Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations

Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations Stark Roux Eichler Senzai Royer Buzsáki

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Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations 2014 Neuron 10.1016/j.neuron.2014.06.023 Stark2014-pyramidal-cell-interneuron-interactions-unde Stark2014-pyramidal-cell-interneuron-interactions-unde.txt, the project's staged copy a378cac3e3ea41a8040ed5e28a9673ce3f2f427b not-redistributable neuroscience

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them which local circuit interactions generate the hippocampal ripple, and which of three long-standing competing models survives a direct test Quotation withheld because this record is not cleared for redistribution. whether pyramidal cells, interneuron-interneuron interactions, or pyramidal-interneuron loops set the ripple rhythm in the intact brain Quotation withheld because this record is not cleared for redistribution. shows pyramidal activation is necessary and fast GABA-A inhibition obligatory, that PV activation alone cannot make a ripple but can pace one, and proposes a hybrid PYR-INT-INT model Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. hippocampal ripple oscillations Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Sharp-wave-driven transient excitation of pyramidal cells combines with the pacing supplied by interneuron-interneuron interactions to produce the ripple (PYR-INT-INT hybrid model) Quotation withheld because this record is not cleared for redistribution. mechanisms CA1 interneuron-interneuron interactions bind multiple independent local ripple oscillators cycle by cycle into one spatially coherent event Quotation withheld because this record is not cleared for redistribution. mechanisms Stronger excitation recruits the PV interneuron population more strongly, and that population sets the oscillation frequency, which is why both sharp-wave amplitude and light intensity raise ripple frequency Quotation withheld because this record is not cleared for redistribution. depolarising 80-100 nearby pyramidal cells is enough to make a ripple-like oscillation, so the minimal generating network is small Quotation withheld because this record is not cleared for redistribution. fast GABA-A inhibition is obligatory: blocking it locally abolishes the oscillation entirely Quotation withheld because this record is not cleared for redistribution. PV interneuron activation cannot create a field ripple but does organise spiking into coherent ripple-frequency patterning Quotation withheld because this record is not cleared for redistribution. coherence across sites is not volume conduction; it comes from correlated input driving several local oscillators at once Quotation withheld because this record is not cleared for redistribution. synchronisation needs only the RISING phase of inhibition to be fast, because each pyramidal cell fires about once per ripple and a different set fires on each cycle Quotation withheld because this record is not cleared for redistribution. removing inhibition does not simply stop the rhythm - it converts it into a faster, pathological one Quotation withheld because this record is not cleared for redistribution. In transgenic mice, light may also have activated CA2/CA3 terminals rather than only CA1 pyramidal cells. what this limits: results from the transgenic animals: IN TRANSGENIC MICE WE CANNOT EXCLUDE THE POSSIBILITY THAT TERMINALS OF THE CA2/CA3 INPUTS WERE ALSO ACTIVATED BY LIGHT - answered by THE CONSISTENT OBSERVATIONS IN VIRUS-INJECTED WILD-TYPE ANIMALS Quotation withheld because this record is not cleared for redistribution. The effect of the induced oscillations on the content and sequence of spiking during natural ripples was not tested. what this limits: any claim that induced oscillations carry native spike content: HOW THE OPTOGENETICALLY INDUCED HFOs AFFECT THE SPIKE CONTENT, INCIDENCE, AND SEQUENTIAL NEURONAL ACTIVITY DURING NATIVE RIPPLES REMAINS TO BE ADDRESSED Quotation withheld because this record is not cleared for redistribution. The pharmacological and some optogenetic experiments were done under urethane anaesthesia. what this limits: the receptor-blockade and some optogenetic results: THEY WERE CARRIED OUT IN ANESTHETIZED ANIMALS, though SEVERAL CONTROL EXPERIMENTS SUGGESTED THAT THE RESULTS APPLY TO THE DRUG-FREE BRAIN Quotation withheld because this record is not cleared for redistribution. Changes in oscillation amplitude and frequency during long light pulses may be an opsin artefact rather than a network property. what this limits: the long-pulse amplitude and frequency observations: THIS CHANGE CAN ALSO REFLECT OPSIN DESENSITISATION rather than a property of the network Quotation withheld because this record is not cleared for redistribution. in transgenic animals the light may also have activated CA2/CA3 terminals, addressed by repeating in virus-injected wild-types duplicate of: limitations[0] · what this limits: the same scope as limitations[0] - the transgenic experiments, checked against Quotation withheld because this record is not cleared for redistribution. induced oscillations differ from spontaneous ones in mean frequency and in the phase separation between cell types what this limits: any claim that induced and spontaneous oscillations are the same thing: A RELATIVELY LOWER MEAN FREQUENCY OF iHFOs ASSOCIATED WITH A RELATIVELY LARGER PHASE SEPARATION BETWEEN PYRAMIDAL CELLS AND INTERNEURONS DURING iHFOs Quotation withheld because this record is not cleared for redistribution. the waxing and waning under long illumination may be opsin desensitisation rather than a network property what this limits: the same scope as limitations[3] - the waxing and waning under PROLONGED ILLUMINATION (E.G., 400 ms SQUARE PULSE) Quotation withheld because this record is not cleared for redistribution. whether induced oscillations carry the same spike content as native ripples is left open what this limits: the same scope as limitations[1] - spike content during native ripples, left open Quotation withheld because this record is not cleared for redistribution. during the pathological fast ripples single neurons cannot be resolved at all, so that state is measurable only at the field level what this limits: single-neuron claims during the pathological state: DURING THE SUPERSYNCHRONOUS FAST RIPPLES, ACTION POTENTIALS OF INDIVIDUAL NEURONS COULD NOT BE DISCRIMINATED DUE TO THE TEMPORALLY SUPERIMPOSED SPIKES OF MANY NEURONS Quotation withheld because this record is not cleared for redistribution. cell-type-specific activation and silencing, used here to convert a correlative question into an interventional one Quotation withheld because this record is not cleared for redistribution. closed-loop feedback: detect the event in real time and perturb it while it is happening Quotation withheld because this record is not cleared for redistribution. spike-train coherence between spatially separated sites as the test of a common timing source Quotation withheld because this record is not cleared for redistribution. light stimulation applied IN ALTERNATION, so every session yields both sham (detection without stimulation) and light (detection with stimulation) conditions eliminates: that a difference between stimulated and unstimulated events is drift across the session - alternation puts both conditions in the same minutes · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. sham events were classified as true or false positives by the same overlap rule applied to offline-detected ripples eliminates: that the detector's hit rate is measured on stimulated events alone, where the stimulation itself could create the thing being detected · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. ripple vs fast-gamma: two names for events separated only by frequency and amplitude, which THIS paper merges by fiat into 'ripples' - the boundary is a convention, not a joint Quotation withheld because this record is not cleared for redistribution. fast ripples = NOT a faster kind of ripple but a nonphysiological epileptic oscillation at 200-300 Hz; the name looks like a subtype and the referent is a pathology Quotation withheld because this record is not cleared for redistribution. iHFO = the optogenetically induced oscillation, deliberately named apart from 'ripple' so that the model is not confused with the thing modelled Quotation withheld because this record is not cleared for redistribution. PYR and INT here are OPTOGENETICALLY tagged, not waveform-guessed: classification uses the light response plus physiological criteria Quotation withheld because this record is not cleared for redistribution. summed PYR = all pyramidal spikes on a shank agglomerated into one train; a unit of analysis constructed for statistical power, which nearly triples the coherent fraction Quotation withheld because this record is not cleared for redistribution. claim_type: mechanism a second reading reaching the same value. Recorded: mechanism — note: a second reading reaching the same value from a different sentence. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: multisite optogenetic activation and closed-loop ripple-triggered silencing in freely behaving rodents, with focal GABA-A blockade and dense extracellular recording a second reading DIFFERING from the recorded value. Recorded: electrophysiology — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. phenomenon: the sharp wave-ripple: a high-frequency field oscillation in CA1 associated with memory consolidation a second reading DIFFERING from the recorded value. Recorded: hippocampal ripple oscillations — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. contradicts → the hypothesis that tonic GABA release facilitates axonally generated spikes in the axon-net model (Traub et al., 2003; Bähner et al., 2011) differs in: the DIRECTION of the effect of more GABA: activation of PV and SOM interneurons, ACCOMPANIED BY PRESUMED INCREASE OF RELEASED GABA, ABORTED RATHER THAN FACILITATED spontaneous ripples Quotation withheld because this record is not cleared for redistribution. contradicts → the simple interneuron-interneuron (INT-INT) model of ripple generation differs in: whether pyramidal cell activity rises: LFP RIPPLES ARE NOT MAINTAINED DURING INTER-NEURON ACTIVATION IN THE ABSENCE OF INCREASED PYRAMIDAL CELL ACTIVITY Quotation withheld because this record is not cleared for redistribution. replicates → Ponomarenko et al., 2004; Nguyen et al., 2009; Sullivan et al., 2011 (within-event deceleration of ripple frequency) Quotation withheld because this record is not cleared for redistribution. builds-on → Stark et al., 2012 (diode-probe optical fibres) Quotation withheld because this record is not cleared for redistribution. contradicts → the axon-net / gap junction model of ripple generation differs in: which cell type the coupling was shown in, and what the blocker also does: CONNEXIN COUPLING BETWEEN CA1 PYRAMIDAL CELLS HAVE NOT BEEN DEMONSTRATED, AND GAP JUNCTION BLOCKERS OFTEN INTERFERE WITH RECEPTOR-MEDIATED INHIBITION - while ELECTRICAL COUPLING BETWEEN INTERNEURONS IS WELL DEMONSTRATED Quotation withheld because this record is not cleared for redistribution. contradicts → the hypothesis that tonic GABA release facilitates axonally generated spikes differs in: the DIRECTION of the effect: ABORTED RATHER THAN FACILITATED Quotation withheld because this record is not cleared for redistribution. contradicts → the simple interneuron-interneuron model, which predicts interneuron activation alone should suffice differs in: which cells are driven, and whether the drive is rhythmic: IN CONTRAST TO PYR ACTIVATION, WHICH READILY GENERATES iHFOs, NON-RHYTHMIC ACTIVATION OF PV INTERNEURONS CANNOT INDUCE LFP OSCILLATIONS Quotation withheld because this record is not cleared for redistribution. contradicts → recurrent collateral excitation as the ripple timer differs in: the region: THIS HYPOTHESIS DOES NOT EXPLAIN WHY RIPPLES IN THE CA3 REGION WITH ITS RICH RECURRENT NETWORK ARE LESS EXPRESSED - the structure with more recurrence has fewer ripples Quotation withheld because this record is not cleared for redistribution. critiques → in vitro studies that dismissed inhibition on the strength of KCl-reinstated oscillations differs in: the frequency and the burst structure of the oscillation being compared: THE KCl-INDUCED OSCILLATIONS WERE VERY FAST (>200 Hz) AND WERE COUPLED WITH LONG SPIKE BURSTS OF PYRAMIDAL CELLS, UNLIKE NATURALLY OCCURRING RIPPLES Quotation withheld because this record is not cleared for redistribution. critiques → systemic diazepam evidence for inhibitory pacing, confounded by effects on ripple occurrence and amplitude differs in: what else the drug changed: THE DRUGS ALSO REDUCED THE OCCURRENCE, AMPLITUDE, AND DURATION OF RIPPLES, so the pacing reading is not isolated Quotation withheld because this record is not cleared for redistribution. reconciles → the interneuron-interneuron and pyramidal-interneuron model families, as a hybrid PYR-INT-INT scheme differs in: whether transient pyramidal excitation is included: a HYBRID MODEL THAT INCLUDES SPW-INDUCED TRANSIENT EXCITATION OF PYRAMIDAL CELLS, COMBINED WITH THE PACING ABILITY OF INTERNEURON INTERACTIONS Quotation withheld because this record is not cleared for redistribution. fast ripples —distinct-from→ ripple fast ripples ripple strength of the relation: 1 · note: CRITERION: 200-300 Hz and nonphysiological/epileptic. The name reads as a subtype of the healthy phenomenon and denotes a pathology Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says PTX was followed by higher-frequency epileptic oscillations; distinct-from is loose. Quotation withheld because this record is not cleared for redistribution. fast gamma —same-as→ ripple fast gamma ripple strength of the relation: 0.6 — the record marks this weak · note: identity asserted BY FIAT for convenience within this paper - 'for simplicity, we will refer to them as ripples'. True here, not licensed elsewhere Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says fast gamma and ripples will be referred to together for simplicity; same-as is a naming choice. Quotation withheld because this record is not cleared for redistribution. iHFOs —contrasted-with→ ripple iHFOs ripple differs in: THE AXIS IS WHERE THE DRIVE COMES FROM. 'Quotation withheld.' Two events that look alike in the local field are separated by the breadth of their input, which is not visible in the signal being compared - so a study classifying events by waveform is classifying by something other than the mechanism. · strength of the relation: 0.8 · note: the induced oscillation is kept terminologically separate from the spontaneous one, and the paper lists where they diverge Quotation withheld because this record is not cleared for redistribution. GABA A —causes→ iHFOs GABA A iHFOs strength of the relation: 1 · note: necessary, shown by abolition under focal blockade - which is also what defeats the axon-net model Quotation withheld because this record is not cleared for redistribution. picrotoxin —causes→ fast ripples picrotoxin fast ripples strength of the relation: 1 · note: removing inhibition does not stop the rhythm, it converts it to the pathological one Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says epileptic oscillations emerged after PTX; causes is loose. Quotation withheld because this record is not cleared for redistribution. PV —is-a→ interneurons PV interneurons strength of the relation: 1 Quotation withheld because this record is not cleared for redistribution. iHFOs —distinct-from→ volume-conducted iHFOs volume-conducted strength of the relation: 0.9 · note: distance falloff excludes passive spread as the source of multi-site coherence Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span says ripple coherence across sites is not a volume-conducted effect; distinct-from iHFOs is loose. Quotation withheld because this record is not cleared for redistribution. superficial —contrasted-with→ deep superficial deep strength of the relation: 0.9 Quotation withheld because this record is not cleared for redistribution. Wilcoxon signed-rank test Wilcoxon signed-rank test Quotation withheld because this record is not cleared for redistribution. Mann-Whitney U test Mann-Whitney U test Quotation withheld because this record is not cleared for redistribution. chi-squared test chi-squared test Quotation withheld because this record is not cleared for redistribution. rank correlation rank correlation Quotation withheld because this record is not cleared for redistribution. circular correlation circular correlation Quotation withheld because this record is not cleared for redistribution. circular-linear correlation circular-linear correlation Quotation withheld because this record is not cleared for redistribution. Rayleigh test Rayleigh test Quotation withheld because this record is not cleared for redistribution. F-test with Bonferroni correction F-test with Bonferroni correction Quotation withheld because this record is not cleared for redistribution. standard deviation standard deviation Quotation withheld because this record is not cleared for redistribution. Wilcoxon's paired signed-rank test Wilcoxon's paired signed-rank test Quotation withheld because this record is not cleared for redistribution. Mann-Whitney U test Mann-Whitney U test Quotation withheld because this record is not cleared for redistribution. coherence coherence Quotation withheld because this record is not cleared for redistribution. rank correlation rank correlation Quotation withheld because this record is not cleared for redistribution. Optogenetically depolarizing a small local group of CA1 pyramidal cells was enough to generate ripple-frequency oscillations, while silencing pyramidal cells directly or indirectly (by driving PV or somatostatin interneurons) terminated ripples that were already underway. Quotation withheld because this record is not cleared for redistribution. Focal blockade of GABA-A receptors completely abolished locally induced high-frequency oscillations, showing that pyramidal-pyramidal interactions by themselves cannot produce ripples and that fast inhibition is required. Quotation withheld because this record is not cleared for redistribution. Non-rhythmic activation of PV interneurons could not induce field-potential ripples, so a simple interneuron-interneuron model cannot account for LFP ripples. Quotation withheld because this record is not cleared for redistribution. Although PV activation produced no field ripple, it did impose ripple-frequency coherence on ensemble spiking, so interneuron-interneuron interactions can set the timing even when they cannot create the oscillation. Quotation withheld because this record is not cleared for redistribution. Blocking fast inhibition reduced the phase coherence between simultaneously induced oscillations at separate sites, showing that interneurons are what keeps spatially separate ripple oscillators locked together. Quotation withheld because this record is not cleared for redistribution. Pyramidal cells fired roughly a quarter-cycle (about 90 degrees) ahead of interneurons on every ripple cycle, with mean phases of 157 degrees for pyramidal cells and 242 degrees for interneurons. Quotation withheld because this record is not cleared for redistribution. Superficial CA1 pyramidal cells were entrained to ripples more often (64% versus 57%) and with higher peak firing gain (12.4 versus 9.2) than deep pyramidal cells. Quotation withheld because this record is not cleared for redistribution. Physiological ripples and pathological "fast ripples" are produced by different mechanisms, because removing fast inhibition destroys the first while creating the second. Quotation withheld because this record is not cleared for redistribution. Locally induced oscillations fell to 2% of local power 400 micrometres away and to baseline beyond that. Quotation withheld because this record is not cleared for redistribution. depolarising a small local group of pyramidal cells is sufficient to induce a ripple-like oscillation Quotation withheld because this record is not cleared for redistribution. focal GABA-A blockade abolishes the induced oscillation completely, so pyramidal-pyramidal interaction alone cannot generate it Quotation withheld because this record is not cleared for redistribution. silencing pyramidal cells, directly or via PV or SOM interneurons, aborts ongoing spontaneous ripples Quotation withheld because this record is not cleared for redistribution. tonic PV activation cannot induce a field ripple, but does organise ensemble spiking into coherent ripple-frequency oscillations Quotation withheld because this record is not cleared for redistribution. simultaneous multisite induction produces coherence at distances where single-site induction gives chance Quotation withheld because this record is not cleared for redistribution. removing inhibition converts the physiological rhythm into 200-300 Hz epileptic fast ripples Quotation withheld because this record is not cleared for redistribution. the same spikes give 12.4% coherent pairs as single units and 35% when agglomerated per shank Quotation withheld because this record is not cleared for redistribution. connexin 36 ablation does not alter in vivo ripples, and pyramidal-pyramidal connexin coupling was never demonstrated Quotation withheld because this record is not cleared for redistribution. superficial pyramidal cells are entrained more often and more strongly than deep ones Quotation withheld because this record is not cleared for redistribution. the same induction works in dentate gyrus and in layer 5 of somatosensory cortex, so the mechanism is not hippocampus-specific Quotation withheld because this record is not cleared for redistribution. induced high-frequency oscillations (iHFOs) induced high-frequency oscillations (iHFOs) Quotation withheld because this record is not cleared for redistribution. gain gain Quotation withheld because this record is not cleared for redistribution. threshold light intensity threshold light intensity Quotation withheld because this record is not cleared for redistribution. summed INT summed INT Quotation withheld because this record is not cleared for redistribution. ripple ripple Quotation withheld because this record is not cleared for redistribution. sharp wave sharp wave Quotation withheld because this record is not cleared for redistribution. iHFOs iHFOs Quotation withheld because this record is not cleared for redistribution. axon-net model axon-net model Quotation withheld because this record is not cleared for redistribution. INT-INT INT-INT Quotation withheld because this record is not cleared for redistribution. PYR-INT loop PYR-INT loop Quotation withheld because this record is not cleared for redistribution. PYR-INT-INT PYR-INT-INT Quotation withheld because this record is not cleared for redistribution. summed PYR summed PYR Quotation withheld because this record is not cleared for redistribution. receptor blockade receptor blockade Quotation withheld because this record is not cleared for redistribution. global frequency global frequency Quotation withheld because this record is not cleared for redistribution. coherence between nearby sites coherence between nearby sites Quotation withheld because this record is not cleared for redistribution. light intensity light intensity Quotation withheld because this record is not cleared for redistribution. distance distance Quotation withheld because this record is not cleared for redistribution. cell type cell type Quotation withheld because this record is not cleared for redistribution. sublayer sublayer Quotation withheld because this record is not cleared for redistribution. 115,204 ripples — total number of spontaneous fast-gamma/ripple events analysed, with median frequency 148 Hz and duration 43 ms Quotation withheld because this record is not cleared for redistribution. 80–100 — upper estimate of the number of CA1 pyramidal cells directly illuminated at maximum light intensity, taken as the size of the minimal ripple-generating network Quotation withheld because this record is not cleared for redistribution. 6-fold — increase in CA1 neuron firing rate during spontaneous ripples relative to no-ripple epochs Quotation withheld because this record is not cleared for redistribution. 3,885 — total putative single cells recorded from CA1 across 47 animals Quotation withheld because this record is not cleared for redistribution. 2% ± 0.3% — induced oscillation power at 400 micrometres from the illuminated shank, relative to power at the illuminated site Quotation withheld because this record is not cleared for redistribution. 258/737 (35%) — proportion of summed-pyramidal/summed-interneuron spike-train pairs showing significant ripple-band coherence during spontaneous ripples Quotation withheld because this record is not cleared for redistribution. 790/6369 (12.4%) — proportion of coherent pairs when the same spikes were analysed as single neurons instead of summed populations Quotation withheld because this record is not cleared for redistribution. 23% — median reduction of inter-site ripple-band coherence after GABA-A receptor blockade Quotation withheld because this record is not cleared for redistribution. 16% — median Bayes error of the classifier separating true from false online ripple detections Quotation withheld because this record is not cleared for redistribution. 80-100 — CA1 pyramidal cells directly illuminated at maximum light - the size of the minimal generating network Quotation withheld because this record is not cleared for redistribution. 148 Hz, 43 ms, 115,204 — median frequency, median duration and total number of ripples recorded Quotation withheld because this record is not cleared for redistribution. 200-300 Hz — frequency of the epileptic fast ripples that follow GABA-A blockade Quotation withheld because this record is not cleared for redistribution. 90-140 Hz vs 140-180 Hz — the published frequency bands separating fast gamma from ripple Quotation withheld because this record is not cleared for redistribution. 2% at 400 um — induced oscillation power two shanks away, against 89% for spontaneous ripples at the same distance Quotation withheld because this record is not cleared for redistribution. 12.4% vs 35% — coherent pairs from the same spikes, as single units versus agglomerated per shank Quotation withheld because this record is not cleared for redistribution. 1 mM picrotoxin, 13-52 nl — the focal GABA-A blockade dose and volume Quotation withheld because this record is not cleared for redistribution.

The full text of this article is not redistributable, so it is not included here. The evidence sentences are withheld with it; the tag layer and its grounding status remain. The article itself is at https://doi.org/10.1016/j.neuron.2014.06.023.