A hippokampális théta aktivitás strukturális alapja és szubkortikális modulációja = Structural basis and subcortical modulation of theta activity in the hippocampus

Kimutattuk, hogy a szeptum és a hippokampusz között a HS sejtek szintjén reciprok gátló kapcsolat áll fent. A HS sejtek érzékelik a hippokampális aktivitás szintjét, elsősorban szeptális gátlás alatt állnak és a szeptumon kívül a hippokampusz távoli területeire is vetítenek ezáltal a szeptum és az egész hippokampusz működését összehangolják. A theta aktivitással együtt előforduló gamma aktivitás kialakításában elsősorban a PV tartalmú kosársejtek játszanak szerepet, aktivitásukat, és így a gamma aktivitást opiát receptorok útján szabályozni lehet. A szeptum és a hippokampusz kölcsönhatását vizsgálva kimutattuk, hogy a medialis septum HCN ioncsatornát es/vagy parvalbumin fehérjét kifejező gátlósejtjei vezérlik a hippocampalis theta ritmust. Részletes CA1-es hálózati modell segítségével jóslatokat fogalmaztunk meg a théta és magasabb frekvenciájú oszcillációk lokális mechanizmusaival, kölcsönhatásaival és extrahippokampális modulációjával kapcsolatban. A felszálló szerotoninerg rendszerben kimutattunk egy az eddig ismerteknél gyorsabb, glutamátot használó hatékony moduláció-típus létezését. | We demonstrated that the reciprocal interaction between the medial septum and the hippocampus is realized at the cellular level via the HS cells. They detect the level of hippocampal activity, are under primarily septal inhibitory control and besides the septum they project to remote hippocampal areas, synchronizing the activity of this two regions. The theta concurrnet gamma activity is primarily controlled by the PV containing basket cells. These cells and thus gamma activity can be modulated via opiate receptors. Studying the interaction of t emedial septum and the hippocampus we proven that HCN/PV expressing medial septal inhibitory neurons drive the hippocampal theta rhythm. Simulations of a detailed network model of area CA1 resulted in predictions regarding the local mechanisms, interactions, and extrahippocampal modulation of theta and higher frequency oscillations. We demonstrated a quick, glutamatergic component in the ascending modulatory raphe-hippocapal serotonergic projection

Mechanisms of sharp wave initiation and ripple generation

Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential in memory formation. To understand the mechanisms underlying the initiation of irregularly occurring SWRs and the generation of periodic ripples, we selectively manipulated different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs and IPSCs to examine the buildup of neuronal activity preceding SWRs and analyzed the distribution of time intervals between subsequent SWR events. Our results suggest that SWRs are initiated through a combined refractory and stochastic mechanism. SWRs initiate when firing in a set of spontaneously active pyramidal cells triggers a gradual, exponential buildup of activity in the recurrent CA3 network. We showed that this tonic excitatory envelope drives reciprocally connected parvalbumin-positive basket cells, which start ripple-frequency spiking that is phase-locked through reciprocal inhibition. The synchronized GABAA receptor-mediated currents give rise to a major component of the ripple-frequency oscillation in the local field potential and organize the phase-locked spiking of pyramidal cells. Optogenetic stimulation of parvalbumin-positive cells evoked full SWRs and EPSC sequences in pyramidal cells. Even with excitation blocked, tonic driving of parvalbumin-positive cells evoked ripple oscillations. Conversely, optogenetic silencing of parvalbumin-positive cells interrupted the SWRs or inhibited their occurrence. Local drug applications and modeling experiments confirmed that the activity of parvalbumin-positive perisomatic inhibitory neurons is both necessary and sufficient for ripple-frequency current and rhythm generation. These interneurons are thus essential in organizing pyramidal cell activity not only during gamma oscillation, but, in a different configuration, during SWRs

Különböző típusú GABAerg interneuronok szerepe a hippokampális gamma oszcillációkban = The role of distinct types of GABAergic interneurons in hippocampal network oscillations at gamma frequency

A kérgi neuronhálózatokban megfigyelt gamma (30-100 Hz) oszcillációk alapvető szerepet játszanak olyan kognitív folyamatokban, mint pl. a szenzoros információfeldolgozás. Funkciójuk megértéséhez ismernünk kell a neuronhálózatokat alkotó serkentő és gátlósejtek viselkedését ill. szerepét az oszcillációk kialakításában. Pályázatunk célja a hippokampális ideghálózatok szinkronizált működését kialakító sejtszintű mechanizmusok felderítése volt. In vitro farmakológiailag indukált oszcillációk során vizualizált patch-clamp méréstechnika segítségével megállapítottuk, hogy a hippokampusz CA3 régiójában keletkező gamma oszcillációkat a gyorsan tüzelő kosársejtek és a piramissejtek időben összehangolt kisülése generálja szinaptikus visszacsatolás révén. A hippokampusz CA1 régiójába a gamma oszcilláció előrecsatoló gátlással terjed át a CA3 régióból. Mindkét régióban a gátlósejtek oszcillációhoz viszonyított fáziskapcsolt tüzelését a rájuk érkező szinaptikus serkentés, míg a piramissejtek kisülését a szinaptikus gátlás határozta meg. Kifejlesztettünk egy szabadalmi bejelentéssel védett szeletkamrát in vitro mérésekhez, melyben az agyszeletek oxigénellátása megközelíti az in vivo körülményeket. Az eredményeinknek klinikai vonatkozása is elképzelhető, hiszen az epilepszia tünetcsoportban tapasztalt hiperszinkonitás kialakulásában is kulcsfontosságú szerepet játszhatnak a gyorsan tüzelő kosársejtek, amely gátlósejtek működésének célzott szabályozása egy potenciális gyógyszercélpont lehet. | Cortical network oscillations at gamma (30-100 Hz) frequencies were suggested to be linked to several cognitive tasks including sensory processing. To understand the role of oscillations in neuronal operation, the behavior and the function of different neuronal types during oscillatory activities need to be revealed. The aim of our project was to uncover the basic cellular mechanisms generating synchronous network activities in hippocampal neuronal circuitries. The combination of visualized patch-clamp recordings with pharmacologically-induced in vitro oscillations allowed us to determine that in CA3 hippocampal region the precisely timed discharge of fast spiking basket cells and pyramidal cells could generate the gamma oscillations via a synaptic feed-back loop. The gamma oscillation emerged intrinsically in CA3 propagates to CA1 via feed-forward inhibition. In both regions, the phase-coupled firing of inhibitory cells was controlled by synaptic excitation, whereas the discharge of pyramidal cells was primarily determined by synaptic inhibition. For in vitro recordings we developed a new type of slice chamber protected by a patent, where the oxygen supply of brain slices approaches the in vivo circumstances. Our results also have clinical relevance implying the pivotal role of fast spiking basket cells in hypersynchrony during epileptic discharges, therefore the modulation of the fast spiking basket cell operation might be a novel target for drug development

Physiological sharp wave-ripples and interictal events in vitro: What’s the difference?

Sharp wave-ripples and interictal events are physiological and pathological forms of transient high activity in the hippocampus with similar features. Sharp wave-ripples have been shown to be essential in memory consolidation, while epileptiform (interictal) events are thought to be damaging. It is essential to grasp the difference between physiological sharp wave-ripples and pathological interictal events in order to understand the failure of control mechanisms in the latter case. We investigated the dynamics of activity generated intrinsically in the CA3 region of the mouse hippocampus in vitro, using four different types of intervention to induce epiletiform activity. As a result, sharp wave-ripples spontaneously occurring in CA3 disappeared, and following an asynchronous transitory phase, activity reorganized into a new form of pathological synchrony. During epileptiform events, all neurons increased their firing rate compared to sharp wave-ripples. Different cell types showed complementary firing: parvalbumin-positive basket cells and some axo-axonic cells stopped firing due to a depolarization block at the climax of the events in high potassium, 4-aminopyridine and zero magnesium models, but not in the gabazine model. In contrast, pyramidal cells started firing maximally at this stage. To understand the underlying mechanism we measured changes of intrinsic neuronal and transmission parameters in the high potassium model. We found that the cellular excitability increased and excitatory transmission was enhanced, whereas inhibitory transmission was compromised. We observed a strong short-term depression in parvalbumin-positive basket cell to pyramidal cell transmission. Thus, the collapse of pyramidal cell perisomatic inhibition appears to be a crucial factor in the emergence of epileptiform events

Dendritic spikes induce ripples in parvalbumin interneurons during hippocampal sharp waves.

Sharp-wave ripples are transient oscillatory events in the hippocampus that are associated with the reactivation of neuronal ensembles within specific circuits during memory formation. Fast-spiking, parvalbumin-expressing interneurons (FS-PV INs) are thought to provide fast integration in these oscillatory circuits by suppressing regenerative activity in their dendrites. Here, using fast 3D two-photon imaging and a caged glutamate, we challenge this classical view by demonstrating that FS-PV IN dendrites can generate propagating Ca(2+) spikes during sharp-wave ripples. The spikes originate from dendritic hot spots and are mediated dominantly by L-type Ca(2+) channels. Notably, Ca(2+) spikes were associated with intrinsically generated membrane potential oscillations. These oscillations required the activation of voltage-gated Na(+) channels, had the same frequency as the field potential oscillations associated with sharp-wave ripples, and controlled the phase of action potentials. Furthermore, our results demonstrate that the smallest functional unit that can generate ripple-frequency oscillations is a segment of a dendrite

Differences in subthreshold resonance of hippocampal pyramidal cells and interneurons: the role of h-current and passive membrane characteristics

The intrinsic properties of distinct types of neuron play important roles in cortical network dynamics. One crucial determinant of neuronal behaviour is the cell's response to rhythmic subthreshold input, characterised by the input impedance, which can be determined by measuring the amplitude and phase of the membrane potential response to sinusoidal currents as a function of input frequency. In this study, we determined the impedance profiles of anatomically identified neurons in the CA1 region of the rat hippocampus (pyramidal cells as well as interneurons located in the stratum oriens, including OLM cells, fast-spiking perisomatic region-targeting interneurons and cells with axonal arbour in strata oriens and radiatum). The basic features of the impedance profiles, as well as the passive membrane characteristics and the properties of the sag in the voltage response to negative current steps, were cell-type specific. With the exception of fast-spiking interneurons, all cell types showed subthreshold resonance, albeit with distinct features. The HCN channel blocker ZD7288 (10 μm) eliminated the resonance and changed the shape of the impedance curves, indicating the involvement of the hyperpolarisation-activated cation current Ih. Whole-cell voltage-clamp recordings uncovered differences in the voltage-dependent activation and kinetics of Ih between different cell types. Biophysical modelling demonstrated that the cell-type specificity of the impedance profiles can be largely explained by the properties of Ih in combination with the passive membrane characteristics. We conclude that differences in Ih and passive membrane properties result in a cell-type-specific response to inputs at given frequencies, and may explain, at least in part, the differential involvement of distinct types of neuron in various network oscillations

Dynamics of sleep oscillations is coupled to brain temperature on multiple scales

Sleep spindle frequency positively, duration negatively correlates with brain temperature. Local heating of the thalamus produces similar effects in the heated area. Thalamic network model corroborates temperature dependence of sleep spindle frequency. Brain temperature shows spontaneous microfluctuations during both anesthesia and natural sleep. Larger fluctuations are associated with epochs of REM sleep. Smaller fluctuations correspond to the alteration of spindling and delta epochs of infra-slow oscillation.Every form of neural activity depends on temperature, yet its relationship to brain rhythms is poorly understood. In this work we examined how sleep spindles are influenced by changing brain temperatures and how brain temperature is influenced by sleep oscillations. We employed a novel thermoelectrode designed for measuring temperature while recording neural activity. We found that spindle frequency is positively correlated and duration negatively correlated with brain temperature. Local heating of the thalamus replicated the temperature dependence of spindle parameters in the heated area only, suggesting biophysical rather than global modulatory mechanisms, a finding also supported by a thalamic network model. Finally, we show that switches between oscillatory states also influence brain temperature on a shorter and smaller scale. Epochs of paradoxical sleep as well as the infra-slow oscillation were associated with brain temperature fluctuations below 0.2°C. Our results highlight that brain temperature is massively intertwined with sleep oscillations on various time scales

Huygens synchronization of medial septal pacemaker neurons generates hippocampal theta oscillation

Episodic learning and memory retrieval are dependent on hippocampal theta oscillation, thought to rely on the GABAergic network of the medial septum (MS). To test how this network achieves theta synchrony, we recorded MS neurons and hippocampal local field potential simultaneously in anesthetized and awake mice and rats. We show that MS pacemakers synchronize their individual rhythmicity frequencies, akin to coupled pendulum clocks as observed by Huygens. We optogenetically identified them as parvalbumin-expressing GABAergic neurons, while MS glutamatergic neurons provide tonic excitation sufficient to induce theta. In accordance, waxing and waning tonic excitation is sufficient to toggle between theta and non-theta states in a network model of single-compartment inhibitory pacemaker neurons. These results provide experimental and theoretical support to a frequency-synchronization mechanism for pacing hippocampal theta, which may serve as an inspirational prototype for synchronization processes in the central nervous system from Nematoda to Arthropoda to Chordate and Vertebrate phyla

Hippocampal sharp wave-ripples and the associated sequence replay emerge from structured synaptic interactions in a network model of area CA3

Hippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated (‘replayed’), either in the same or reversed order, during bursts of activity (sharp wave-ripples [SWRs]) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and maintenance of long-term memory. In order to identify the cellular and network mechanisms of SWRs and replay, we constructed and simulated a data-driven model of area CA3 of the hippocampus. Our results show that the chain-like structure of recurrent excitatory interactions established during learning not only determines the content of replay, but is essential for the generation of the SWRs as well. We find that bidirectional replay requires the interplay of the experimentally confirmed, temporally symmetric plasticity rule, and cellular adaptation. Our model provides a unifying framework for diverse phenomena involving hippocampal plasticity, representations, and dynamics, and suggests that the structured neural codes induced by learning may have greater influence over cortical network states than previously appreciated