Widespread and Multifaceted Binocular Integration in the Mouse Primary Visual Cortex.

The brain combines two-dimensional images received from the two eyes to form a percept of three-dimensional surroundings. This process of binocular integration in the primary visual cortex (V1) serves as a useful model for studying how neural circuits generate emergent properties from multiple input signals. Here, we perform a thorough characterization of binocular integration using electrophysiological recordings in the V1 of awake adult male and female mice by systematically varying the orientation and phase disparity of monocular and binocular stimuli. We reveal widespread binocular integration in mouse V1 and demonstrate that the three commonly studied binocular properties-ocular dominance, interocular matching, and disparity selectivity-are independent of each other. For individual neurons, the responses to monocular stimulation can predict the average amplitude of binocular response but not its selectivity. Finally, the extensive and independent binocular integration of monocular inputs is seen across cortical layers in both regular-spiking and fast-spiking neurons, regardless of stimulus design. Our data indicate that the current model of simple feedforward convergence is inadequate to account for binocular integration in mouse V1, thus suggesting an indispensable role played by intracortical circuits in binocular computation.SIGNIFICANCE STATEMENT Binocular integration is an important step of visual processing that takes place in the visual cortex. Studying the process by which V1 neurons become selective for certain binocular disparities is informative about how neural circuits integrate multiple information streams at a more general level. Here, we systematically characterize binocular integration in mice. Our data demonstrate more widespread and complex binocular integration in mouse V1 than previously reported. Binocular responses cannot be explained by a simple convergence of monocular responses, contrary to the prevailing model of binocular integration. These findings thus indicate that intracortical circuits must be involved in the exquisite computation of binocular disparity, which would endow brain circuits with the plasticity needed for binocular development and processing.

Neural circuits for binocular vision: Ocular dominance, interocular matching, and disparity selectivity.

The brain creates a single visual percept of the world with inputs from two eyes. This means that downstream structures must integrate information from the two eyes coherently. Not only does the brain meet this challenge effortlessly, it also uses small differences between the two eyes' inputs, i.e., binocular disparity, to construct depth information in a perceptual process called stereopsis. Recent studies have advanced our understanding of the neural circuits underlying stereoscopic vision and its development. Here, we review these advances in the context of three binocular properties that have been most commonly studied for visual cortical neurons: ocular dominance of response magnitude, interocular matching of orientation preference, and response selectivity for binocular disparity. By focusing mostly on mouse studies, as well as recent studies using ferrets and tree shrews, we highlight unresolved controversies and significant knowledge gaps regarding the neural circuits underlying binocular vision. We note that in most ocular dominance studies, only monocular stimulations are used, which could lead to a mischaracterization of binocularity. On the other hand, much remains unknown regarding the circuit basis of interocular matching and disparity selectivity and its development. We conclude by outlining opportunities for future studies on the neural circuits and functional development of binocular integration in the early visual system.

Strong tuning for stereoscopic depth indicates orientation-specific recurrent circuitry in tree shrew V1.

Neurons in the primary visual cortex (V1) are tuned to specific disparities between the two retinal images, which form the neural substrate for stereoscopic vision. We show that V1 neurons in tree shrews, but not in mice, display highly selective responses to narrow ranges of disparity in random-dot stereograms. Surprisingly, V1 neurons in both species show similarly strong tuning to gratings of varying interocular phase differences. This stimulus-dependent dissociation of disparity tuning can be explained by a network model that combines both feedforward and recurrent connections. The features of the model connections are supported by cortical organizations specific to each species. We validate this model by identifying putative inhibitory neurons and confirming their predicted disparity tuning in both species. Together, our studies establish a foundation for using tree shrews in studying binocular vision and raise an exciting possibility of how cortical columns could be uniquely important in computing stereoscopic depth.

Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes.

PURPOSE: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse model of early diabetic retinopathy (DR). METHODS: Adult C57BL/6J mice were treated with streptozotocin (STZ) and made diabetic at 8-10 weeks of age. Control and diabetic mice were treated with vehicle or TUDCA starting 1 or 3 weeks after induction of diabetes, and were assessed bimonthly for visual function via an optomotor response and monthly for retinal function via scotopic electroretinograms. RESULTS: Diabetic mice showed significantly reduced spatial frequency and contrast sensitivity thresholds compared to control mice, while diabetic mice treated early with TUDCA showed preservation at all timepoints. A-wave, b-wave, and oscillatory potential 2 (OP2) amplitudes decreased in diabetic mice. Diabetic mice also exhibited delays in a-wave and OP2-implicit times. Early TUDCA treatment ameliorated a-wave, b-wave, and OP2 deficits. Late TUDCA treatment showed reduced preservation effects compared to early treatment. CONCLUSIONS: Early TUDCA treatment preserved visual function in an STZ-mouse model of Type I diabetes. These data add to a growing body of preclinical research that may support testing whether TUDCA may be an effective early clinical intervention against declining visual function caused by diabetic retinopathy.

Menopause exacerbates visual dysfunction in experimental glaucoma.

Glaucoma is the leading cause of irreversible blindness worldwide. Recently, estrogen deficiencies caused by early menopause, alterations in estrogen signaling via mutations in estrogen receptors, and polymorphisms along estrogen metabolic pathways have all been linked to an increased risk of developing glaucoma. Here, we examined how menopause and age impact visual function and retinal structure in an experimental model of glaucoma. Young (3-4 months) and aged (9-10 months) female Brown Norway rats were divided into pre- and post-menopausal cohorts by surgically inducing menopause via ovariectomy (OVX). After six weeks, ocular hypertension (OHT) was induced unilaterally for a period of eight weeks. Four cohorts were successfully followed to eight weeks: young sham (n = 8), young OVX (n = 9), aged sham (n = 10), and aged OVX (n = 11) animals. Intraocular pressure (IOP) was monitored weekly in all groups. Prior to inducing OHT (baseline) and at four and eight weeks after inducing OHT, we assessed visual acuity via the optomotor response (OMR) and retinal structure using optical coherence tomography (OCT). OHT decreased the OMR in all cohorts. We found that spatial frequency thresholds decreased by 54% in OVX animals after OHT compared to sham animals after OHT, regardless of age (p < 0.001). We also found thinning of the retinal nerve fiber layer (RNFL) and loss of total retinal thickness after induction of OHT. Aged animals had more thinning of the RNFL and loss of total retinal thickness compared to young animals (p < 0.001). Overall, OHT caused significant changes in visual function and retinal structure. Observing that OVX in young and aged animals further decreased spatial frequency thresholds after OHT suggests that an estrogen deficiency may intensify visual impairment after OHT.

Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists with differential selectivity for α1- vs. α2-receptors, yohimbine (YOH, 1:40 selectivity) and atipamezole (ATI, 1:8500). Adult mice received intraperitoneal injections of either YOH (4.3 mg/kg), ATI (0.4 mg/kg), or saline after achieving sustained loss of righting following injection of ketamine/xylazine (ketamine: 65.0 mg/kg; xylazine: 9.9 mg/kg). Behaviors indicative of the post-anesthesia, re-animation sequence were carefully monitored and the timing of each behavior relative to anesthesia induction was compared. Both YOH and ATI hastened behaviors indicative of emergence, but ATI was faster than YOH to produce certain behaviors, including whisker movement (YOH: 21.9±1.5 min, ATI: 17.5±0.5 min, p = 0.004) and return of righting reflex (RORR) (YOH: 40.6±8.8 min, ATI: 26.0±1.2 min, p<0.001). Interestingly, although YOH administration hastened early behavioral markers of emergence relative to saline (whisking), the completion of the emergence sequence (time from first marker to appearance of RORR) was delayed with YOH. We attribute this effect to antagonism of α1 receptors by yohimbine. Also notable was the failure of either antagonist to hasten the re-establishment of coordinated motor behavior (e.g., attempts to remove adhesive tape on the forepaw placed during anesthesia) relative to the end of emergence (RORR). In total, our work suggests that in addition to pharmacokinetic effects, re-establishment of normal waking behaviors after anesthesia involves neuronal circuits dependent on time and/or activity.

Daily visual stimulation in the critical period enhances multiple aspects of vision through BDNF-mediated pathways in the mouse retina.

Visual experience during the critical period modulates visual development such that deprivation causes visual impairments while stimulation induces enhancements. This study aimed to determine whether visual stimulation in the form of daily optomotor response (OMR) testing during the mouse critical period (1) improves aspects of visual function, (2) involves retinal mechanisms and (3) is mediated by brain derived neurotrophic factor (BDNF) and dopamine (DA) signaling pathways. We tested spatial frequency thresholds in C57BL/6J mice daily from postnatal days 16 to 23 (P16 to P23) using OMR testing. Daily OMR-treated mice were compared to littermate controls that were placed in the OMR chamber without moving gratings. Contrast sensitivity thresholds, electroretinograms (ERGs), visual evoked potentials, and pattern ERGs were acquired at P21. To determine the role of BDNF signaling, a TrkB receptor antagonist (ANA-12) was systemically injected 2 hours prior to OMR testing in another cohort of mice. BDNF immunohistochemistry was performed on retina and brain sections. Retinal DA levels were measured using high-performance liquid chromatography. Daily OMR testing enhanced spatial frequency thresholds and contrast sensitivity compared to controls. OMR-treated mice also had improved rod-driven ERG oscillatory potential response times, greater BDNF immunoreactivity in the retinal ganglion cell layer, and increased retinal DA content compared to controls. VEPs and pattern ERGs were unchanged. Systemic delivery of ANA-12 attenuated OMR-induced visual enhancements. Daily OMR testing during the critical period leads to general visual function improvements accompanied by increased DA and BDNF in the retina, with this process being requisitely mediated by TrkB activation. These results suggest that novel combination therapies involving visual stimulation and using both behavioral and molecular approaches may benefit degenerative retinal diseases or amblyopia.