increased NREM β power during light (sleep) period, and increased sleep during dark (active) period. Based on these results, we suggest that mice exposed to POT display severe and protracted sleep disturbances mimicking sleep disturbance observed in human PTSD.

Disruption of Hippocampal Multisynaptic Networks by General Anesthetics.

Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function. Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal). Monosynaptic population excitatory postsynaptic potentials at the basal and apical dendrites of CA1 were significantly decreased at greater than or equal to 0.25% (n = 4) and greater than or equal to 1.0% (n = 6) isoflurane, respectively. The perforant path evoked multisynaptic response at CA1 was decreased by ~50% at greater than or equal to 0.25% isoflurane (n = 5). A decreased population excitatory postsynaptic potential was accompanied by increased paired-pulse facilitation. Population spike amplitude in relation to apical dendritic population excitatory postsynaptic potential was not significantly altered by isoflurane. Spontaneous hippocampal local field potential at 0.8 to 300 Hz was dose-dependently suppressed by isoflurane (n = 6), with local field potential power in the 50- to 150-Hz band showing the highest decrease with isoflurane dose, commensurate with the decrease in trisynaptic CA1 response. Low-dose pentobarbital (n = 7) administration decreased the perforant path evoked trisynaptic CA1 response and hippocampal local field potentials at 78 to 125 Hz. Hippocampal networks are sensitive to low doses of isoflurane and pentobarbital, possibly through both glutamatergic and γ-aminobutyric acid-mediated transmission. Network disruption could help explain the impairment of hippocampal-dependent cognitive functions with low-dose anesthetic.

Human hippocampal theta power indicates movement onset and distance travelled

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a self-paced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movement-onset periods are associated with a significant increase in both low (2-5 Hz)- and high (6-9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation.

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.

In vitro and in vivo biostability assessment of chronically-implanted Parylene C neural sensors

Parylene C has rapidly gained attention as a flexible biomaterial for a new generation of chronic neural probes. However, polymeric material failure in the form of delamination, swelling or tearing, often compromises device biostability in the long term. This work constitutes a first step towards lifetime assessment of Parylene C implanted devices. We have conceived a Parylene C-based neural probe with PEDOT-nanostructured gold electrodes for the recording of brain activity. The material response to its biological environment was studied through in vitro soaking tests and in vivo wireless recordings in mice brain, both carried out for up to 6 months. Impedance monitoring and SEM images indicate that over the length of this trial, none of the implants presented with apparent signs of material degradation. Packaging reliability was a predominant factor in device failure, with a certain number of faulty connection appearing over time. This parameter aside, all soaked devices were stable in Artificial Cerebro-Spinal Fluid, with impedances within 10% of their initial value after 6 months at 37°C. Besides, at least 70% of the implanted device were able to accurately record wirelessly high amplitude hippocampal Local Field Potentials from freely-moving mice, with steady Signal-to-Noise Ratio. In other terms, Parylene C implantable sensors responded minimally to artificial and actual physiological conditions during a period of 6 months, which makes them promising candidates for reliable, chronically implanted sensors in the biomedical field.

Hippocampal CA1 local field potential oscillations induced by olfactory cue of liked food

Eating motivation is induced not only by negative energy balance but also food related cues. However, neural processing for acquisition of learned food preference remains to be established. This study aimed to identify hippocampal neural signaling in response to olfactory cue (chocolate scent) after completion of repetitive chocolate sessions. Male Swiss albino mice implanted with intracranial electrode into the hippocampus were used for local field potential (LFP) recording. Animals were given chocolate sessions (a piece of 2g chocolate per each mouse to eat on day 1, 3, 5 and 7). Hippocampal CA1 LFP signals and exploratory behavior of animals receiving chocolate scent were analyzed before and after chocolate sessions. The experiment was performed in a place preference-like apparatus with the zones of normal food pellet and chocolate (both kept in a small perforated cup for smell dispersion) at the opposite ends. Following chocolate sessions, time spent in a chocolate zone and CA1 LFP patterns were analyzed in comparison to control levels. Two-way ANOVA revealed significant increase in time spent seeking for chocolate. Frequency analysis of LFP power spectra revealed significant increases in delta and theta powers. Phase-amplitude analysis showed significant increase in maximal modulation index and decrease in frequency for phase of theta-high gamma coupling. Taken together, neural signaling in the hippocampus was sensitive to chocolate olfactory cue that might underlie learning process in response to repeated chocolate consumptions that primed intense food approaching behavior. Ultimately, these LFP patterns might reflect motivation to eat and predict feeding probability.

Low Activity Microstates During Sleep.

Study Objectives:To better understand the distinct activity patterns of the brain during sleep, we observed and investigated periods of diminished oscillatory and population spiking activity lasting for seconds during non-rapid eye movement (non-REM) sleep, which we call “LOW” activity sleep.Methods:We analyzed spiking and local field potential (LFP) activity of hippocampal CA1 region alongside neocortical electroencephalogram (EEG) and electromyogram (EMG) in 19 sessions from four male Long-Evans rats (260–360 g) during natural wake/sleep across the 24-hr cycle as well as data from other brain regions obtained from http://crcns.org.1,2Results:LOW states lasted longer than OFF/DOWN states and were distinguished by a subset of “LOW-active” cells. LOW activity sleep was preceded and followed by increased sharp-wave ripple activity. We also observed decreased slow-wave activity and sleep spindles in the hippocampal LFP and neocortical EEG upon LOW onset, with a partial rebound immediately after LOW. LOW states demonstrated activity patterns consistent with sleep but frequently transitioned into microarousals and showed EMG and LFP differences from small-amplitude irregular activity during quiet waking. Their likelihood decreased within individual non-REM epochs yet increased over the course of sleep. By analyzing data from the entorhinal cortex of rats,1 as well as the hippocampus, the medial prefrontal cortex, the postsubiculum, and the anterior thalamus of mice,2 obtained from http://crcns.org, we confirmed that LOW states corresponded to markedly diminished activity simultaneously in all of these regions.Conclusions:We propose that LOW states are an important microstate within non-REM sleep that provide respite from high-activity sleep and may serve a restorative function.

ZIP It: Neural Silencing Is an Additional Effect of the PKM-Zeta Inhibitor Zeta-Inhibitory Peptide.

Protein kinase M ζ (PKMζ), an atypical isoform of protein kinase C, has been suggested to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long-term memory (LTM). This evidence is heavily based on the use of ζ inhibitory peptide (ZIP), a supposed specific inhibitor of PKMζ that interferes with both LTP and LTM. Problematically, both LTP and LTM are unaffected in both constitutive and conditional PKMζ knock-out mice, yet both are still impaired by ZIP application, suggesting a nonspecific mechanism of action. Because translational interference can disrupt neural activity, we assessed network activity after a unilateral intrahippocampal infusion of ZIP in anesthetized rats. ZIP profoundly reduced spontaneous hippocampal local field potentials, comparable in magnitude to infusions of lidocaine, but with a slower onset and longer duration. Our results highlight a serious confound in interpreting the behavioral effects of ZIP. We suggest that future molecular approaches in neuroscience consider the intervening level of cellular and systems neurophysiology before claiming influences on behavior. Long-term memory in the brain is thought to arise from a sustained molecular process that can maintain changes in synaptic plasticity. A so-called candidate for the title of "the memory molecule" is protein kinase M ζ (PKMζ), mainly because its inhibition by ζ inhibitory peptide (ZIP) interferes with previously established synaptic plasticity and memory. We show that brain applications of ZIP that can impair memory actually profoundly suppress spontaneous brain activity directly or can cause abnormal seizure activity. We suggest that normal brain activity occurring after learning may be a more primary element of memory permanence.

Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid β protein in male rats

Alzheimer's disease (AD) is an age-related mental disorder characterized by progressive loss of memory and multiple cognitive impairments. The overproduction and aggregation of Amyloid β protein (Aβ) in the brain, especially in the hippocampus, are closely involved in the memory loss in the patients with AD. Accumulating evidence indicates that the Aβ-induced imbalance of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in the brain plays an important role in the AD pathogenesis and progression. The level of DHEA is elevated, while DHEAS is dramatically decreased in the AD brain. The present study tried to restore the balance between DHEA and DHEAS by using a non-steroidal sulfatase inhibitor DU-14, which increases endogenous DHEAS through preventing DHEAS converted back into DHEA. We found that: (1) DU-14 effectively attenuated the Aβ1–42-induced cognitive deficits in spatial learning and memory of rats in Morris water maze test; (2) DU-14 prevented Aβ1–42-induced decrease in the cholinergic theta rhythm of hippocampal local field potential (LFP) in the CA1 region; (3) DU-14 protected hippocampal synaptic plasticity against Aβ1–42-induced suppression of long term potentiation (LTP). These results provide evidence for the neuroprotective action of DU-14 against neurotoxic Aβ, suggesting that up-regulation of endogenous DHEAS by DU-14 could be beneficial to the alleviation of Aβ-induced impairments in spatial memory and synaptic plasticity.

A Respiration-Coupled Rhythm in the Rat Hippocampus Independent of Theta and Slow Oscillations.

During slow-wave sleep and deep anesthesia, the rat hippocampus displays a slow oscillation (SO) that follows "up-and-down" state transitions in the neocortex. There has been recent debate as to whether this local field potential (LFP) rhythm reflects internal processing or entrains with respiratory inputs. To solve this issue, here we have concomitantly recorded respiration along with hippocampal, neocortical, and olfactory bulb (OB) LFPs in rats anesthetized with urethane. During the course of anesthesia, LFPs transitioned between activity states characterized by the emergence of different oscillations. By jointly analyzing multisite LFPs and respiratory cycles, we could distinguish three types of low-frequency hippocampal oscillations: (1) SO, which coupled to neocortical up-and-down transitions; (2) theta, which phase-reversed across hippocampal layers and was largest at the fissure; and (3) a low-frequency rhythm with largest amplitude in the dentate gyrus, which coupled to respiration-entrained oscillations in OB and to respiration itself. In contrast, neither theta nor SO coupled to respiration. The hippocampal respiration-coupled rhythm and SO had frequency <1.5 Hz, whereas theta tended to be faster (>3 Hz). Tracheotomy abolished hippocampal respiration-coupled rhythm, which was restored by rhythmic delivery of air puffs into the nasal cavity. These results solve the apparent contradictions among previous studies by demonstrating that the rat hippocampus produces multiple types of low-frequency oscillations. Because they synchronize with different brain circuits, however, we postulate that each activity pattern plays a unique role in information processing. The rat hippocampus exhibits a large-amplitude slow oscillation (<1.5 Hz) during deep sleep and anesthesia. It is currently debated whether this rhythm reflects internal processing with the neocortex or entrainment by external inputs from rhythmic nasal respiration, which has similar frequency. Here we reconcile previous studies by showing that the hippocampus can actually produce two low-frequency rhythms at nearby frequencies: one that indeed couples to respiration and another that is coupled to the neocortex. We further show that the respiration-coupled rhythm differs from theta oscillations. The results support a role for brain oscillations in connecting distant brain regions, and posit the respiratory cycle as an important reference for neuronal communication between olfactory and memory networks.