Functional Specialization of eye-specific visual pathways into higher visual cortex

The brain is able to construct a visual representation of the world by parallel processing of cortical neurons that prefer increasingly complex stimuli. One way the visual cortex has accomplished parallel processing is by creating functionally organized modules that are tuned to unique features and linking them in multiple processing stages of cortex. For example, primary visual cortex (V1) sends functionally distinct information to higher visual areas (HVAs), which are more specialized in their processing of spatiotemporal information. Inherently coupled to this process is the convergence of eye-specific inputs in visual cortex. Shifting the eye-specific tuning of neurons in primary visual cortex by monocular deprivation in early life is known to disrupt tuning for spatial frequency in adulthood. Combining space and time better characterizes the segregation of HVAs. To begin to understand if eye-specific responses could be linked to tuning properties important for the segregation of HVAs, we characterized eye-specific spatiotemporal tuning of layer 2/3 excitatory cells within the binocular zone of V1 and two HVAs grouped into the putative ventral and dorsal streams, LM and PM, using two-photon GCaMP6s imaging of awake mice. An asymmetry was found at the level of V1, such that responses driven primarily by the contralateral eye were biased towards high spatial frequencies, low speeds, cardinal directions, and were more direction selective than binocular or ipsilateral eye-driven responses. Eye-specific inputs in V1 are tuned to different speeds and also have different degrees of speed tuning, where contralateral eye inputs are more speed tuned than ipsilateral eye inputs. The proportions of eye-specific neurons of LM and PM matched the expected preferences based on eye-specific spatial frequency tuning found at the level of V1. A similar contralateral bias for distinct features, most notably, spatiotemporal tuning, was found within LM and PM, linking neurons with similar eye-specific preferences to their tuning for early feature detectors important for stream specialization. To determine if V1 sends eye-specific functionally distinct information to HVAs, we injected AAV-Syn-GCaMP6s into the binocular zone of V1 and imaged the afferents that targeted either LM or PM. We found that V1 afferents to LM and PM were distinct in their distributions for ocular dominance, suggesting that eye-specific projections from V1 to HVAs contribute to their functional specificity. To determine if the functional specialization of HVAs depend upon eye-specific developmental mechanisms, we deprived mice of visual experience through the contralateral eye (CMD) during the ocular dominance critical period and assessed eye-specific spatiotemporal tuning of V1, LM and PM in adulthood. We found that CMD diminished the functional specificity of V1, LM and PM, resulting in areas without differentiated spatiotemporal preferences. Moreover, the eye-specific functional segregation was also disrupted with CMD. Altogether, our data demonstrates that the maturation of higher visual areas is dependent on proper binocular visual experience and suggests that the functional specialization of eye-specific responses could be an efficient routing mechanism to differentiate higher visual areas

Functional Differentiation of Mouse Visual Cortical Areas Depends upon Early Binocular Experience

The mammalian visual cortex contains multiple retinotopically defined areas that process distinct features of the visual scene. Little is known about what guides the functional differentiation of visual cortical areas during development. Recent studies in mice have revealed that visual input from the two eyes provides spatiotemporally distinct signals to primary visual cortex (V1), such that contralateral eye-dominated V1 neurons respond to higher spatial frequencies than ipsilateral eye-dominated neurons. To test whether binocular visual input drives the differentiation of visual cortical areas, we used two-photon calcium imaging to characterize the effects of juvenile monocular deprivation (MD) on the responses of neurons in V1 and two higher visual areas, LM (lateromedial) and PM (posteromedial). In adult mice of either sex, we find that MD prevents the emergence of distinct spatiotemporal tuning in V1, LM, and PM. We also find that, within each of these areas, MD reorganizes the distinct spatiotemporal tuning properties driven by the two eyes. Moreover, we find a relationship between speed tuning and ocular dominance in all three areas that MD preferentially disrupts in V1, but not in LM or PM. Together, these results reveal that balanced binocular vision during development is essential for driving the functional differentiation of visual cortical areas. The higher visual areas of mouse visual cortex may provide a useful platform for investigating the experience-dependent mechanisms that set up the specialized processing within neocortical areas during postnatal development.SIGNIFICANCE STATEMENT Little is known about the factors guiding the emergence of functionally distinct areas in the brain. Using in vivo Ca2+ imaging, we recorded visually evoked activity from cells in V1 and higher visual areas LM (lateromedial) and PM (posteromedial) of mice. Neurons in these areas normally display distinct spatiotemporal tuning properties. We found that depriving one eye of normal input during development prevents the functional differentiation of visual areas. Deprivation did not disrupt the degree of speed tuning, a property thought to emerge in higher visual areas. Thus, some properties of visual cortical neurons are shaped by binocular experience, while others are resistant. Our study uncovers the fundamental role of binocular experience in the formation of distinct areas in visual cortex

Contralateral Bias of High Spatial Frequency Tuning and Cardinal Direction Selectivity in Mouse Visual Cortex

Binocular mechanisms for visual processing are thought to enhance spatial acuity by combining matched input from the two eyes. Studies in the primary visual cortex of carnivores and primates have confirmed that eye-specific neuronal response properties are largely matched. In recent years, the mouse has emerged as a prominent model for binocular visual processing, yet little is known about the spatial frequency tuning of binocular responses in mouse visual cortex. Using calcium imaging in awake mice of both sexes, we show that the spatial frequency preference of cortical responses to the contralateral eye is ∼35% higher than responses to the ipsilateral eye. Furthermore, we find that neurons in binocular visual cortex that respond only to the contralateral eye are tuned to higher spatial frequencies. Binocular neurons that are well matched in spatial frequency preference are also matched in orientation preference. In contrast, we observe that binocularly mismatched cells are more mismatched in orientation tuning. Furthermore, we find that contralateral responses are more direction-selective than ipsilateral responses and are strongly biased to the cardinal directions. The contralateral bias of high spatial frequency tuning was found in both awake and anesthetized recordings. The distinct properties of contralateral cortical responses may reflect the functional segregation of direction-selective, high spatial frequency-preferring neurons in earlier stages of the central visual pathway. Moreover, these results suggest that the development of binocularity and visual acuity may engage distinct circuits in the mouse visual system.SIGNIFICANCE STATEMENT Seeing through two eyes is thought to improve visual acuity by enhancing sensitivity to fine edges. Using calcium imaging of cellular responses in awake mice, we find surprising asymmetries in the spatial processing of eye-specific visual input in binocular primary visual cortex. The contralateral visual pathway is tuned to higher spatial frequencies than the ipsilateral pathway. At the highest spatial frequencies, the contralateral pathway strongly prefers to respond to visual stimuli along the cardinal (horizontal and vertical) axes. These results suggest that monocular, and not binocular, mechanisms set the limit of spatial acuity in mice. Furthermore, they suggest that the development of visual acuity and binocularity in mice involves different circuits

Contralateral Bias of High Spatial Frequency Tuning and Cardinal Direction Selectivity in Mouse Visual Cortex

Binocular mechanisms for visual processing are thought to enhance spatial acuity by combining matched input from the two eyes. Studies in the primary visual cortex of carnivores and primates have confirmed that eye-specific neuronal response properties are largely matched. In recent years, the mouse has emerged as a prominent model for binocular visual processing, yet little is known about the spatial frequency tuning of binocular responses in mouse visual cortex. Using calcium imaging in awake mice of both sexes, we show that the spatial frequency preference of cortical responses to the contralateral eye is ∼35% higher than responses to the ipsilateral eye. Furthermore, we find that neurons in binocular visual cortex that respond only to the contralateral eye are tuned to higher spatial frequencies. Binocular neurons that are well matched in spatial frequency preference are also matched in orientation preference. In contrast, we observe that binocularly mismatched cells are more mismatched in orientation tuning. Furthermore, we find that contralateral responses are more direction-selective than ipsilateral responses and are strongly biased to the cardinal directions. The contralateral bias of high spatial frequency tuning was found in both awake and anesthetized recordings. The distinct properties of contralateral cortical responses may reflect the functional segregation of direction-selective, high spatial frequency-preferring neurons in earlier stages of the central visual pathway. Moreover, these results suggest that the development of binocularity and visual acuity may engage distinct circuits in the mouse visual system.SIGNIFICANCE STATEMENT Seeing through two eyes is thought to improve visual acuity by enhancing sensitivity to fine edges. Using calcium imaging of cellular responses in awake mice, we find surprising asymmetries in the spatial processing of eye-specific visual input in binocular primary visual cortex. The contralateral visual pathway is tuned to higher spatial frequencies than the ipsilateral pathway. At the highest spatial frequencies, the contralateral pathway strongly prefers to respond to visual stimuli along the cardinal (horizontal and vertical) axes. These results suggest that monocular, and not binocular, mechanisms set the limit of spatial acuity in mice. Furthermore, they suggest that the development of visual acuity and binocularity in mice involves different circuits

Host interneurons mediate plasticity reactivated by embryonic inhibitory cell transplantation in mouse visual cortex.

The adult brain lacks sensitivity to changes in the sensory environment found in the juvenile brain. The transplantation of embryonic interneurons has been shown to restore juvenile plasticity to the adult host visual cortex. It is unclear whether transplanted interneurons directly mediate the renewed cortical plasticity or whether these cells act indirectly by modifying the host interneuron circuitry. Here we find that the transplant-induced reorganization of mouse host circuits is specifically mediated by Neuregulin (NRG1)/ErbB4 signaling in host parvalbumin (PV) interneurons. Brief visual deprivation reduces the visual activity of host PV interneurons but has negligible effects on the responses of transplanted PV interneurons. Exogenous NRG1 both prevents the deprivation-induced reduction in the visual responses of host PV interneurons and blocks the transplant-induced reorganization of the host circuit. While deletion of ErbB4 receptors from host PV interneurons blocks cortical plasticity in the transplant recipients, deletion of the receptors from the donor PV interneurons does not. Altogether, our results indicate that transplanted embryonic interneurons reactivate cortical plasticity by rejuvenating the function of host PV interneurons

Host interneurons mediate plasticity reactivated by embryonic inhibitory cell transplantation in mouse visual cortex.

The adult brain lacks sensitivity to changes in the sensory environment found in the juvenile brain. The transplantation of embryonic interneurons has been shown to restore juvenile plasticity to the adult host visual cortex. It is unclear whether transplanted interneurons directly mediate the renewed cortical plasticity or whether these cells act indirectly by modifying the host interneuron circuitry. Here we find that the transplant-induced reorganization of mouse host circuits is specifically mediated by Neuregulin (NRG1)/ErbB4 signaling in host parvalbumin (PV) interneurons. Brief visual deprivation reduces the visual activity of host PV interneurons but has negligible effects on the responses of transplanted PV interneurons. Exogenous NRG1 both prevents the deprivation-induced reduction in the visual responses of host PV interneurons and blocks the transplant-induced reorganization of the host circuit. While deletion of ErbB4 receptors from host PV interneurons blocks cortical plasticity in the transplant recipients, deletion of the receptors from the donor PV interneurons does not. Altogether, our results indicate that transplanted embryonic interneurons reactivate cortical plasticity by rejuvenating the function of host PV interneurons

Long-term Monocular Deprivation during Juvenile Critical Period Disrupts Binocular Integration in Mouse Visual Thalamus.

Study of the neural deficits caused by mismatched binocular vision in early childhood has predominantly focused on circuits in the primary visual cortex (V1). Recent evidence has revealed that neurons in mouse dorsolateral geniculate nucleus (dLGN) can undergo rapid ocular dominance plasticity following monocular deprivation (MD). It remains unclear, however, whether the long-lasting deficits attributed to MD during the critical period originate in the thalamus. Using in vivo two-photon Ca2+ imaging of dLGN afferents in superficial layers of V1 in female and male mice, we demonstrate that 14 d MD during the critical period leads to a chronic loss of binocular dLGN inputs while sparing response strength and spatial acuity. Importantly, MD leads to profoundly mismatched visual tuning properties in remaining binocular dLGN afferents. Furthermore, MD impairs binocular modulation, reducing facilitation of responses of both binocular and monocular dLGN inputs during binocular viewing. As predicted by our findings in thalamic inputs, Ca2+ imaging from V1 neurons revealed spared spatial acuity but impaired binocularity in L4 neurons. V1 L2/3 neurons in contrast displayed deficits in both binocularity and spatial acuity. Our data demonstrate that critical-period MD produces long-lasting disruptions in binocular integration beginning in early binocular circuits in dLGN, whereas spatial acuity deficits first arise from circuits further downstream in V1. Our findings indicate that the development of normal binocular vision and spatial acuity depend upon experience-dependent refinement of distinct stages in the mammalian visual system.SIGNIFICANCE STATEMENT Abnormal binocular vision and reduced acuity are hallmarks of amblyopia, a disorder that affects 2%-5% of the population. It is widely thought that the neural deficits underlying amblyopia begin in the circuits of primary visual cortex. Using in vivo two-photon calcium imaging of thalamocortical axons in mice, we show that depriving one eye of input during a critical period in development chronically impairs binocular integration in thalamic inputs to primary visual cortex. In contrast, visual acuity is spared in thalamic inputs. These findings shed new light on the role for developmental mechanisms in the thalamus in establishing binocular vision and may have critical implications for amblyopia