Noninvasive optical inhibition with a red-shifted microbial rhodopsin

Chuong, Miri, Busskamp, Matthews, Acker, Sørensen, Young, Klapoetke · Nature neuroscience · 2014 · neuroscience · 10.1038/nn.3752 · record Chuong2014-noninvasive-optical-inhibition-with-a-red-sh
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Where this record's text came from. faceted 2026-08 by reading the locally held text (xml); every evidence string verified as an exact substring of that text before merging. Claim type is method because the contribution is a reagent (a new opsin) plus its validation, not a claim about how the brain works; 'system-or-tool-building' from the supplied vocabulary fits the protein-engineering-plus-characterisation design, although the validation itself uses patch clamp, extracellular recording and Monte Carlo light-propagation simulation. The 'extends' relation names a class of prior tools rather than a single citation, but the comparison is explicit in the paper's own words and eNpHR3.0/ArchT are the named comparators in the experiments. Replication status untested: the paper reports no independent replication of Jaws. 2026-08-13, 2026-08-14 and 2026-08-15 schema-0.3 passes: every quote verified as an exact substring of the staged text and anchored at merge time; concept terms verified present; every edge endpoint an existing node.
12 quotations on this page contain a reference number where the paper printed a superscript. This journal style prints citations as raised numerals — parameters12,13 — and the extraction flattened them into the line, so the sentence reads parameters 12 , 13 . The digits are citation markers and not part of what the author wrote. The quotes keep them for the same reason they keep every other extraction fault: a quote is reproduced exactly or it proves nothing.
How to read this page. The article itself is not reproduced here — this paper is not cleared for redistribution, so what follows is the tag layer alone. The evidence sentences are withheld with the article. The table at the foot lists every tag the record carries; each row names the facet it belongs to, and the whose words column says whether the tag records the paper's own wording or the tagger's sentence about the paper. Every tag links to each other paper in the corpus carrying it. The machine-readable edition of the same thing is the TEI file beside this one, where the tags live in standOff, and the article is at its publisher via the link below. When we have changed our mind. Some entries in the table begin with a word in capitals and the reason for it. EVIDENCE CORRECTED — the finding still stands, but we had quoted the wrong sentence from the paper, and the quotation has been replaced with the right one. RETRACTED — the entry itself was wrong; it stays on the page, marked, with the reason, rather than being deleted. WITHDRAWN AND REPLACED — the entry was wrong, and a corrected version of it appears in the entries below. Each mark carries its own reason, in brackets, because the reasons differ from one entry to the next. An entry we have WITHDRAWN is removed from this page and kept in the record, with its reason. A line reading Audit and a date is a later re-reading of the entry against its whole sentence: DOUBTFUL means it was kept, and the reason says what is loose about it. Quotation marks inside the tagger's sentence. Where a tag is the tagger's own sentence, a phrase in quotation marks inside it is borrowed from the paper — the tagger's wording around it is not. The paper's own sentence is the evidence quote for that row; on this page it is withheld with the article, and the article is at its publisher. Nothing inside quotation marks anywhere on this page is ours: if it is quoted, it is the paper's. Whose words a concept carries. A concept entry records a term the paper itself uses, so the term, the sense given for it, and its evidence are the paper's own words, quoted where the paper fixes them. This is the opposite of a sense entry in the tag table, which is the tagger's sentence about how the paper uses a term. Where a concept entry could not be grounded in the paper's words, the entry says so on its own row.
Other fields define these differently the same word, defined another way in another discipline
principal component analysis 5 fields

Tags on this paper

Every tag the record carries, each linking to every other paper in the corpus that carries it. A tag appears here whether or not its words occur in the article — the spans below are only the ones a sentence in this paper licenses. Of the 20 concept tags on this paper, 4 are grounded in a quoted sentence. All carry the tagger's gloss of what the term means in this paper, which is not something the article can license.
Jaws cruxhalorhodopsin eNpHR3.0 ArchT photocurrents action spectra rebound transcranial transdurally optical fiber retinitis pigmentosa cone photoreceptors retinal ganglion hemoglobin myelination tdTomato trafficking sequences point mutations network inhibition apical dendrites Haemoglobin absorbs red light less than shorter wavelengths, so red-shifting the opsin's action spectrum lets usable light reach deeper brain tissue, which is what makes large-volume and transcranial inhibition possible. A minority of recorded neurons increase firing under illumination because inhibition of upstream neurons removes their drive (network disinhibition), not because the opsin excites them. optogenetic inhibition Halo57 light power degree of suppression uninfected dentate granule cells ANOVA ANOVA followed by a Newman-Keuls multiple comparison post-test ANOVA with Dunnett's post hoc test ANOVA with Dunnett’s post hoc test paired t-test two-tailed paired sample t -test Shapiro-Wilk normality test tested for normality with a Shapiro-Wilk test Kolmogorov-Smirnov test principal component analysis principal component analysis discrimination ANOVA with Newman-Keuls post hoc test paired t -test Dunnett system-or-tool-building

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second readingalternativesan independent re-reading of a facet, recorded whether or not it agrees
relation to other workclaim_relationshow this paper stands to another: agrees, contradicts, extends, qualifies
claim typeclaim_typethe shape of the claim: existence, mechanism, method, critique, prediction, null
concept edgeconcept_edgesan asserted relation between two concepts, with the sentence asserting it
conceptconceptsan idea the paper works with, quoted where the paper uses it
content tagcontent_tagsa finding, definition, quantity, statistic or variable named in the paper
contributioncontributionwhat the paper claims to add
controlcontrolsan experiment run to eliminate a rival explanation
limitationlimitationswhat the paper says its evidence cannot support
mechanismmechanismshow the reported effect is said to come about
methodmethodhow the paper produced its evidence
object of studyobject_of_studywhat the paper is about — the thing it investigates
phenomenonphenomenonthe effect or regularity under study
research questionresearch_questionthe question the paper sets itself
sensesensesa distinct use of a term, quoted where the paper fixes it
transfertransfersa method or concept carried in from another field

The paper

The full text is not reproduced here. This article is not cleared for redistribution, so the page carries the tag layer only. Its evidence sentences are withheld; the grounding status remains with each tag, and the article itself is at https://doi.org/10.1038/nn.3752. The reading view exists for the papers whose licence permits it.

Every tag on this page

alternatives 3 · claim_relations 8 · claim_type 1 · concept_edges 3 · concepts 4 · content_tags 54 · contribution 1 · controls 2 · limitations 9 · mechanisms 7 · method 1 · object_of_study 1 · phenomenon 1 · research_question 1 · senses 5 · transfers 4

Relations on this page carry a quotation for the claim. Where a relation was separately evidenced — and so tested against the vocabulary for its type — the row says so; none of 3 relations here carry that mark. The rest are the tagger’s reading of the sentence quoted beside them.

facettagfieldconf.whose words
object_of_studyhow to silence neurons over large volumes and at depth without putting anything into the brain
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object_of_studythe paper's words
research_questionwhether a red-shifted chloride pump can be engineered to give enough photocurrent for inhibition through intact skull
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research_questionthe paper's words
contributionJaws, a cruxhalorhodopsin with the most red-shifted spectrum of any inhibitor, giving roughly threefold photocurrents at red wavelengths and enabling transcranial silencing 1-3 mm deep in awake mice
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contributionthe paper's words
claim_typemethod
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claim_typethe paper's words
phenomenonoptogenetic neural inhibition
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phenomenonthe paper's words
methodsystem-or-tool-building
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methodthe paper's words
mechanismsmechanisms
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mechanisms[0]the tagger's words
mechanismsmechanisms
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mechanisms[1]the tagger's words
mechanismsred light reaches deeper because hemoglobin, myoglobin and lipid absorb it less than blue or yellow
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mechanisms[2]1.0the tagger's words
mechanismsthe gain came from two point mutations plus trafficking sequences borrowed from a potassium channel
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mechanisms[3]1.0the tagger's words
mechanismsrebound after illumination is attributed variously to hyperpolarisation-activated currents or to chloride accumulation shifting the reversal potential
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mechanisms[4]0.9the tagger's words
mechanismsramping the light down rather than switching it off halves the rebound rate and delays it fourfold
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mechanisms[5]1.0the tagger's words
mechanismsthe few neurons that increased firing are attributed to inhibition of upstream neurons rather than a direct effect
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mechanisms[6]0.9the tagger's words
limitationsThe noninvasive results cannot be shown to be direct rather than mediated by network effects or illumination of superficial apical dendrites.
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what this limits: the noninvasive results specifically: WE CANNOT EXPLICITLY RULE OUT THE POSSIBILITY THAT THE OBSERVED NONINVASIVE RESULTS WERE THE RESULT OF INDIRECT NETWORK ACTIVITY OR APICAL DENDRITIC ILLUMINATION
limitations[0]the tagger's words
limitationsTranscranial illumination cannot be confined to deep tissue with this setup.
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what this limits: any claim of depth-specific inhibition: IT IS NOT POSSIBLE TO NONINVASIVELY ILLUMINATE ONLY DEEP VOLUMES WITH OUR EXPERIMENTAL SETUP WITHOUT ALSO TARGETING SURFACE AND INTERMEDIATE LAYERS
limitations[1]the tagger's words
limitationsJaws still produces post-illumination rebound spiking, which constrains experimental design.
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what this limits: experimental designs built on this inhibitor: JAWS DOES YIELD POST-ILLUMINATION REBOUND, WHICH LIKELY HAS IMPLICATIONS FOR CAREFUL EXPERIMENT DESIGN
limitations[2]the tagger's words
limitationsExperiments were essentially unblinded and unrandomised.
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what this limits: every comparison in the paper: NO BLINDING WAS CARRIED OUT, WITH THE EXCEPTION OF COTRANSFECTED OPSIN-GFP AND TDTOMATO DATA SETS
limitations[3]the tagger's words
limitationsthe method cannot illuminate deep tissue without also illuminating everything above it, so direct deep inhibition cannot be separated from surface or dendritic effects
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what this limits: the same scope as items 0 and 1 - surface and intermediate layers are illuminated too, so deep effects are not isolated
limitations[4]1.0the tagger's words
limitationsJaws produces MORE post-illumination rebound than the inhibitors it replaces
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what this limits: the choice between inhibitors: Quotation withheld - more post-illumination rebound than the tools it replaces
limitations[5]1.0the tagger's words
limitationsmyelination still affects light propagation, so red penetrance is not uniform across preparations
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what this limits: the transfer of the penetrance advantage between preparations: MYELINATION MAY STILL AFFECT OPTICAL PROPAGATION IN NEURAL TISSUE
limitations[6]1.0the tagger's words
limitationsthe two beneficial mutations do not transfer to the halorhodopsin they were modelled on, so the engineering is scaffold-specific
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what this limits: the generality of the engineering strategy: THE TWO HOMOLOGOUS POINT MUTATIONS DID NOT ENHANCE THE N. PHARAONIS HALORHODOPSIN - the mutations do not transfer
limitations[7]1.0the tagger's words
limitationseven improved, the restored retinal spiking reaches about 190 Hz against a wild-type range of 15-450 Hz
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what this limits: the vision-restoration claim: THE RESULTANT SPIKING RATES ARE LIMITED TO LESS THAN 200 HZ, SUBSTANTIALLY LESS THAN THE FULL WILD-TYPE RANGE OF 15-450 HZ
limitations[8]0.9the tagger's words
transfersMonte Carlo simulation of light propagation with Henyey-Greenstein and Gegenbauer-kernel anisotropic scattering phase functions, imported to predict how deep red light penetrates brain tissue and skull
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transfers[0]the tagger's words
transfersa rhodopsin from a halophilic archaeon, screened as a scaffold rather than studied for itself
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transfers[1]1.0the tagger's words
transferstrafficking sequences taken from the Kir2.1 potassium channel to improve membrane delivery
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transfers[2]1.0the tagger's words
transfersMonte Carlo modelling of light transport, used to justify the wavelength choice before any protein was made
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transfers[3]1.0the tagger's words
controlsyellow light at 593 nm, close to the spectral peak of both opsins, used to identify which neurons express the opsin, with paired recordings of the same neurons across wavelengths
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eliminates: mistaking a non-expressing neuron for an expressing one when assessing performance at the red-shifted wavelength · outcome (stated by the tagger, no quotation): held
controls[0]0.9the tagger's words
controlspaired recordings with an acutely inserted 200-um fiber as a positive control against transcranial illumination through the intact skull - marked PARTIAL because the paper reports in its own words that this did not settle the question
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eliminates: hyperpolarisation of superficial apical dendrites, producing somatic or downstream network inhibition, as the explanation of the noninvasive result - the paper states it CANNOT EXPLICITLY RULE OUT that possibility · outcome (stated by the tagger, no quotation): partial
controls[1]0.9the tagger's words
conceptsJaws
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also in: Jaws
concepts[0]the paper's words
conceptsphotocurrents
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also in: photocurrents
concepts[4]the paper's words
conceptsrebound
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also in: rebound
concepts[6]the paper's words
conceptspoint mutations
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concepts[17]the paper's words
sensesoptogenetic inhibition here means a light-driven ION PUMP moving chloride inward, not a channel and not a synaptic silencer - the class matters because rebound and reversal behave differently
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senses[0]1.0the tagger's words
sensesnoninvasive means no implanted optical device; the skull is intact but the virus was still injected surgically, and the paper's no-surgery scenario is explicitly future work with a transgenic line
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senses[1]1.0the tagger's words
sensesred-shifted is relative and small in absolute terms - a 14 nm shift from the standard halorhodopsin - and the practical gain comes from where that sits on the tissue absorption curve
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senses[2]0.9the tagger's words
sensespercent inhibition here is computed over neurons SHOWING suppression, with unchanged and increased-firing units reported separately rather than folded in
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senses[3]1.0the tagger's words
sensesJaws and Jaws-ER2 are two molecules differing in trafficking sequence and are reported separately throughout
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senses[4]1.0the tagger's words
alternativesclaim_type: method
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a second reading reaching the same value. Recorded: method — note: a second reading reaching the same value from a different sentence. Not applied - a person decides.
alternatives.claim_typethe tagger's words
alternativesmethod: screening of a rhodopsin class, two point mutations and trafficking sequences, then comparison against existing inhibitors in culture, retina, slice and awake cortex
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a second reading DIFFERING from the recorded value. Recorded: system-or-tool-building — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides.
alternatives.methodthe tagger's words
alternativesphenomenon: light-driven hyperpolarisation of genetically targeted neurons
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a second reading DIFFERING from the recorded value. Recorded: optogenetic neural inhibition — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides.
alternatives.phenomenonthe tagger's words
claim_relationsbuilds-on → the authors' earlier identification of red-shifted cruxhalorhodopsins from H. marismortui and H. vallismortis (the paper's refs 1, 18)
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claim_relations[0]the tagger's words
claim_relationsextends → previous halorhodopsin silencers (eNpHR, eNpHR3.0)
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claim_relations[1]the tagger's words
claim_relationsreplicates → previous reports of a minority of neurons increasing firing during optogenetic inhibition (the paper's refs 3, 40, 41)
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claim_relations[2]the tagger's words
claim_relationsextends → earlier hyperpolarising pumps, which addressed about a cubic millimetre
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claim_relations[3]1.0the tagger's words
claim_relationscontradicts → the standing position that noninvasive optical inhibition was not achievable
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claim_relations[4]1.0the tagger's words
claim_relationscritiques → existing inhibitors' red-light performance, at 10-30% of peak capacity
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claim_relations[5]1.0the tagger's words
claim_relationsextends → eNpHR-based cone reactivation in retinitis pigmentosa models, by widening the restored spike frequency range
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claim_relations[6]1.0the tagger's words
claim_relationsconfirms → prior reports that a minority of neurons increase firing under optogenetic inhibition
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claim_relations[7]1.0the tagger's words
concept_edgesEVIDENCE CORRECTED (RE-GROUNDED) · Jaws —is-a→ cruxhalorhodopsin
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EVIDENCE CORRECTED: RE-GROUNDED. The old span described a screen of the class without naming Jaws. This sentence names both IN APPOSITION - 'a red-shifted cruxhalorhodopsin, Jaws' - which is kind-membership stated as directly as a paper ever states it. — strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but 'Jaws' is not named in this span, which identifies Halo57 as the cruxhalorhodopsin Jaws was engineered from; the relation holds only through that chain.
concept_edges[0]1.0the tagger's words
concept_edgespoint mutations —causes→ photocurrents
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direction on the measure: increases · strength of the relation: 1 · note: SIGN: increases, without moving the action spectrum - the two properties were separable
concept_edges[1]1.0the tagger's words
concept_edgesJaws —causes→ rebound
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holds when: relative to eNpHR3.0 and ArchT - the comparison is between opsins, not against no opsin · direction on the measure: increases · strength of the relation: 0.9 · note: SIGN: worse than the tools it replaces. The paper reports the axis on which its own tool loses
also in: Jaws · rebound
concept_edges[5]1.0the tagger's words
content_tagsANOVA
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also in: ANOVA
content_tags.statistics[0]the tagger's words
content_tagsANOVA with Dunnett's post hoc test
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content_tags.statistics[1]the tagger's words
content_tagspaired t-test
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also in: paired t-test
content_tags.statistics[2]the tagger's words
content_tagsShapiro-Wilk normality test
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content_tags.statistics[3]the tagger's words
content_tagsKolmogorov-Smirnov test
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content_tags.statistics[4]the tagger's words
content_tagsprincipal component analysis
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content_tags.statistics[5]the tagger's words
content_tagsANOVA with Newman-Keuls post hoc test
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content_tags.statistics[6]1.0the tagger's words
content_tagsKolmogorov-Smirnov test
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content_tags.statistics[7]1.0the tagger's words
content_tagspaired t -test
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content_tags.statistics[8]1.0the tagger's words
content_tagsDunnett
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also in: Dunnett
content_tags.statistics[9]1.0the tagger's words
content_tagsJaws produced significantly larger red-light photocurrents than the existing silencers eNpHR3.0 and ArchT at every light power tested in cultured neurons.
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content_tags.findings[0]the tagger's words
content_tagsJaws strongly suppressed visually evoked cortical activity in vivo and restored light-driven retinal ganglion spiking in retinitis pigmentosa model mice.
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content_tags.findings[1]the tagger's words
content_tagsJaws can mediate noninvasive transcranial optical inhibition of neurons deep in the brain of awake mice.
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content_tags.findings[2]the tagger's words
content_tagsTranscranial red-light illumination cut firing by roughly 92% in suppressed units across motor, somatosensory, insular and piriform cortex.
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content_tags.findings[3]the tagger's words
content_tagsGradually ramping the light down cut mean rebound firing from about 52 to 23 Hz, suggesting that shaping light pulses may reduce rebound.
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content_tags.findings[4]the tagger's words
content_tagsJaws gave significantly larger red-light photocurrents than eNpHR3.0 or ArchT at every power tested
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content_tags.findings[5]1.0the tagger's words
content_tagsvisually evoked activity fell by about 86% in Jaws-expressing cortex
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content_tags.findings[6]1.0the tagger's words
content_tagsunder red light Jaws inhibited about 89-97% while eNpHR3.0 fell to 27.5%, against 76% at its own yellow peak
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content_tags.findings[7]1.0the tagger's words
content_tagstranscranial illumination through intact skull suppressed firing by about 92% in neurons showing suppression, 1-3 mm deep
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content_tags.findings[8]1.0the tagger's words
content_tagstransdural illumination suppressed firing by about 86% in medial prefrontal cortex
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content_tags.findings[9]1.0the tagger's words
content_tagsefficacy was similar across several millimetres of depth and across baseline firing rates
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content_tags.findings[10]1.0the tagger's words
content_tagsin the retinitis pigmentosa model Jaws drove mean ganglion spiking of 189.5 Hz against 67.8 Hz for eNpHR, roughly tripling the bandwidth
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content_tags.findings[11]1.0the tagger's words
content_tagsREPORTED AGAINST ITSELF: Jaws produced greater post-illumination rebound than eNpHR3.0 or ArchT
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content_tags.findings[12]1.0the tagger's words
content_tagsramping the light down cut mean rebound firing from 52 Hz to 23 Hz
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content_tags.findings[13]1.0the tagger's words
content_tagsthe two homologous point mutations did not enhance N. pharaonis halorhodopsin
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content_tags.findings[14]1.0the tagger's words
content_tagsCONTROL NULL: expressing Jaws did not alter basal cell properties in culture or in slice, and its kinetics matched other inhibitors
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content_tags.findings[15]1.0the tagger's words
content_tagsCONTROL BY DESIGN: cells were selected by an independent tdTomato marker so the photocurrent comparison could not be driven by opsin expression level
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content_tags.findings[16]1.0the tagger's words
content_tagsDECLARED UNRESOLVABLE: surface and intermediate layers are necessarily illuminated too, so direct deep inhibition cannot be separated from dendritic or network effects
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content_tags.findings[17]1.0the tagger's words
content_tagsthe conclusion is downgraded accordingly to highly suggestive of direct inhibition rather than demonstrated
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content_tags.findings[18]1.0the tagger's words
content_tagsoptogenetic inhibition
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content_tags.definitions[0]the tagger's words
content_tagsJaws
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also in: Jaws
content_tags.definitions[1]the tagger's words
content_tagsHalo57
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also in: Halo57
content_tags.definitions[2]the tagger's words
content_tagscruxhalorhodopsin
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content_tags.definitions[3]1.0the tagger's words
content_tagsrebound
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also in: rebound
content_tags.definitions[4]1.0the tagger's words
content_tagsretinitis pigmentosa
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content_tags.definitions[5]0.85the tagger's words
content_tagsJaws
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also in: Jaws
content_tags.definitions[6]1.0the tagger's words
content_tagslight power
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also in: light power
content_tags.variables[1]the tagger's words
content_tagsdegree of suppression
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content_tags.variables[2]the tagger's words
content_tagsuninfected dentate granule cells
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content_tags.variables[4]the tagger's words
content_tagsphotocurrents
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also in: photocurrents
content_tags.variables[5]1.0the tagger's words
content_tagsrebound
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also in: rebound
content_tags.variables[6]1.0the tagger's words
content_tagstranscranial
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also in: transcranial
content_tags.variables[7]1.0the tagger's words
content_tags86 ± 3% — reduction of visually evoked cortical activity in Jaws-expressing visual cortex under yellow light
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content_tags.quantities[0]the tagger's words
content_tags67.8 ± 7.0 Hz versus 189.5 ± 15.9 Hz — mean retinal ganglion cell spiking frequency driven through eNpHR versus through Jaws in blind mouse retina (a threefold bandwidth increase)
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content_tags.quantities[1]the tagger's words
content_tags14-nm — red shift of the Jaws action spectrum relative to the N. pharaonis halorhodopsin family
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content_tags.quantities[2]the tagger's words
content_tags10–30% — fraction of peak capacity at which pre-existing optogenetic inhibitors operate under red light
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content_tags.quantities[3]the tagger's words
content_tags1–3 mm — depth below the brain surface at which neurons were inhibited transcranially in awake mice
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content_tags.quantities[4]the tagger's words
content_tags14 nm — spectral shift of Jaws relative to the standard halorhodopsin - small in absolute terms, decisive on the absorption curve
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content_tags.quantities[5]0.8the tagger's words
content_tags10-30% — fraction of peak capacity at which existing inhibitors work under red light
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content_tags.quantities[6]1.0the tagger's words
content_tags27.5 ± 30.3% — eNpHR3.0 red-light inhibition - note the spread exceeds the mean
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content_tags.quantities[7]1.0the tagger's words
content_tags189.5 vs 67.8 Hz — mean restored ganglion spiking with Jaws against eNpHR, against a wild-type range of 15-450 Hz
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content_tags.quantities[8]1.0the tagger's words
content_tags52 to 23 Hz — rebound firing before and after ramping the light down
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content_tags.quantities[9]1.0the tagger's words
content_tags1-3 mm — depth range at which transcranial inhibition was effective
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content_tags.quantities[10]1.0the tagger's words
content_tags13 suppressed, 9 unchanged, 3 increased — unit outcomes under transcranial illumination, reported separately
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content_tags.quantities[11]1.0the tagger's words

Interpretive choices

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