No abstract

During brain development, before sensory systems become functional, neuronal networks spontaneously generate repetitive bursts of neuronal activity, which are typically synchronized across many neurons. Such activity patterns have been described on the level of networks and cells, but the fine-structure of inputs received by an individual neuron during spontaneous network activity has not been studied. Here, we used calcium imaging to record activity at many synapses of hippocampal pyramidal neurons simultaneously to establish the activity patterns in the majority of synapses of an entire cell. Analysis of the spatiotemporal patterns of synaptic activity revealed a fine-scale connectivity rule: neighboring synapses (<16 μm intersynapse distance) are more likely to be coactive than synapses that are farther away from each other. Blocking spiking activity or NMDA receptor activation revealed that the clustering of synaptic inputs required neuronal activity, demonstrating a role of developmentally expressed spontaneous activity for connecting neurons with subcellular precision.

Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (<12 μm) become depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75(NTR) prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an "out-of-sync, lose-your-link" fashion through proBDNF/p75(NTR) signaling to refine neuronal connectivity. VIDEO ABSTRACT.

The mammalian hippocampus, comprised of serially connected subfields, participates in diverse behavioral and cognitive functions. It has been postulated that parallel circuitry embedded within hippocampal subfields may underlie such functional diversity. We sought to identify, delineate, and manipulate this putatively parallel architecture in the dorsal subiculum, the primary output subfield of the dorsal hippocampus. Population and single-cell RNA-seq revealed that the subiculum can be divided into two spatially adjacent subregions associated with prominent differences in pyramidal cell gene expression. Pyramidal cells occupying these two regions differed in their long-range inputs, local wiring, projection targets, and electrophysiological properties. Leveraging gene-expression differences across these regions, we use genetically restricted neuronal silencing to show that these regions differentially contribute to spatial working memory. This work provides a coherent molecular-, cellular-, circuit-, and behavioral-level demonstration that the hippocampus embeds structurally and functionally dissociable streams within its serial architecture.

13 14Activity in motor cortex predicts specific movements, seconds before they are initiated. This preparatory 15 activity has been observed in L5 descending 'pyramidal tract' (PT) neurons. A key question is how 16 preparatory activity can be maintained without causing movement, and how preparatory activity is 17 eventually converted to a motor command to trigger appropriate movements. We used single cell 18 transcriptional profiling and axonal reconstructions to identify two types of PT neuron. Both types share 19 projections to multiple targets in the basal ganglia and brainstem. One type projects to thalamic regions 20 that connect back to motor cortex. In a delayed-response task, these neurons produced early preparatory 21 activity that persisted until the movement. The second type projects to motor centers in the medulla and 22 produced late preparatory activity and motor commands. These results indicate that two motor cortex 23 output neurons are specialized for distinct roles in motor control. 25peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/229260 doi: bioRxiv preprint first posted online Dec. 5, 2017; 2 INTRODUCTION 26Motor cortex plays critical roles in planning and executing voluntary movements. Activity in motor 27 cortex anticipates specific future movements, often seconds before movement onset (reviewed in Refs 28 [1,2]). This dynamic neural process, referred to as preparatory activity, is thought to move the state of the 29 motor cortex to an initial condition appropriate for eliciting rapid, accurate movements 3 . In addition, 30 motor cortex activity is highly modulated during movement onset, consistent with commands that control 31 the timing and direction of movements 4,5 . 32Reconciling the dual roles of motor cortex requires an understanding of the cell types that make up the 33 cortical circuit, and how these cell types integrate into the multi-regional circuits that maintain short-term 34 memories and produce voluntary movements. Motor cortex comprises distinct cell types that differ in 35 their location, gene expression pattern, electrophysiology, and connectivity. Intratelencephalic (IT) 36 neurons in layers (L) 2-6 receive diverse input from other cortical areas and excite pyramidal tract (PT) 37 neurons [6][7][8] . PT neurons, whose somata define neocortical L5b 9, are of particular significance as they make 38 the only long-range connections linking the motor cortex with premotor centers in the brainstem and 39 spinal cord 10 . PT neurons thus coordinate cortical and subcortical brain regions to produce behavior 11,12 . 40Lesioning PT axons causes persistent motor deficits 12,13 . PT neurons also constitute a major component of 41 the cortical projection to the thalamus [14][15][16] . Previous studies have shown that preparatory activity is not 42 maintained by motor cortex in isolation, instead requiring reverberations in a thalamocortical l...

Activity in motor cortex predicts specific movements, seconds before they are initiated. This preparatory activity has been observed in L5 descending 'pyramidal tract' (PT) neurons. A key question is how preparatory activity can be maintained without causing movement, and how preparatory activity is eventually converted to a motor command to trigger appropriate movements. We used single cell transcriptional profiling and axonal reconstructions to identify two types of PT neuron. Both types share projections to multiple targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex. In a delayed-response task, these neurons produced early preparatory activity that persisted until the movement. The second type projects to motor centers in the medulla and produced late preparatory activity and motor commands. These results indicate that two motor cortex output neurons are specialized for distinct roles in motor control.

Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neurons in the mouse brain have been reconstructed in their entirety. Here we present a robust and efficient platform for imaging and reconstructing complete neuronal morphologies, including axonal arbors that span substantial portions of the brain. We used this platform to reconstruct more than 1,000 projection neurons in the motor cortex, thalamus, subiculum, and hypothalamus. Together, the reconstructed neurons comprise more than 75 meters of axonal length and are available in a searchable online database. Axonal shapes revealed previously unknown subtypes of projection neurons and suggest organizational principles of long-range connectivity.

The striatum shows general topographic organization and regional differences in behavioral functions. How corticostriatal topography differs across cortical areas and cell types to support these distinct functions is unclear. This study contrasted corticostriatal projections from two layer 5 cell types, intratelencephalic (IT-type) and pyramidal tract (PT-type) neurons, using viral vectors expressing fluorescent reporters in Cre-driver mice. Corticostriatal projections from sensory and motor cortex are somatotopic, with a decreasing topographic specificity as injection sites move from sensory to motor and frontal areas. Topographic organization differs between IT-type and PT-type neurons, including injections in the same site, with IT-type neurons having higher topographic stereotypy than PT-type neurons. Furthermore, IT-type projections from interconnected cortical areas have stronger correlations in corticostriatal targeting than PT-type projections do. As predicted by a longstanding model, corticostriatal projections of interconnected cortical areas form parallel circuits in the basal ganglia.