Publications using TDT

The auditory biology of Monachinae seals is poorly understood. Limited audiometric data and certain anatomical features suggest that these seals may have reduced sensitivity to airborne sounds compared to related species. Here, we describe the in-air hearing abilities of a Hawaiian monk seal ( Neomonachus schauinslandi ) trained to participate in a psychophysical paradigm. We report absolute (unmasked) thresholds for narrowband signals measured in quiet conditions across the range of hearing and masked thresholds measured in the presence of octave-band noise at two frequencies. The behavioral audiogram indicates a functional hearing range from 0.1 to 33 kHz and poor sensitivity, with detection thresholds above 40 dB re 20 µPa. Critical ratio measurements are elevated compared to those of other seals. The apparently reduced terrestrial hearing ability of this individual—considered with available auditory data for a northern elephant seal ( Mirounga angustirostris )—suggests that hearing in Monachinae seals differs from that of the highly sensitive Phocinae seals. Exploration of phylogenetic relationships and anatomical traits support this claim. This work advances understanding of the evolution of hearing in amphibious marine mammals and provides updated information that can be used for management and conservation of endangered Hawaiian monk seals.

Clinical evidence indicates dorsal root ganglion (DRG) stimulation effectively reduces pain without the need to evoke paresthesia. This paresthesia-free anesthesia by DRG stimulation can be promising to treat pain from the viscera, where paresthesia usually cannot be produced. Here, we explored the mechanisms and parameters for DRG stimulation using an ex vivo preparation with mouse distal colon and rectum (colorectum), pelvic nerve, L6 DRG, and dorsal root in continuity. We conducted single-fiber recordings from split dorsal root filaments and assessed the effect of DRG stimulation on afferent neural transmission. We determined the optimal stimulus pulse width by measuring the chronaxies of DRG stimulation to be below 216 µs, indicating spike initiation likely at attached axons rather than somata. Subkilohertz DRG stimulation significantly attenuates colorectal afferent transmission (10, 50, 100, 500, and 1000 Hz), of which 50 and 100 Hz show superior blocking effects. Synchronized spinal nerve and DRG stimulation reveals a progressive increase in conduction delay by DRG stimulation, suggesting activity-dependent slowing in blocked fibers. Afferents blocked by DRG stimulation show a greater increase in conduction delay than the unblocked counterparts. Midrange frequencies (50-500 Hz) are more efficient at blocking transmission than lower or higher frequencies. In addition, DRG stimulation at 50 and 100 Hz significantly attenuates in vivo visceromotor responses to noxious colorectal balloon distension. This reversible conduction block in C-type and Aδ-type afferents by subkilohertz DRG stimulation likely underlies the paresthesia-free anesthesia by DRG stimulation, thereby offering a promising new approach for managing chronic visceral pain.

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O 2 ) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O 2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte–specific ADORA2B (e Adora2b −/− ) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b -/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in e Adora2b −/− mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O 2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B–BPGM axis is a key component for anti-aging and anti-age–related functional decline.

Deafness is known to occur in more than 400 syndromes and accounts for almost 30% of hereditary hearing loss. The molecular mechanisms underlying such syndromic deafness remain unclear. Furthermore, deafness has been a common feature in patients with three main syndromes, the BÖrjeson-Forssman-Lehmann syndrome, Wildervanck syndrome, and Congenital Generalized Hirsutism, all of which are characterized by loss-of-function mutations in the Fgf13 gene. Whether the pathogenesis of deafness in these syndromes is associated with the Fgf13 mutation is not known. To elucidate its role in auditory function, we generated a mouse line with conditional knockout of the Fgf13 gene in the inner ear ( Fgf13 cKO). FGF13 is expressed predominantly in the organ of Corti, spiral ganglion neurons (SGNs), stria vascularis, and the supporting cells. Conditional knockout of the gene in the inner ear led to sensorineural deafness with low amplitude and increased latency of wave I in the auditory brainstem response test but had a normal distortion product otoacoustic emission threshold. Fgf13 deficiency resulted in decreased SGN density from the apical to the basal region without significant morphological changes and those in the number of hair cells. TUNEL and caspase-3 immunocytochemistry assays showed that apoptotic cell death mediated the loss of SGNs. Further detection of apoptotic factors through qRT-PCR suggested the activation of the mitochondrial apoptotic pathway in SGNs. Together, this study reveals a novel role for Fgf13 in auditory function, and indicates that the gene could be a potential candidate for understanding deafness. These findings may provide new perspectives on the molecular mechanisms and novel therapeutic targets for treatment deafness.

Objectives: To investigate the role of auditory cues for spatial release from masking (SRM) in children with bilateral cochlear implants (BiCIs) and compare their performance with children with normal hearing (NH). To quantify the contribution to speech intelligibility benefits from individual auditory cues: head shadow, binaural redundancy, and interaural differences; as well as from multiple cues: SRM and binaural squelch. To assess SRM using a novel approach of adaptive target-masker angular separation, which provides a more functionally relevant assessment in realistic complex auditory environments. Design: Children fitted with BiCIs (N = 11) and with NH (N = 18) were tested in virtual acoustic space that was simulated using head-related transfer functions measured from individual children with BiCIs behind the ear and from a standard head and torso simulator for all NH children. In experiment I, by comparing speech reception thresholds across 4 test conditions that varied in target-masker spatial separation (colocated versus separated at 180°) and listening conditions (monaural versus binaural/bilateral listening), intelligibility benefits were derived for individual auditory cues for SRM. In experiment II, SRM was quantified using a novel measure to find the minimum angular separation (MAS) between the target and masker to achieve a fixed 20% intelligibility improvement. Target speech was fixed at either +90 or –90° azimuth on the side closer to the better ear (+90° for all NH children) and masker locations were adaptively varied. Results: In experiment I, children with BiCIs as a group had smaller intelligibility benefits from head shadow than NH children. No group difference was observed in benefits from binaural redundancy or interaural difference cues. In both groups of children, individuals who gained a larger benefit from interaural differences relied less on monaural head shadow, and vice versa. In experiment II, all children with BiCIs demonstrated measurable MAS thresholds <180° and on average larger than that from NH children. Eight of 11 children with BiCIs and all NH children had a MAS threshold <90°, requiring interaural differences only to gain the target intelligibility benefit; whereas the other 3 children with BiCIs had a MAS between 120° and 137°, requiring monaural head shadow for SRM. Conclusions: When target and maskers were separated at 180° on opposing hemifields, children with BiCIs demonstrated greater intelligibility benefits from head shadow and interaural differences than previous literature showed with a smaller separation. Children with BiCIs demonstrated individual differences in using auditory cues for SRM. From the MAS thresholds, more than half of the children with BiCIs demonstrated robust access to interaural differences without needing additional monaural head shadow for SRM. Both experiments led to the conclusion that individualized fitting strategies in the bilateral devices may be warranted to maximize spatial hearing for children with BiCIs in complex auditory environments.

The Lateral Geniculate Nucleus (LGN) represents one of the major processing sites along the visual pathway. Despite its crucial role in processing visual information and its utility as one target for recently developed visual prostheses, it is much less studied compared to the retina and the visual cortex. In this paper, we introduce a deep learning encoder to predict LGN neuronal firing in response to different visual stimulation patterns. The encoder comprises a deep Convolutional Neural Network (CNN) that incorporates visual stimulus spatiotemporal representation in addition to LGN neuronal firing history to predict the response of LGN neurons. Extracellular activity was recorded in vivo using multi-electrode arrays from single units in the LGN in 12 anesthetized rats with a total neuronal population of 150 units. Neural activity was recorded in response to single-pixel, checkerboard and geometrical shapes visual stimulation patterns. Extracted firing rates and the corresponding stimulation patterns were used to train the model. The performance of the model was assessed using different testing data sets and different firing rate windows. An overall mean correlation coefficient between the actual and the predicted firing rates of 0.57 and 0.7 was achieved for the 10 ms and the 50 ms firing rate windows, respectively. Results demonstrate that the model is robust to variability in the spatiotemporal properties of the recorded neurons outperforming other examined models including the state-of-the-art Generalized Linear Model (GLM). The results indicate the potential of deep convolutional neural networks as viable models of LGN firing.

Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients.

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

In the cochlea, non-sensory supporting cells are directly connected to adjacent supporting cells via gap junctions that allow the exchange of small molecules. We have previously shown that the pharmacological regulation of gap junctions alleviates cisplatin (CDDP)-induced ototoxicity in animal models. In this study, we aimed to identify specific small molecules that pass through gap junctions in the process of CDDP-induced auditory cell death and suggest new mechanisms to prevent hearing loss. We found that the cyclic adenosine monophosphate (cAMP) inducer forskolin (FSK) significantly attenuated CDDP-induced auditory cell death in vitro and ex vivo. The activation of cAMP/PKA/CREB signaling was observed in organ of Corti primary cells treated with FSK, especially in supporting cells. Co-treatment with gap junction enhancers such as all-trans retinoic acid (ATRA) and quinoline showed potentiating effects with FSK on cell survival via activation of cAMP/PKA/CREB. In vivo, the combination of FSK and ATRA was more effective for preventing ototoxicity compared to either single treatment. Our study provides the new insight that gap junction-mediated intercellular communication of cAMP may prevent CDDP-induced ototoxicity.

Elucidating neural signatures of sensory processing across consciousness states is a major focus in neuroscience. Noninvasive human studies using the general anesthetic propofol reveal differential effects on auditory cortical activity, with a greater impact on nonprimary and auditory-related areas than primary auditory cortex. This study used intracranial electroencephalography to examine cortical responses to vowel sequences during induction of general anesthesia with propofol. Subjects were adult neurosurgical patients with intracranial electrodes placed to identify epileptic foci. Data were collected before electrode removal surgery. Stimuli were vowel sequences presented in a target detection task during awake, sedated, and unresponsive states. Averaged evoked potentials (AEPs) and high gamma (70–150 Hz) power were measured in auditory, auditory-related, and prefrontal cortex. In the awake state, AEPs were found throughout studied brain areas; high gamma activity was limited to canonical auditory cortex. Sedation led to a decrease in AEP magnitude. Upon LOC, there was a decrease in the superior temporal gyrus and adjacent auditory-related cortex and a further decrease in AEP magnitude in core auditory cortex, changes in the temporal structure and increased trial-to-trial variability of responses. The findings identify putative biomarkers of LOC and serve as a foundation for future investigations of altered sensory processing.

Active responses to stressors involve motor planning, execution, and feedback. Here we identify an insular cortex to BNST (insula →BNST ) circuit recruited during restraint stress-induced active struggling that modulates affective behavior. We demonstrate that activity in this circuit tightly follows struggling behavioral events and that the size of the fluorescent sensor transient reports the duration of the struggle event, an effect that fades with repeated exposure to the homotypic stressor. Struggle events are associated with enhanced glutamatergic- and decreased GABAergic signaling in the insular cortex, indicating the involvement of a larger circuit. We delineate the afferent network for this pathway, identifying substantial input from motor- and premotor cortex, somatosensory cortex, and the amygdala. To begin to dissect these incoming signals, we examine the motor cortex input, and show that the cells projecting from motor regions to insular cortex are engaged shortly before struggle event onset. This study thus demonstrates a role for the insula →BNST pathway in monitoring struggling activity and regulating affective behavior.

Objective To describe and study the population statistics, hearing phenotype, and pathological changes of a porcine congenital single-sided deafness (CSSD) pedigree. Methods Click auditory brainstem response (ABR), full-frequency ABR, and distortion product otoacoustic emission (DPOAE) were used to assess the hearing phenotype of the strain. Tympanogram was used to assess the middle ear function since birth. Celloidin embedding–hematoxylin–eosin (CE-HE) stain and scanning electron microscopy (SEM) were used to study the pathological changes of cochlear microstructures. Chi-square analysis was used to analyze the relation between hearing loss and other phenotypes. Results The mating mood of CSSD with CSSD was most efficient in breeding-targeted CSSD phenotype (47.62%), and the prevalence of CSSD reached 46.67% till the fifth generation, where 42.22% were bilateral hearing loss (BHL) and 9.00% were normal hearing (NH) individuals. Hearing loss was proved to have no relation with coat color ( P = 0.0841 > 0.05) and gender ( P = 0.4621 > 0.05) by chi-square analysis. The deaf side of CSSD offspring in the fifth generation had no relation with that of their maternal parent ( P = 0.2387 > 0.05). All individuals in this strain exhibited congenital severe to profound sensorineural hearing loss with no malformation and dysfunction of the middle ear. The good hearing ear of CSSD stayed stable over age. The deaf side of CSSD and BHL presented cochlear and saccular degeneration, and the hair cell exhibited malformation since birth and degenerated from the apex to base turn through time. The pathology in BHL cochlea progressed more rapidly than CSSD and till P30, the hair cell had been totally gone. The stria vascularis (SV) was normal since birth and degenerated through time and finally exhibited disorganization of three layers of cells. Conclusion This inbred porcine strain exhibited high and stable prevalence of CSSD, which highly resembled human non-syndromic CSSD disease. This porcine model could be used to further explore the etiology of CSSD and serve as an ideal tool for the studies of the effects of single-sided hearing deprivation on neural, cognitive, and behavioral developments and the benefits brought by CI in CSSD individuals.

Ca 2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca 2+ binding protein preferentially expressed in outer hair cells of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM prevents early progressive hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57BI/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated ARHL of the Ocm KO illustrates the importance of Ca 2+ signaling in maintaining hearing health.

It is widely accepted that even a single acute noise exposure at moderate intensity that induces temporary threshold shift (TTS) can result in permanent loss of ribbon synapses between inner hair cells and afferents. However, effects of repeated or chronic noise exposures on the cochlear synapses especially medial olivocochlear (MOC) efferent synapses remain elusive. Based on a weeklong repeated exposure model of bandwidth noise over 2-20 kHz for 2 hours at seven intensities (88 to 106 dB SPL with 3 dB increment per gradient) on C57BL/6J mice, we attempted to explore the dose-response mechanism of prolonged noise-induced audiological dysfunction and cochlear synaptic degeneration. In our results, mice repeatedly exposed to relatively low-intensity noise (88, 91, and 94 dB SPL) showed few changes on auditory brainstem response (ABR), ribbon synapses, or MOC efferent synapses. Notably, repeated moderate-intensity noise exposures (97 and 100 dB SPL) not only caused hearing threshold shifts and the inner hair cell ribbon synaptopathy but also impaired MOC efferent synapses, which might contribute to complex patterns of damages on cochlear function and morphology. However, repeated high-intensity (103 and 106 dB SPL) noise exposures induced PTSs mainly accompanied by damages on cochlear amplifier function of outer hair cells and the inner hair cell ribbon synaptopathy, rather than the MOC efferent synaptic degeneration. Moreover, we observed a frequency-dependent vulnerability of the repeated acoustic trauma-induced cochlear synaptic degeneration. This study provides a sight into the hypothesis that noise-induced cochlear synaptic degeneration involves both afferent (ribbon synapses) and efferent (MOC terminals) pathology. The pattern of dose-dependent pathological changes induced by repeated noise exposure at various intensities provides a possible explanation for the complicated cochlear synaptic degeneration in humans. The underlying mechanisms remain to be studied in the future.

Usher syndrome type I (USH1) is characterized by congenital deafness, vestibular areflexia, and progressive retinal degeneration with age. The protein-truncating p.Arg245* founder variant of PCDH15 has an ~2% carrier frequency among Ashkenazi Jews, accounting for nearly 60% of their USH1 cases. Here, longitudinal ocular phenotyping in thirteen USH1F individuals harboring the p.Arg245* variant revealed progressive retinal degeneration, leading to severe loss of vision with macular atrophy by the sixth decade. Half of the affected individuals met either the visual acuity or visual field loss definition for legal blindness by the middle of their fifth decade of life. Mice homozygous for p.Arg250* ( Pcdh15 R250X ; equivalent to human p.Arg245*) also have early visual deficits evaluated using electroretinography. Light-dependent translocation of phototransduction cascade proteins, arrestin and transducin, was found to be impaired in Pcdh15 R250X mice. Retinal pigment epithelium-(RPE) specific visual retinoid cycle proteins, RPE65 which converts all- trans retinoids to 11- cis retinoids and CRALBP that transports retinoids, and key retinoid levels were also reduced in Pcdh15 R250X mice, suggesting a dual role for protocadherin-15 in photoreceptors and RPE. Administration of exogenous 9- cis retinal, an analog of the naturally occurring 11- cis retinal, improved ERG amplitudes in these mutant mice, suggesting a basis for a clinical trial of exogenous FDA approved retinoids to preserve vision in USH1F patients. Summary In a preclinical setting studying exogenous retinoids using a novel Usher syndrome mouse model, we describe a potential therapy to treat PCDH15 -mediated visual dysfunction.

To understand the underlying mechanisms of progressive neurophysiological phenomena, neural interfaces should interact bi-directionally with brain circuits over extended periods of time. However, such interfaces remain limited by the foreign body response that stems from the chemo-mechanical mismatch between the probes and the neural tissues. To address this challenge, we developed a multifunctional sensing and actuation platform consisting of multimaterial fibers intimately integrated within a soft hydrogel matrix mimicking the brain tissue. These hybrid devices possess adaptive bending stiffness determined by the hydration states of the hydrogel matrix. This enables their direct insertion into the deep brain regions, while minimizing tissue damage associated with the brain micromotion after implantation. The hydrogel hybrid devices permit electrophysiological, optogenetic, and behavioral studies of neural circuits with minimal foreign body responses and tracking of stable isolated single neuron potentials in freely moving mice over 6 months following implantation.

Aging-related cognitive decline is an emerging health crisis; however, no established unifying mechanism has been identified for the cognitive impairments seen in an aging population. A vascular hypothesis of cognitive decline has been proposed but is difficult to test given the contradictory radiologic needs of high-fidelity microvascular imaging resolution and a broad and deep brain imaging field of view. Super-resolution ultrasound localization microscopy (ULM) offers a potential solution by exploiting circulating microbubbles to achieve a vascular resolution approaching the capillary scale without sacrificing imaging depth. In this report, we apply ULM imaging to a mouse model of aging and quantify differences in cerebral vascularity, blood velocity, and vessel tortuosity across several brain regions. We found significant decreases in blood velocity, and significant increases in vascular tortuosity, across all brain regions in the aged cohort, and significant decreases in blood volume in the cortex. These data provide the first-ever measurements of subcortical microvascular dynamics in vivo and reveal that aging has a major impact on these measurements.

Collagens are major constituents of the extracellular matrix (ECM) that play an essential role in the structure of the inner ear and provide elasticity and rigidity when the signals of sound are received and transformed into electrical signals. LOXL3 is a member of the lysyl oxidase (LOX) family that are copper-dependent amine oxidases, generating covalent cross-links to stabilize polymeric elastin and collagen fibers in the ECM. Biallelic missense variant of LOXL3 was found in Stickler syndrome with mild conductive hearing loss. However, available information regarding the specific roles of LOXL3 in auditory function is limited. In this study, we showed that the Col2a1-Cre-mediated ablation of Loxl3 in the inner ear can cause progressive hearing loss, degeneration of hair cells and secondary degeneration of spiral ganglion neurons. The abnormal distribution of type II collagen in the spiral ligament and increased inflammatory responses were also found in Col2a1–Loxl3 –/– mice. Amino oxidase activity exerts an effect on collagen; thus, Loxl3 deficiency was expected to result in the instability of collagen in the spiral ligament and the basilar membrane, which may interfere with the mechanical properties of the organ of Corti and induce the inflammatory responses that are responsible for the hearing loss. Overall, our findings suggest that Loxl3 may play an essential role in maintaining hearing function.

Annexin A4 (ANXA4) is a Ca 2+ -dependent phospholipid-binding protein that is specifically expressed in the cochlear and vestibular hair cells, but its function in the hair cells remains unknown. In the present study, we show that besides localizing on the plasma membrane, ANXA4 immunoreactivity is also localized at the tips of stereocilia in the hair cells. In order to investigate the role of ANXA4 in the hair cells, we established Anxa4 knockout mice using CRISPR/Cas9 technique. Unexpectedly, the development of both cochlear and vestibular hair cells is normal in Anxa4 knockout mice. Moreover, stereocilia morphology of Anxa4 knockout mice is normal, so is the mechano-electrical transduction (MET) function. Consistently, the auditory and vestibular functions are normal in the knockout mice. In conclusion, we show here that ANXA4 is dispensable for the development and function of hair cells, which might result from functional redundancy between ANXA4 and other annexin(s) in the hair cells.

Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has proven more elusive. Here, we leveraged the natural ability of inhibitory presynaptic GPCRs to suppress synaptic transmission and characterize parapinopsin (PPO) as a GPCR-based opsin for terminal inhibition. PPO is a photoswitchable opsin that couples to Gi/o signaling cascades and is rapidly activated by pulsed blue light, switched off with amber light, and effective for repeated, prolonged, and reversible inhibition. PPO rapidly and reversibly inhibits glutamate, GABA, and dopamine release at presynaptic terminals. Furthermore, PPO alters reward behaviors in a time-locked and reversible manner in vivo. These results demonstrate that PPO fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition and has broad utility for spatiotemporal control of inhibitory GPCR signaling cascades.