Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior

Kim, Dong-Wook; Yao, Zizhen; Graybuck, Lucas T.; Kim, Tae Kyung; Nguyen, Thuc Nghi; Smith, Kimberly A.; Fong, Olivia; Yi, Lynn; Koulena, Noushin; Pierson, Nico; Shah, Sheel; Lo, Liching; Pool, Allan-Hermann; Oka, Yuki; Pachter, Lior; Cai, Long; Tasic, Bosiljka; Zeng, Hongkui; Anderson, David J.

doi:10.1016/j.cell.2019.09.020

Cited by 223 publications

(297 citation statements)

References 104 publications

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“…The observed persistent 150 activity can be modeled best by recurrent excitatory networks incorporating fast feedback inhibition 151 and slow peptidergic transmission 43 . VMHdm SF1 neurons are exclusively glutamatergic, densely 152 interconnected 44 , and express several neuropeptides as well as neuropeptide receptors 45 , properties 153 consistent with optimal model features. While our data do not exclude a role for interconnected 154 structures 10,46 in establishing persistent activity in VMHdm, they demonstrate that hypothalamic 155 neuronal population dynamics contribute to the persistence of emotional behaviors.…”

Section: Extended Datamentioning

confidence: 68%

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Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Kennedy

et al. 2019

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14Persistent neural activity has been described in cortical, hippocampal, and motor networks as 15 mediating short-term working memory of transiently encountered stimuli 1-4 . Internal emotion states 16 such as fear also exhibit persistence following exposure to an inciting stimulus 5,6 , but such 17 persistence is typically attributed to circulating stress hormones 7-9 ; whether persistent neural activity 18 also plays a role has not been established. SF1 + /Nr5a1 + neurons in the dorsomedial and central 19 subdivision of the ventromedial hypothalamus (VMHdm/c) are necessary for innate and learned 20 defensive responses to predators 10-13 . Optogenetic activation of VMHdm SF1 neurons elicits defensive 21 behaviors that can outlast stimulation 11,14 , suggesting it induces a persistent internal state of fear or 22 anxiety. Here we show that VMHdm SF1 neurons exhibit persistent activity lasting tens of seconds, in 23 response to naturalistic threatening stimuli. This persistent activity was correlated with, and 24 required for, persistent thigmotaxic (anxiety-like) behavior in an open-field assay. Microendoscopic 25 imaging of VMHdm SF1 neurons revealed that persistence reflects dynamic temporal changes in 26 population activity, rather than simply synchronous, slow decay of simultaneously activated 27 neurons. Unexpectedly, distinct but overlapping VMHdm SF1 subpopulations were persistently 28 activated by different classes of threatening stimuli. Computational modeling suggested that 29 recurrent neural networks (RNNs) incorporating slow excitation and a modest degree of 30 neurochemical or spatial bias can account for persistent activity that maintains stimulus identity, 31 without invoking genetically determined "labeled lines" 15 . Our results provide causal evidence that 32 persistent neural activity, in addition to well-established neuroendocrine mechanisms, can 33 contribute to the ability of emotion states to outlast their inciting stimuli, and suggest a mechanism 34 3 that could prevent over-generalization of defensive responses without the need to evolve hardwired 35 circuits specific for each type of threat. (267 words) 36 Main Text 37We performed fiber photometry 16 in VMHdm SF1 neurons expressing GCaMP6s 17 in freely behaving mice 38 during a 10s presentation of a predator (an anesthetized rat 18 ) ( Fig. 1a-c). We observed a rapid 39 increase in the bulk calcium signal at the onset of rat presentation ( Fig. 1d, e). Remarkably, this activity 40 persisted for over a minute following rat removal, decaying exponentially with time constant τdecay = 41 26.7±2.2 seconds ( Fig. 1d-e, h-i; Supplemental Video 1). In contrast, a toy rat presented in the same 42 manner produced a far weaker and less persistent response ( Fig. 1d, e). 43 To better control the timing and location of stimulus presentation, we repeated this experiment 44 using a head-fixed preparation. The magnitude, decay constants and specificity of VMHdm SF1 persistent 45 responses were comparable to those measured in freely behaving mice ( Fig...

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Section: Extended Datamentioning

confidence: 68%

“…Stimuli were presented either in the mouse's home cage or in a head-fixation set 44 up. In the home cage, a hand-held anesthetized rat weighing 400-600 g was brought in close proximity to 45 the mouse. A stuffed toy rat of approximately the same size as the live rat was used as a control.…”

Section: Extended Datamentioning

confidence: 99%

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Kennedy

et al. 2019

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“…Our approach should be useful not only prospectively, but also for studies such as Kim et al 2019 25 which collected data using multiple scRNA-seq technologies but focused primarily on cell type identification using gene-level analyses. Our quantification of 6,160 SMART-Seq cells with kallisto 23 shows that it is straightforward to produce accurate, reproducible quantifications efficiently for any SMART-Seq dataset.…”

Section: Discussionmentioning

confidence: 99%

Isoform cell type specificity in the mouse primary motor cortex

Booeshaghi

Yao

Velthoven

et al. 2020

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Full-length SMART-Seq single-cell RNA-seq can be used to measure gene expression at isoform resolution, making possible the identification of isoform markers for cell types and for an isoform atlas. In a comprehensive analysis of 6,160 mouse primary motor cortex cells assayed with SMART-Seq, we find numerous examples of isoform specificity in cell types, including isoform shifts between cell types that are masked in gene-level analysis. These findings can be used to refine spatial gene expression information to isoform resolution. Our results highlight the utility of full-length single-cell RNA-seq when used in conjunction with other single-cell RNA-seq technologies.

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“…Although the purpose of each of these techniques is to subdivide measurements down to the level of single neurons, the goal of integrating these data is to understand where the functionally meaningful levels of subdivision are. Experiments that simultaneously interrogate neurons across multiple modalities, particularly involving behavior-based classification (Moffitt et al, 2018;Kim et al, 2019), are critical for anchoring and informing this issue. Our study has integrated single-cell sequencing and Ca 2+ imaging data within a highly dynamic behavioral context, and paves the way for future studies that achieve co-registration of cell type, axon projection, and activity patterns during cognitive behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…Interrogation of two subcortically-projecting transcriptomic types in mouse anterolateral motor cortex (ALM) during a motor planning task revealed differences in the encoding of preparatory activity and motor commands (Economo et al, 2018). Transcriptomic profiling of neuronal diversity in the mouse hypothalamus revealed a more complex situation (Moffitt et al, 2018;Kim et al, 2019). While high levels of transcriptomic cell diversity were found in all subregions profiled, multimodal analysis of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) revealed little one-to-one matching between transcriptomic types, behavior-specific activation, and connectivity .…”

Section: Introductionmentioning

confidence: 99%

Differential encoding in prefrontal cortex projection neuron classes across cognitive tasks

Lui

Nguyen

Grutzner

et al. 2020

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Single-cell transcriptomics has been widely applied to classify neurons in the mammalian brain, while systems neuroscience has historically analyzed the encoding properties of cortical neurons without considering cell types. Here we examine how specific transcriptomic types of mouse prefrontal cortex (PFC) projection neurons relate to axonal projections and encoding properties across multiple cognitive tasks. We found that most types projected to multiple targets, and most targets received projections from multiple types, except PFC→PAG (periaqueductal gray). By comparing Ca 2+ -activity of the molecularly homogeneous PFC→PAG type against two heterogeneous classes in several two-alternative choice tasks in freely-moving mice, we found that all task-related signals assayed were qualitatively present in all examined classes. However, PAG-projecting neurons most potently encoded choice in cued tasks, whereas contralateral PFC-projecting neurons most potently encoded reward context in an uncued task. Thus, task signals are organized redundantly, but with clear quantitative biases across cells of specific molecular-anatomical characteristics.

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Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior

Cited by 223 publications

References 104 publications

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

Isoform cell type specificity in the mouse primary motor cortex

Differential encoding in prefrontal cortex projection neuron classes across cognitive tasks

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