Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons

Mickelsen, Laura E; Bolisetty, Mohan; Chimileski, Brock; Fujita, Akie; Beltrami, Eric J.; Costanzo, James T; Naparstek, Jacob; Robson, Paul; Jackson, Alexander C.

doi:10.1038/s41593-019-0349-8

Cited by 275 publications

(337 citation statements)

References 79 publications

(137 reference statements)

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“…In particular, GABAergic neurons that do not co-express MCH or Orexin have been shown to be responsive to food cues and are sufficient to stimulate food intake in mammals (Jennings et al, 2015). Whether these GABAergic and glutamatergic neurons of the zebrafish LH co-express other neuromodulators, as has been recently discovered in mammals (Mickelsen et al, 2019) remains to be explored. Overall, these data suggest that the zebrafish LH may play an important role in driving food intake during hunger, despite some differences in peptidergic expression from mammalian LH.…”

Section: Discussionmentioning

confidence: 99%

A Bidirectional Network for Appetite Control in Larval Zebrafish

Wee

Song

Johnson

et al. 2019

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14Medial and lateral hypothalamic loci are known to suppress and enhance appetite, respectively, 15 but the dynamics and functional significance of their interaction have yet to be explored. Here 16we report that, in larval zebrafish, primarily serotonergic neurons of the ventromedial caudal 17 hypothalamus (cH) become increasingly active during food deprivation, whereas activity in the 18 lateral hypothalamus (LH) is reduced. Exposure to food sensory and consummatory cues 19 reverses the activity patterns of these two nuclei, consistent with their representation of 20 opposing internal hunger states. Baseline activity is restored as food-deprived animals return to 21 satiety via voracious feeding. The antagonistic relationship and functional importance of cH and 22 LH activity patterns were confirmed by targeted stimulation and ablation of cH neurons. 23Collectively, the data allow us to propose a model in which these hypothalamic nuclei regulate 24 different phases of hunger and satiety and coordinate energy balance via antagonistic control of 25 distinct behavioral outputs. convergence point for the neural and biochemical pathways that underlie this regulatory 30 mechanism. Early studies demonstrated by way of electrical stimulation or lesions that specific 31 hypothalamic regions play important roles in the regulation of appetite. For example, while 32 stimulation of ventromedial hypothalamic loci in rodents and cats reduced feeding, activation of 33 more lateral hypothalamic loci increased both hunting behavior and food intake (Anand and 34 Brobeck, 1951; Brobeck et al., 1956; Delgado and Anand, 1953; Krasne, 1962). Conversely, 35 lateral hypothalamic lesions were found to reduce feeding to the point of starvation, whereas 36 medial hypothalamic lesions resulted in overeating (Anand and Brobeck, 1951; Hoebel, 1965; 37 Teitelbaum and Epstein, 1962). Thus, the lateral and medial hypothalamic regions came to be 38 regarded as "hunger" and "satiety" centers, respectively. 39Recent experiments employing optical and electrophysiological methods have lent 40 support to these early studies. For example, GABAergic neurons in the lateral hypothalamus 41 were observed to be activated during feeding and essential for enhanced food intake during 42 hunger (Jennings et al., 2015; Stuber and Wise, 2016). However, these experiments have 43 examined only subsets of hypothalamic neurons; their activity patterns and function within the 44 context of the entire network remain unknown. This limited view hampers our understanding of 45 the dynamical interactions between the ensemble of brain circuits thought to be important for 46 the initiation, maintenance and termination of food consumption (Sternson and Eiselt, 2017). 48 modulatory regions central to the control of appetite and to shed light on their specific roles and 49 dynamical activity patterns in relation to behavior. Using pERK-based brain-wide activity 50 mapping (Randlett et al., 2015), we first identified neuronal populations that display differential 51 neural a...

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Section: Discussionmentioning

confidence: 99%

A Bidirectional Network for Appetite Control in Larval Zebrafish

Wee

Song

Johnson

et al. 2019

Preprint

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“…The total number of cell types in the hypothalamus has been significantly underestimated 31 , therefore to assess whether the lack of enrichment for hypothalamic cell types was due to sparse sampling of hypothalamic cells in the Mouse Nervous System dataset, we computed enrichments for an additional set of 347 cell types sampled from the mediobasal hypothalamus 17 , the ventromedial hypothalamus 31 , the lateral hypothalamus 32 , the preoptic nucleus of the hypothalamus 33 and the entire hypothalamus 34,35 ( Supplementary Table 12). We identified four non-overlapping significantly enriched cell types, namely a ventromedial hypothalamic glutamatergic cell type (ARCME−NEURO29; P=4.9x10 -5 ) expressing Sf1 (ESμ=0.98 and ESμ=0.99), Cckbr (cholecystokinin B receptor; ESμ=0.98, ESμ=0.95); a glutamatergic cell type from the lateral hypothalamus (LHA-NEURO20; P=4.9x10 -5 ); two cell types from the preoptic area of the hypothalamus (POA-NEURO21 and POA-NEURO66; P<1.0x10 -4 ; Fig.…”

Section: Ventromedial Hypothalamic Sf1-and Cckbr-expressing Cells Enrmentioning

confidence: 99%

“…17 ) from the arcuate nucleus and median eminence complex, and LHA-NEURO20 (top marker genes Ebf3 and Otb in ref. 32 ) from the lateral hypothalamus. POA, preoptic area of the hypothalamus; LHA, lateral hypothalamus; ARCME, arcuate nucleus and median eminence complex; S-LDSC, stratified-linkage disequilibrium score regression.…”

Section: Cell Type Enrichment Of Co-expressed Gene Networkmentioning

confidence: 99%

Mapping heritability of obesity by brain cell types

Thompson

Pers

2020

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The underlying cell types mediating predisposition to obesity remain largely obscure. Here we first integrated recently published single-cell RNA-sequencing (scRNA-seq) data from >380 peripheral and nervous system cell types spanning 19 mouse organs with body mass index (BMI) genome-wide association study (GWAS) data from >450,000 individuals. Leveraging a novel strategy for integrating scRNA-seq data with GWAS data, we identified 22, exclusively neuronal, cell types from the subthalamus, midbrain, hippocampus, thalamus, cortex, pons, medulla, pallidum that were significantly enriched for BMI heritability (P<1.6x10 -4 ). Using genes harboring coding mutations leading to syndromic forms of obesity, we replicate four midbrain cell types from the anterior pretectal nucleus, superior nucleus, periaqueductal gray and pallidum (P<1.7x10 -4 ). Testing an additional set of 347 hypothalamic cell types, ventromedial hypothalamic steroidogenic-factor 1 (SF1) and cholecystokinin b receptor (CCKBR)-expressing neurons (P=4.9x10 -5 ) previously implicated in energy homeostasis and glucose control and three cell types from the preoptic area of the hypothalamus and the lateral hypothalamus enriched for BMI GWAS associations (P<4.9x10 -5 ).Together, our results suggest brain nuclei regulating integration of sensory stimuli, learning and memory are likely to play a key role in obesity and provide testable hypotheses for mechanistic follow-up studies.

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“…Future work should inspect synaptic interactions between orexin cells and other movement controlling neurons to elucidate how these populations orchestrate decisions to move. It should also assess whether orexin cell movement-subtypes correlate with known electrophysiological, molecular or anatomical subtypes (Apergis-Schoute et al, 2015;Iyer et al, 2018;Mickelsen et al, 2019Mickelsen et al, , 2017Schöne et al, 2011). It has been hypothesized that orexin neurons promote exploratory activity, hunger-driven food-seeking or any motivated behaviour (Mahler et al, 2014;Tyree et al, 2018;Yamanaka et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Rapid sensory integration in orexin neurons governs probability of future movements

Karnani

SchoÌˆne

Bracey

et al. 2019

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Internally and externally triggered movement is crucial for survival and is controlled by multiple interconnected neuronal populations spanning many brain areas. Lateral hypothalamic orexin/hypocretin neurons are thought to play a slow, modulatory part in this scheme through their key role in promoting metabolism and wakefulness. However, it is unknown whether orexin/hypocretin neurons participate in rapid neural processing, leading to immediate movement. Furthermore, their role in sensorimotor transformations remains unknown. Here we use cellular-resolution Ca 2+ imaging and optogenetics to show that orexin/hypocretin cells are instantaneous regulators of self-generated and sensory-evoked movement. They are activated before and during movement, preventing this activation reduces self-generated locomotion, and optogenetic mimicry of this transient activation rapidly initiates locomotion. We find that the same orexin neurons whose activity predicts movement initiation are rapidly controllable by external sensory stimuli, and silencing orexin cells during sensation prevents normal motor performance. These findings place orexin neurons in a physiological position of unexpectedly rapid and strong sensorimotor control. * -( Figure 3E), where S is spike output, F is light pulse frequency, P is movement probability, EC50 is half-maximal response and IC50 half-maximal decrease. Fitting was done using custom routines in Matlab.

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Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons

Cited by 275 publications

References 79 publications

A Bidirectional Network for Appetite Control in Larval Zebrafish

A Bidirectional Network for Appetite Control in Larval Zebrafish

Mapping heritability of obesity by brain cell types

Rapid sensory integration in orexin neurons governs probability of future movements

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