An inhomogeneous direction selective map in the superior colliculus

Vision allows animals to extract salient features of a visual scene such as spatial orientations and motion direction. The retina is the first stage of visual processing and targets brain areas including the superior colliculus. Here the visual scene is represented by a set of overlapping, retinotopically organized feature maps. Recently it has been shown that orientation selective neurons with the same orientation selectivity cluster together, forming an inhomogeneous orientation map where, unlike in other visual areas, not all orientations are represented at each retinotopic location. However, the topographical organization of other feature maps remains unknown. Using twophoton calcium imaging, we recorded the activity of neurons spanning more than half of the superior colliculus, while simultaneously measuring their receptive field and determining their orientation and direction selectivity. We found that the preferred direction of direction selective neurons is dependent on their retinotopic position. When comparing preferred directions with orientation in the same retinotopic location, direction selective neurons showed a strong preference for directions of movement orthogonal to the preferred orientation of nearby orientation selective neurons. These findings uncover a second inhomogeneous map accounting for motion detection that can be superimposed with the spatial orientation map. Such maps appear to underlie the structure of the superior colliculus, and understanding their relationships will allow us to understand how the colliculus contributes to visually guided orientating behaviours.status: publishe

Retinotopic Separation of Nasal and Temporal Motion Selectivity in the Mouse Superior Colliculus

Sensory neurons often display an ordered spatial arrangement that enhances the encoding of specific features on different sides of natural borders in the visual field (for example, [1-3]). In central visual areas, one prominent natural border is formed by the confluence of information from the two eyes, the monocular-binocular border [4]. Here, we investigate whether receptive field properties of neurons in the mouse superior colliculus show any systematic organization about the monocular-binocular border. The superior colliculus is a layered midbrain structure that plays a significant role in the orienting responses of the eye, head, and body [5]. Its superficial layers receive direct input from the majority of retinal ganglion cells and are retinotopically organized [6, 7]. Using two-photon calcium imaging, we recorded the activity of collicular neurons from the superficial layers of awake mice and determined their direction selectivity, orientation selectivity, and retinotopic location. This revealed that nearby direction-selective neurons have a strong tendency to prefer the same motion direction. In retinotopic space, the local preference of direction-selective neurons shows a sharp transition in the preference for nasal versus temporal motion at the monocular-binocular border. The maps representing orientation and direction appear to be independent. These results illustrate the important coherence between the spatial organization of inputs and response properties within the visual system and suggest a re-analysis of the receptive field organization within the superior colliculus from an ecological perspective.status: Published onlin

Genomic stability of self-inactivating rabies

Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic ΔG-Rabies has been widely used in neuroscience research. A recently developed engineered version of the ΔG-Rabies, the non-toxic self-inactivating (SiR) virus, allows the long term genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical ΔG-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiR in vitro and in vivo. We found that “revertant” mutations are rare and accumulate only when SiR is extensively amplified in vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical ΔG-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emerge in vivo during long-term experiments

Genomic stability of self-inactivating rabies.

Peer reviewed: TrueAcknowledgements: We thank Elena Williams for comments on the manuscript. We thank Jerome Boulanger for writing the script for the 3d-alignment of 2-photon recordings, Nicolas Alexandre for the help with the bioinformatic analysis of the NGS datasets, the Laboratory of Molecular Biology (LMB) workshops for the help with software and hardware development, and members of the Biological Service Group for their support with the in vivo work. This study was supported by the Medical Research Council (MC_UP_1201/2), the European Research Council (STG 677029 to MT), the European Union’s Horizon 2020 research and innovation program with the Marie Sklodowska-Curie fellowship to DdM (894697), the Cambridge Philosophical Society and St. Edmund’s College (University of Cambridge) with the Henslow Research Fellowship to AGR, the Rosetrees Trust with an MBPhD fellowship to HL (M598). For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising. All data are stored on the LMB server. All materials described in this paper can be obtained upon reasonable request and for non-commercial purposes after signing a material transfer agreement (MTA) with the MRC.Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic ΔG-Rabies has been widely used in neuroscience research. A recently developed engineered version of the ΔG-Rabies, the non-toxic self-inactivating (SiR) virus, allows the long term genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical ΔG-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiR in vitro and in vivo. We found that "revertant" mutations are rare and accumulate only when SiR is extensively amplified in vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical ΔG-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emerge in vivo during long-term experiments

Kinetic features dictate sensorimotor alignment in the superior colliculus.

Acknowledgements: The authors thank the Laboratory of Molecular Biology electronics and mechanical workshops for the help with hardware development, members of the Biological Service Group for their support with animal husbandry and F. Morgese for assistance in viral production. This study was supported by the Medical Research Council core funds to M.T. (MC_UP_1201/2), the UKRI (ERC Consolidator Replacement Grant, EP/X034666/1) to M.T., the European Research Council with an ERC Starting Grant to M.T. (STG 677029), the ERANET-NEURON (Micronet, MC_PC_16036) grant to M.T. and the Wellcome Trust (J.P., 211258/Z/18/Z). A.G.-R. held a Henslow Fellowship, awarded by the Cambridge Philosophical Society and St Edmund’s College (University of Cambridge). K.J. was funded by a Cambridge Gates Scholarship. M.N. was funded by a Trinity Henry Barlow scholarship, by M. C. Payne at the TCM Group and, for the last phase of revisions, by Nokia Bell Labs for research unrelated to this manuscript. D.d.M. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 894697. J.K. was supported by a PhD studentship funded by Wolfson College, the Department of Physiology, Development and Neuroscience and the School of Biological Sciences DTP at the University of Cambridge.The execution of goal-oriented behaviours requires a spatially coherent alignment between sensory and motor maps. The current model for sensorimotor transformation in the superior colliculus relies on the topographic mapping of static spatial receptive fields onto movement endpoints1-6. Here, to experimentally assess the validity of this canonical static model of alignment, we dissected the visuo-motor network in the superior colliculus and performed in vivo intracellular and extracellular recordings across layers, in restrained and unrestrained conditions, to assess both the motor and the visual tuning of individual motor and premotor neurons. We found that collicular motor units have poorly defined visual static spatial receptive fields and respond instead to kinetic visual features, revealing the existence of a direct alignment in vectorial space between sensory and movement vectors, rather than between spatial receptive fields and movement endpoints as canonically hypothesized. We show that a neural network built according to these kinetic alignment principles is ideally placed to sustain ethological behaviours such as the rapid interception of moving and static targets. These findings reveal a novel dimension of the sensorimotor alignment process. By extending the alignment from the static to the kinetic domain this work provides a novel conceptual framework for understanding the nature of sensorimotor convergence and its relevance in guiding goal-directed behaviours

Secreted amyloid-beta precursor protein functions as a GABABR1a ligand to modulate synaptic transmission

Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer's disease, yet its physiological function remains unresolved. Accumulating evidence suggests that APP has a synaptic function mediated by an unidentified receptor for the shed APP ectodomain (sAPP). Here, we showed that the sAPP extension domain directly bound the sushi 1 domain specific to the gamma-aminobutyric acid type B receptor subunit 1a (GABABR1a). sAPP-GABABR1a binding suppressed synaptic transmission and enhanced short-term facilitation in hippocampal synapses via inhibition of synaptic vesicle release. A 17 amino acid peptide corresponding to the GABABR1a binding region within APP suppressed spontaneous neuronal activity in vivo. Our findings identify GABABR1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABABR1a function to modulate synaptic transmission.status: publishe