RESUMO
Memory conformity may develop when people are confronted with distinct memories reported by others in social situations and knowingly/unknowingly adhere to these exogenous memories. Earlier research on memory conformity suggests that (1) subjects were more likely to conform to confederate with high confidence; (2) subjects with low confidence on their memory accuracy were more likely to conform, and; (3) this subjective confidence could be adjusted by social manipulations. Nonetheless, it remains unclear how the confidence levels of ours and others may interact and produce a combined effect on our degree of conformity. More importantly, is memory conformity, defined by a complete adoption of the opposite side, the result of a gradual accumulation of subtler changes at the confidence level, i.e., a buildup of confidence conformity? Here, we followed participant's confidence transformation quantitatively over three confederate sessions in a memory test. After studying a set of human motion videos, participants had to answer simultaneously whether a target or lure video had appeared before by indicating their side (i.e., Yes/No) and their associated confidence rating. Participants were allowed to adjust their responses as they were being shown randomly-generated confederates' answers and confidence values. Results show that participants indeed demonstrated confidence conformity. Interestingly, they tended to become committed to their side early on and gain confidence gradually over subsequent sessions. This polarizing behaviour may be explained by two kinds of preferences: (1) Participant's confidence enhancement towards same-sided confederates was greater in magnitude compared to the decrement towards an opposite-sided confederate; and (2) Participants had the most effective confidence boost when the same-sided confederates shared similar, but not considerably different, confidence level to theirs. In other words, humans exhibit side- and similarity-biases during confidence conformity.
Assuntos
Comportamento Social , Adulto , Humanos , Memória , Conformidade Social , Adulto JovemRESUMO
Numerous rhodopsin mutations have been implicated in night blindness and retinal degeneration, often with unclear etiology. D190N-rhodopsin (D190N-Rho) is a well-known inherited human mutation causing retinitis pigmentosa. Both higher-than-normal spontaneous-isomerization activity and misfolding/mistargeting of the mutant protein have been proposed as causes of the disease, but neither explanation has been thoroughly examined. We replaced wild-type rhodopsin (WT-Rho) in RhoD190N/WT mouse rods with a largely "functionally silenced" rhodopsin mutant to isolate electrical responses triggered by D190N-Rho activity, and found that D190N-Rho at the single-molecule level indeed isomerizes more frequently than WT-Rho by over an order of magnitude. Importantly, however, this higher molecular dark activity does not translate into an overall higher cellular dark noise, owing to diminished D190N-Rho content in the rod outer segment. Separately, we found that much of the degeneration and shortened outer-segment length of RhoD190N/WT mouse rods was not averted by ablating rod transducin in phototransduction-also consistent with D190N-Rho's higher isomerization activity not being the primary cause of disease. Instead, the low pigment content, shortened outer-segment length, and a moderate unfolded protein response implicate protein misfolding as the major pathogenic problem. Finally, D190N-Rho also provided some insight into the mechanism of spontaneous pigment excitation.
Assuntos
Degeneração Retiniana/metabolismo , Rodopsina/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Humanos , Transdução de Sinal Luminoso/fisiologia , Camundongos , Mutação/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinose Pigmentar/metabolismo , Segmento Externo da Célula Bastonete/metabolismoRESUMO
G protein-coupled receptor (GPCR) signaling is crucial for many physiological processes. A signature of such pathways is high amplification, a concept originating from retinal rod phototransduction, whereby one photoactivated rhodopsin molecule (Rho*) was long reported to activate several hundred transducins (GT*s), each then activating a cGMP-phosphodiesterase catalytic subunit (GT*·PDE*). This high gain at the Rho*-to-GT* step has been challenged more recently, but estimates remain dispersed and rely on some nonintact rod measurements. With two independent approaches, one with an extremely inefficient mutant rhodopsin and the other with WT bleached rhodopsin, which has exceedingly weak constitutive activity in darkness, we obtained an estimate for the electrical effect from a single GT*·PDE* molecular complex in intact mouse rods. Comparing the single-GT*·PDE* effect to the WT single-photon response, both in Gcaps-/- background, gives an effective gain of only â¼12-14 GT*·PDE*s produced per Rho*. Our findings have finally dispelled the entrenched concept of very high gain at the receptor-to-G protein/effector step in GPCR systems.
Assuntos
Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Transducina/metabolismo , Motivos de Aminoácidos , Animais , GMP Cíclico/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Transdução de Sinal Luminoso , Camundongos Transgênicos , Mutação/genética , Diester Fosfórico Hidrolases/metabolismo , Fótons , Rodopsina/química , Rodopsina/metabolismoRESUMO
Non-image-forming vision in mammals is mediated primarily by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, by far the best-studied subtype, melanopsin activates PLCß4 (phospholipase C-ß4) to open TRPC6,7 channels, mechanistically similar to phototransduction in fly rhabdomeric (microvillous) photoreceptors. We report here that, surprisingly, mouse M4-ipRGCs rely on a different and hitherto undescribed melanopsin-driven, ciliary phototransduction mechanism involving cyclic nucleotide as the second messenger and HCN channels rather than CNG channels as the ion channel for phototransduction. Even more surprisingly, within an individual mouse M2-ipRGC, this HCN-channel-dependent, ciliary phototransduction pathway operates in parallel with the TRPC6,7-dependent rhabdomeric pathway. These findings reveal a complex heterogeneity in phototransduction among ipRGCs and, more importantly, break a general dogma about segregation of the two phototransduction motifs, likely with strong evolutionary implications.
Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Células Ganglionares da Retina/metabolismo , Visão Ocular , Animais , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nucleotídeos Cíclicos/metabolismo , Células Ganglionares da Retina/fisiologia , Canais de Cátion TRPC/metabolismoRESUMO
The molecular circadian clocks in the mammalian retina are locally synchronized by environmental light cycles independent of the suprachiasmatic nuclei (SCN) in the brain. Unexpectedly, this entrainment does not require rods, cones, or melanopsin (OPN4), possibly suggesting the involvement of another retinal photopigment. Here, we show that the ex vivo mouse retinal rhythm is most sensitive to short-wavelength light but that this photoentrainment requires neither the short-wavelength-sensitive cone pigment [S-pigment or cone opsin (OPN1SW)] nor encephalopsin (OPN3). However, retinas lacking neuropsin (OPN5) fail to photoentrain, even though other visual functions appear largely normal. Initial evidence suggests that OPN5 is expressed in select retinal ganglion cells. Remarkably, the mouse corneal circadian rhythm is also photoentrainable ex vivo, and this photoentrainment likewise requires OPN5. Our findings reveal a light-sensing function for mammalian OPN5, until now an orphan opsin.
Assuntos
Córnea/fisiologia , Proteínas de Membrana/fisiologia , Opsinas/fisiologia , Retina/fisiologia , Núcleo Supraquiasmático/fisiologia , Animais , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Opsinas/genética , Raios UltravioletaRESUMO
Vision begins with photoisomerization of visual pigments. Thermal energy can complement photon energy to drive photoisomerization, but it also triggers spontaneous pigment activation as noise that interferes with light detection. For half a century, the mechanism underlying this dark noise has remained controversial. We report here a quantitative relation between a pigment's photoactivation energy and its peak-absorption wavelength, λ(max). Using this relation and assuming that pigment activations by light and heat go through the same ground-state isomerization energy barrier, we can predict the relative noise of diverse pigments with multi-vibrational-mode thermal statistics. The agreement between predictions and our measurements strongly suggests that pigment noise arises from canonical isomerization. The predicted high noise for pigments with λ(max) in the infrared presumably explains why they apparently do not exist in nature.