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The cerebral cortex contains diverse neural representations of the visual scene, each enabling distinct visual and spatial abilities. However, the extent to which representations are distributed or segregated across cortical areas remains poorly understood. By determining the spatial and temporal responses of >30,000 layer 2/3 pyramidal neurons, we characterize the functional organization of parallel visual streams across eight areas of the mouse cortex. While dorsal and ventral areas form complementary representations of spatiotemporal frequency, motion speed, and spatial patterns, the anterior and posterior dorsal areas show distinct specializations for fast and slow oriented contrasts. At the cellular level, while diverse spatiotemporal tuning lies along a continuum, oriented and non-oriented spatial patterns are encoded by distinct tuning types. The identified tuning types are present across dorsal and ventral streams. The data underscore the highly specific and highly distributed nature of visual cortical representations, which drives specialization of cortical areas and streams. The cerebral cortex contains different neural representations of the visual scene. Here, the authors show diverse and stereotyped tuning composing specialized representations in the dorsal and ventral areas of the mouse visual cortex, suggesting parallel processing channels and streams.

Sparse orthogonal coding is a key feature of hippocampal neural activity, which is believed to increase episodic memory capacity and to assist in navigation. Some retrosplenial cortex (RSC) neurons convey distributed spatial and navigational signals, but place-field representations such as observed in the hippocampus have not been reported. Combining cellular Ca 2+ imaging in RSC of mice with a head-fixed locomotion assay, we identified a population of RSC neurons, located predominantly in superficial layers, whose ensemble activity closely resembles that of hippocampal CA1 place cells during the same task. Like CA1 place cells, these RSC neurons fire in sequences during movement, and show narrowly tuned firing fields that form a sparse, orthogonal code correlated with location. RSC ‘place’ cell activity is robust to environmental manipulations, showing partial remapping similar to that observed in CA1. This population code for spatial context may assist the RSC in its role in memory and/or navigation. Neurons in the retrosplenial cortex (RSC) encode spatial and navigational signals. Here the authors use calcium imaging to show that, similar to the hippocampus, RSC neurons also encode place cell-like activity in a sparse orthogonal representation, partially anchored to the allocentric cues on the linear track.

Two-photon calcium imaging and electron microscopy were used to explore the relationship between structure and function in mouse primary visual cortex, showing that layer 2/3 neurons are connected in subnetworks, that pyramidal neurons with similar orientation selectivity preferentially form synapses with each other, and that neurons with similar orientation tuning form larger synapses; this study exemplifies functional connectomics as a powerful method for studying the organizational logic of cortical networks. The connectomics of excitatory cortical networks To explore the relationship between structure and function in cortical networks, Wei-Chung Allen Lee and colleagues combined two-photon calcium imaging and electron microscopy in mouse primary visual cortex. They found that layer 2/3 neurons are organized into subnetworks, that pyramidal neurons with similar orientation selectivity preferentially form synapses with each other, and that neurons with similar orientation tuning form larger synapses. This study exemplifies functional connectomics as a powerful method for studying the organizational logic of cortical networks. Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other 1 , 2 , 3 , 4 , 5 , but the anatomical basis of this recurrent synaptic network is unknown. Here we combined physiological imaging and large-scale electron microscopy to study an excitatory network in V1. We found that layer 2/3 neurons organized into subnetworks defined by anatomical connectivity, with more connections within than between groups. More specifically, we found that pyramidal neurons with similar orientation selectivity preferentially formed synapses with each other, despite the fact that axons and dendrites of all orientation selectivities pass near (<5 μm) each other with roughly equal probability. Therefore, we predict that mechanisms of functionally specific connectivity take place at the length scale of spines. Neurons with similar orientation tuning formed larger synapses, potentially enhancing the net effect of synaptic specificity. With the ability to study thousands of connections in a single circuit, functional connectomics is proving a powerful method to uncover the organizational logic of cortical networks.

Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions. Overall, spatial activity in RSC was experience-dependent, emerging gradually over time, but, as seen in the hippocampus, the spatial code changed dynamically across days. Bilateral but not unilateral hippocampal lesions impeded the development of spatial activity in RSC. Thus, the emergence of spatial activity in RSC, a major recipient of hippocampal information, depends critically on an intact hippocampus; the indirect connections between the dysgranular RSC and the hippocampus further indicate that hippocampus may exert such influences polysynaptically within neocortex.

Tuning of neurons in higher visual cortices is less diverse than in primary visual cortex (V1), but the mechanisms underlying this specialization are unknown. In this paper, Glickfeld and colleagues used two-photon imaging in awake mice to measure the visual responses of boutons from V1 projection neurons in the higher visual areas and found that bouton tunings matched the preference of their target areas. These findings suggest that inter-areal visual stimulus feature segregation occurs via the target-specific routing of visual information as it ascends the cortical hierarchy. Neurons in primary sensory cortex have diverse response properties, whereas higher cortical areas are specialized. Specific connectivity may be important for areal specialization, particularly in the mouse, where neighboring neurons are functionally diverse. To examine whether higher visual areas receive functionally specific input from primary visual cortex (V1), we used two-photon calcium imaging to measure responses of axons from V1 arborizing in three areas with distinct spatial and temporal frequency preferences. We found that visual preferences of presynaptic boutons in each area were distinct and matched the average preferences of recipient neurons. This specificity could not be explained by organization within V1 and instead was due to both a greater density and greater response amplitude of functionally matched boutons. Projections from a single layer (layer 5) and from secondary visual cortex were also matched to their target areas. Thus, transmission of specific information to downstream targets may be a general feature of cortico-cortical communication.

The visual system is composed of diverse cell types that encode distinct aspects of the visual scene and may form separate processing channels. Here we present further evidence for that hypothesis whereby functional cell groups in the dorsal lateral geniculate nucleus (dLGN) are differentially modulated during behavior. Using simultaneous multi-electrode recordings in dLGN and primary visual cortex (V1) of behaving mice, we characterized the impact of locomotor activity on response amplitude, variability, correlation and spatiotemporal tuning. Locomotion strongly impacts the amplitudes of dLGN and V1 responses but the effects on variability and correlations are relatively minor. With regards to tunings, locomotion enhances dLGN responses to high temporal frequencies, preferentially affecting ON transient cells and neurons with nonlinear responses to high spatial frequencies. Channel specific modulations may serve to highlight particular visual inputs during active behaviors. Locomotion is known to modulate neuronal firing in both the visual thalamus (LGN) and V1. Here, the authors characterize the LGN modulation in detail and report that neurons with transient ON responses for high spatial frequency stimuli show the strongest gain modulation.

This protocol describes how to implant a removable cranial window, enabling manipulations such as targeted virus injections and microprism insertion, for one- and two-photon calcium imaging of the same cortical brain regions for several months. Cranial window implants in head-fixed rodents are becoming a preparation of choice for stable optical access to large areas of the cortex over extended periods of time. Here we provide a highly detailed and reliable surgical protocol for a cranial window implantation procedure for chronic wide-field and cellular imaging in awake, head-fixed mice, which enables subsequent window removal and replacement in the weeks and months after the initial craniotomy. This protocol has facilitated awake, chronic imaging in adolescent and adult mice over several months from a large number of cortical brain regions; targeted virus and tracer injections from data obtained using prior awake functional mapping; and functionally targeted two-photon imaging across all cortical layers in awake mice using a microprism attachment to the cranial window. Collectively, these procedures extend the reach of chronic imaging of cortical function and dysfunction in behaving animals.

Silicon neuroprobes hold great potential for studies of large-scale neural activity and brain computer interfaces, but data on brain response in chronic implants is limited. Here we explored with in vivo  cellular imaging the response to multisite silicon probes for neural recordings. We tested a chronic implant for mice consisting of a CMOS-compatible silicon probe rigidly implanted in the cortex under a cranial imaging window. Multiunit recordings of cortical neurons with the implant showed no degradation of electrophysiological signals weeks after implantation (mean spike and noise amplitudes of 186 ± 42 µV pp and 16 ± 3.2 µV rms , respectively, n = 5 mice). Two-photon imaging through the cranial window allowed longitudinal monitoring of fluorescently-labeled astrocytes from the second week post implantation for 8 weeks (n = 3 mice). The imaging showed a local increase in astrocyte-related fluorescence that remained stable from the second to the tenth week post implantation. These results demonstrate that, in a standard electrophysiology protocol in mice, rigidly implanted silicon probes can provide good short to medium term chronic recording performance with a limited astrocyte inflammatory response. The precise factors influencing the response to silicon probe implants remain to be elucidated.

The early visual system is endowed with adaptive mechanisms that rapidly adjust gain and integration time based on the local luminance (mean intensity) and contrast (standard deviation of intensity relative to the mean). Here we show that these mechanisms are matched to the statistics of the environment. First, we measured the joint distribution of luminance and contrast in patches selected from natural images and found that luminance and contrast were statistically independent of each other. This independence did not hold for artificial images with matched spectral characteristics. Second, we characterized the effects of the adaptive mechanisms in lateral geniculate nucleus (LGN), the direct recipient of retinal outputs. We found that luminance gain control had the same effect at all contrasts and that contrast gain control had the same effect at all mean luminances. Thus, the adaptive mechanisms for luminance and contrast operate independently, reflecting the very independence encountered in natural images.