@article {68647, title = {Brain-wide neural activity underlying memory-guided movement}, journal = {bioRxiv}, year = {2023}, month = {2023 Mar 02}, abstract = {

Behavior requires neural activity across the brain, but most experiments probe neurons in a single area at a time. Here we used multiple Neuropixels probes to record neural activity simultaneously in brain-wide circuits, in mice performing a memory-guided directional licking task. We targeted brain areas that form multi-regional loops with anterior lateral motor cortex (ALM), a key circuit node mediating the behavior. Neurons encoding sensory stimuli, choice, and actions were distributed across the brain. However, in addition to ALM, coding of choice was concentrated in subcortical areas receiving input from ALM, in an ALM-dependent manner. Choice signals were first detected in ALM and the midbrain, followed by the thalamus, and other brain areas. At the time of movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation.

}, doi = {10.1101/2023.03.01.530520}, url = {https://doi.org/10.1101/2023.03.01.530520}, author = {Susu Chen and Yi Liu and Ziyue Wang and Jennifer Colonell and Liu D. Liu and Han Hou and Nai-Wen Tien and Tim Wang and Timothy Harris and Shaul Druckmann and Nuo Li and Karel Svoboda} } @article {69104, title = {Connectivity underlying motor cortex activity during naturalistic goal-directed behavior.}, journal = {bioRxiv}, year = {2023}, month = {2023 Nov 26}, abstract = {

Neural representations of information are shaped by local network interactions. Previous studies linking neural coding and cortical connectivity focused on stimulus selectivity in the sensory cortex\ 1{\textendash}4. Here we study neural activity in the motor cortex during naturalistic behavior in which mice gathered rewards with multidirectional tongue reaching. This behavior does not require training and thus allowed us to probe neural coding and connectivity in motor cortex before its activity is shaped by learning a specific task. Neurons typically responded during and after reaching movements and exhibited conjunctive tuning to target location and reward outcome. We used an all-optical\ 5,4,6,7\ method for large-scale causal functional connectivity mapping\ in vivo. Mapping connectivity between \> 20,000,000 excitatory neuronal pairs revealed fine-scale columnar architecture in layer 2/3 of the motor cortex. Neurons displayed local (\< 100 {\textmu}m) like-to-like connectivity according to target-location tuning, and inhibition over longer spatial scales. Connectivity patterns comprised a continuum, with abundant weakly connected neurons and sparse strongly connected neurons that function as network hubs. Hub neurons were weakly tuned to target-location and reward-outcome but strongly influenced neighboring neurons. This network of neurons, encoding location and outcome of movements to different motor goals, may be a general substrate for rapid learning of complex, goal-directed behaviors.

}, doi = {10.1101/2023.11.25.568673}, url = {https://doi.org/10.1101/2023.11.25.568673}, author = {Arseny Finkelstein and Kayvon Daie and M{\'a}rton R{\'o}zsa and Ran Darshan and Karel Svoboda} } @article {68829, title = {Not everything, not everywhere, not all at once: a study of brain-wide encoding of movement}, journal = {bioRxiv}, year = {2023}, month = {2023 Jun 09}, abstract = {

Activity related to movement is found throughout sensory and motor regions of the brain. However, it remains unclear how movement-related activity is distributed across the brain and whether systematic differences exist between brain areas. Here, we analyzed movement related activity in brain-wide recordings containing more than 50,000 neurons in mice performing a decision-making task. Using multiple techniques, from markers to deep neural networks, we find that movement-related signals were pervasive across the brain, but systematically differed across areas. Movement-related activity was stronger in areas closer to the motor or sensory periphery. Delineating activity in terms of sensory- and motor-related components revealed finer scale structures of their encodings within brain areas. We further identified activity modulation that correlates with decision-making and uninstructed movement. Our work charts out a largescale map of movement encoding and provides a roadmap for dissecting different forms of movement and decision-making related encoding across multi-regional neural circuits.

}, doi = {10.1101/2023.06.08.544257}, url = {https://doi.org/10.1101/2023.06.08.544257}, author = {Ziyue Aiden Wang and Susu Chen and Yi Liu and Dave Liu and Karel Svoboda and Nuo Li and Shaul Druckmann} } @article {68503, title = {Brain-wide measurement of protein turnover with high spatial and temporal resolution}, journal = {bioRxiv}, year = {2022}, month = {2022 Nov 13}, abstract = {

Cells regulate function by synthesizing and degrading proteins. This turnover ranges from minutes to weeks, as it varies across proteins, cellular compartments, cell types, and tissues. Current methods for tracking protein turnover lack the spatial and temporal resolution needed to investigate these processes, especially in the intact brain, which presents unique challenges. We describe a pulse-chase method (DELTA) for measuring protein turnover with high spatial and temporal resolution throughout the body, including the brain. DELTA relies on rapid covalent capture by HaloTag of fluorophores that were optimized for bioavailability\ in vivo. The nuclear protein MeCP2 showed brain region- and cell type-specific turnover. The synaptic protein PSD95 was destabilized in specific brain regions by behavioral enrichment. A novel variant of expansion microscopy further facilitated turnover measurements at individual synapses. DELTA enables studies of adaptive and maladaptive plasticity in brain-wide neural circuits.

}, doi = {10.1101/2022.11.12.516226}, url = {https://doi.org/10.1101/2022.11.12.516226}, author = {Boaz Mohar and Jonathan B. Grimm and Ronak Patel and Timothy A. Brown and Paul Tillberg and Luke D. Lavis and Nelson Spruston and Karel Svoboda} } @article {68166, title = {Distributing task-related neural activity across a cortical network through task-independent connections}, journal = {bioRxiv}, year = {2022}, month = {2022 Jun 18}, abstract = {

Task-related neural activity is widespread across populations of neurons during goal-directed behaviors. However, little is known about the synaptic reorganization and circuit mechanisms that lead to broad activity changes. Here we trained a limited subset of neurons in a spiking network with strong synaptic interactions to reproduce the activity of neurons in the motor cortex during a decision-making task. We found that task-related activity, resembling the neural data, emerged across the network, even in the untrained neurons. Analysis of trained networks showed that strong untrained synapses, which were independent of the task and determined the dynamical state of the network, mediated the spread of task-related activity. Optogenetic perturbations suggest that the motor cortex is strongly-coupled, supporting the applicability of the mechanism to cortical networks. Our results reveal a cortical mechanism that facilitates distributed representations of task-variables by spreading the activity from a subset of plastic neurons to the entire network through task-independent strong synapses.

}, doi = {10.1101/2022.06.17.496618}, url = {https://doi.org/10.1101/2022.06.17.496618}, author = {Christopher M. Kim and Arseny Finkelstein and Carson C. Chow and Karel Svoboda and Ran Darshan} } @article {67243, title = {Expansion-Assisted Iterative-FISH defines lateral hypothalamus spatio-molecular organization}, journal = {bioRxiv}, year = {2021}, month = {2021 Mar 8}, abstract = {

Determining the spatial organization and morphological characteristics of molecularly defined cell types is a major bottleneck for characterizing the architecture underpinning brain function. We developed\ Expansion-Assisted Iterative\ Fluorescence\ In\ Situ\ Hybridization (EASI-FISH) to survey gene expression in brain tissue, as well as a turnkey computational pipeline to rapidly process large EASI-FISH image datasets. EASI-FISH was optimized for thick brain sections (300 {\textmu}m) to facilitate reconstruction of spatio-molecular domains that generalize across brains. Using the EASI-FISH pipeline, we investigated the spatial distribution of dozens of molecularly defined cell types in the lateral hypothalamic area (LHA), a brain region with poorly defined anatomical organization. Mapping cell types in the LHA revealed nine novel spatially and molecularly defined subregions. EASI-FISH also facilitates iterative re-analysis of scRNA-Seq datasets to determine marker-genes that further dissociated spatial and morphological heterogeneity. The EASI-FISH pipeline democratizes mapping molecularly defined cell types, enabling discoveries about brain organization.

}, doi = {10.1101/2021.03.08.434304}, url = {https://doi.org/10.1101/2021.03.08.434304}, author = {Yuhan Wang and Mark Eddison and Greg Fleishman and Martin Weigert and Shengjin Xu and Frederick E. Henry and Tim Wang and Andrew L. Lemire and Uwe Schmidt and Hui Yang and Konrad Rokicki and Cristian Goina and Karel Svoboda and Eugene W. Myers and Stephan Saalfeld and Wyatt Korff and Scott M. Sternson and Paul W. Tillberg} } @article {46307, title = {A motor cortex circuit for motor planning and movement}, journal = {Nature}, volume = {519}, year = {2015}, month = {2015 Feb 25}, pages = {51-6}, abstract = {

Activity in motor cortex predicts specific movements seconds before they occur, but how this preparatory activity relates to upcoming movements is obscure. We dissected the conversion of preparatory activity to movement within a structured motor cortex circuit. An anterior lateral region of the mouse cortex (a possible homologue of premotor cortex in primates) contains equal proportions of intermingled neurons predicting ipsi- or contralateral movements, yet unilateral inactivation of this cortical region during movement planning disrupts contralateral movements. Using cell-type-specific electrophysiology, cellular imaging and optogenetic perturbation, we show that layer 5 neurons projecting within the cortex have unbiased laterality. Activity with a contralateral population bias arises specifically in layer 5 neurons projecting to the brainstem, and only late during movement planning. These results reveal the transformation of distributed preparatory activity into movement commands within hierarchically organized cortical circuits.

}, doi = {10.1038/nature14178}, author = {Nuo Li and Tsai-Wen Chen and Zengcai V. Guo and Charles R. Gerfen and Karel Svoboda} }