Biology subjects

Lagos, W. N.

Publications and source records attributed to Lagos, W. N..

4 recordsLinked to original sources

bioRxiv2024

Complementary Organization of Driver and Modulator Cortico-Thalamo-Cortical Circuits

Corticocortical (CC) projections in the visual system facilitate the hierarchical processing of sensory information. In addition to direct CC connections, indirect cortico-thalamo-cortical (CTC) pathways through the pulvinar nucleus of the thalamus can relay sensory signals and mediate interactions between areas according to behavioral demands. While the pulvinar is extensively connected to the entire visual cortex, it is unknown whether transthalamic pathways link all cortical areas or whether they follow systematic organizational rules. Because pulvinar neurons projecting to different cortical areas are spatially intermingled, their input/output relationships have been difficult to characterize using traditional anatomical methods. To determine the organization of CTC circuits, we mapped the higher visual areas (HVAs) of mice with intrinsic signal imaging and targeted five pulvinar[->]HVA pathways for projection-specific rabies tracing. We aligned post- mortem cortical tissue to in vivo maps for precise quantification of the areas and cell types projecting to each pulvinar[->]HVA population. Layer 5 corticothalamic (L5CT) "driver" inputs to the pulvinar originate predominantly from primary visual cortex (V1), consistent with the CC hierarchy. L5CT inputs from lateral HVAs specifically avoid driving reciprocal connections, consistent with the "no-strong-loops" hypothesis. Conversely, layer 6 corticothalamic (L6CT) "modulator" inputs are distributed across areas and are biased toward reciprocal connections. Unlike previous studies in primates, we find that every HVA receives disynaptic input from the superior colliculus. CTC circuits in the pulvinar thus depend on both target HVA and input cell type, such that driving and modulating higher-order pathways follow complementary connection rules similar to those governing first-order CT circuits. Significance StatementUnderstanding the functional role of the visual pulvinar will require knowledge of its anatomical connections. Using state-of-the-art rabies tracing, we establish a comprehensive map of brain-wide and CTC pulvinar connections. While the tectopulvinar pathway in primates selectively targets dorsal visual areas, we find SC input to every projection population in the mouse. This extrageniculate projection can support unconscious visually-guided behavior, suggesting that in mice all visual cortical areas contribute to such functions. Our results also unify several longstanding theories of thalamocortical anatomy. Namely, "driver" CTC inputs are feedforward relays that mirror the CC hierarchy and adhere to the "no-strong-loops" hypothesis. "Modulator" L6CT inputs to pulvinar[->]HVA projections are overrepresented in the target HVA, reflecting the reciprocal connectivity described in previous bulk tracing studies. Together, these findings constitute a definitive and comprehensive map which can inform future physiological experiments and theoretical models of pulvinar function.

neuroscience↗

bioRxiv2023

Parallel pathways carrying direction and orientation selective retinal signals to layer 4 of mouse visual cortex

Parallel functional and anatomical visual pathways from the retina to primary visual cortex (V1) via the lateral geniculate nucleus (LGN) are common to many mammalian species, including mice, carnivores and primates. However, the much larger number of retinal ganglion cell (RGC) types that project to the LGN, as well as the more limited lamination of both the LGN and the thalamocortical-recipient layer 4 (L4) in mice, leaves considerable uncertainty about which visual features present in both retina and V1 might be inherited from parallel pathways versus extracted by V1 circuits in the mouse visual system. Here, we explored the relationships between functional properties of L4 V1 neurons and their RGC inputs by taking advantage of two Cre-expressing mouse lines -- Nr5a1-Cre and Scnn1a-Tg3-Cre -- that each label functionally and anatomically distinct populations of L4 neurons. Visual tuning properties of L4 V1 neurons were evaluated using Cre-dependent expression of GCaMP6s followed by 2-photon calcium imaging. RGCs providing input to these neurons (via LGN) were labeled and characterized using Cre-dependent trans-synaptic retrograde labeling with G-deleted rabies virus. We find significant differences in the tuning of Nr5a1-Cre versus Scnn1a-Tg3-Cre neurons for direction, orientation, spatial frequency, temporal frequency, and speed. Strikingly, a subset of the RGCs had tuning properties that matched the direction and orientation tuning properties of the L4 V1 neurons to which they provided input. Altogether, these results suggest that direction and orientation tuning of V1 neurons may be at least partly inherited from parallel pathways originating in the retina.

neuroscience↗

bioRxiv2023

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Single-cell genetic and epigenetic analyses parse the brains billions of neurons into thousands of "cell-type" clusters, each residing in different brain structures. Many of these cell types mediate their unique functions by virtue of targeted long-distance axonal projections to allow interactions between specific cell types. Here we have used Epi-Retro-Seq to link single cell epigenomes and associated cell types to their long-distance projections for 33,034 neurons dissected from 32 different source regions projecting to 24 different targets (225 source [->]target combinations) across the whole mouse brain. We highlight uses of this large data set for interrogating both overarching principles relating projection cell types to their transcriptomic and epigenomic properties and for addressing and developing specific hypotheses about cell types and connections as they relate to genetics. We provide an overall synthesis of the data set with 926 statistical comparisons of the discriminability of neurons projecting to each target for every dissected source region. We integrate this dataset into the larger, annotated BICCN cell type atlas composed of millions of neurons to link projection cell types to consensus clusters. Integration with spatial transcriptomic data further assigns projection-enriched clusters to much smaller source regions than afforded by the original dissections. We exemplify these capabilities by presenting in-depth analyses of neurons with identified projections from the hypothalamus, thalamus, hindbrain, amygdala, and midbrain to provide new insights into the properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription factor binding motifs, and neurotransmitter usage.

neuroscience↗

bioRxiv2022

Quantification of Monosynaptic Rabies Tracing Efficiency

Retrograde monosynaptic tracing using glycoprotein-deleted rabies virus is an important component of the toolkit for investigation of neural circuit structure and connectivity. It allows for the identification of first-order presynaptic connections to cell populations of interest across both the central and peripheral nervous system, helping to decipher the complex connectivity patterns of neural networks that give rise to brain function. Despite its utility, the efficiency with which genetically modified rabies virus spreads retrogradely across synapses remains uncertain. While past studies have revealed conditions that can increase or decrease the numbers of presynaptic cells labeled, it is unknown what proportion of total inputs to a starter cell of interest are labeled. It is also unknown whether synapses that are more proximal or distal to the cell body are labeled with different efficiencies. Here we use a new rabies virus construct that allows for the simultaneous labeling of pre and postsynaptic specializations to quantify efficiency of spread at the synaptic level in mouse primary visual cortex. We demonstrate that with typical conditions about 40% of first-order presynaptic excitatory inputs are labeled. We show that using matched tracing conditions there is similar efficiency of spread from excitatory or inhibitory starter cell types. Furthermore, we find no difference in the efficiency of labeling of excitatory inputs to postsynaptic sites at different subcellular locations.

neuroscience↗