High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy

Jordi, Josua; Guggiana-Nilo, Drago; Bolton, Andrew D.; Prabha, Srishti; Ballotti, Kaitlyn; Herrera, Kristian J.; Rennekamp, Andrew J.; Peterson, Randall T.; Lutz, Thomas; Engert, Florian

doi:10.1126/sciadv.aav1966

Cited by 49 publications

(36 citation statements)

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“…Larval zebrafish hunt prey such as paramecia through a sequence of motor actions that has been considered a hardwired reflex response to external prey stimuli (Bianco et al, 2011; Semmelhack et al, 2015; Trivedi and Bollmann, 2013). Only recently has evidence emerged that this behavior is flexibly modulated by satiation state (Filosa et al, 2016; Jordi et al, 2015, 2018) and that larvae at 7 d ays p ost- f ertilization (dpf) display enhanced hunting and enhanced food intake after a period of food-deprivation. A robust readout of food intake in larval zebrafish was obtained both by the ingestion of fluorescently-labeled paramecia and by behavioral analysis, both of which have been adapted for this study (Johnson et al, 2019; Jordi et al, 2015, 2018; Shimada et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

A Bidirectional Network for Appetite Control in Larval Zebrafish

Wee

Song

Johnson

et al. 2019

Preprint

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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: Resultsmentioning

confidence: 99%

A Bidirectional Network for Appetite Control in Larval Zebrafish

Wee

Song

Johnson

et al. 2019

Preprint

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“…To evaluate the influence of hunger on their behavior, each fish was either given abundant paramecia (fed group, n=73) or deprived of food for 2.5-5 hours (starved group, n=57) prior to observation. Previous studies have shown that brief food deprivation is sufficient to robustly increase larval zebrafish food intake 47,48 and to increase their likelihood to approach, rather than avoid, prey-like visual stimuli 49,50 . We therefore expect the fed and starved fish groups to display different behavioral patterns and aim to construct behavioral models to quantify and characterize these effects.…”

Section: Acquiring Behavioral Data With Beastmentioning

confidence: 99%

Probabilistic Models of Larval Zebrafish Behavior: Structure on Many Scales

Johnson

Linderman

Panier

et al. 2019

Preprint

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Nervous systems have evolved to combine environmental information with internal state to select and generate adaptive behavioral sequences. To better understand these computations and their implementation in neural circuits, natural behavior must be carefully measured and quantified. Here, we collect high spatial resolution video of single zebrafish larvae swimming in a naturalistic environment and develop models of their action selection across exploration and hunting. Zebrafish larvae swim in punctuated bouts separated by longer periods of rest called interbout intervals. We take advantage of this structure by categorizing bouts into discrete types and representing their behavior as labeled sequences of bout-types emitted over time. We then construct probabilistic models -specifically, marked renewal processes -to evaluate how bout-types and interbout intervals are selected by the fish as a function of its internal hunger state, behavioral history, and the locations and properties of nearby prey. Finally, we evaluate the models by their predictive likelihood and their ability to generate realistic trajectories of virtual fish swimming through simulated environments. Our simulations capture multiple timescales of structure in larval zebrafish behavior and expose many ways in which hunger state influences their action selection to promote food seeking during hunger and safety during satiety.

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“…To this end, initiatives like the NIA MODEL‐AD initiative (King, ), a collaboration between Indiana University, the Jackson Laboratory, and Sage Bionetworks that led to the App KO/APOE4/Trem2*R47 mouse, is funded to produce 10 new mouse models per year for the next 5 years to add yet another 50 AD rodent transgenic models to the current 170, surely the largest number available for any single disease state, and a perfect example of technology driving reductionism in biomedical research. Additionally, the EU's IMPRiND (Inhibiting Misfolded protein Propagation In Neurodegenerative Diseases; https://www.imprind.org/IMPRiND_PS1_0.7.pdf) consortium is assessing the value of Drosophila or zebrafish models [the latter of which have shown promise as first‐in‐class high‐throughput phenotypic compound screens for appetite modulators (Jordi et al., )] in neurodegenerative diseases research and the enhanced development of whole animal models of AD by transplanting human iPSC neurons into the macque monkey, which leads to plaque and tangle development, as well as cognitive impairment. A marmoset model of AD is also under development at RIKEN using CRISPR to insert mutations of the gene PSEN1 into fertilized eggs.…”

Section: Future Directions: New Models and Broader Testingmentioning

confidence: 99%

“…Additionally, the EU's IMPRiND (Inhibiting Misfolded protein Propagation In Neurodegenerative Diseases; https://www.imprind.org/IMPRiND_PS1_0.7. pdf) consortium is assessing the value of Drosophila or zebrafish models [the latter of which have shown promise as first-inclass high-throughput phenotypic compound screens for appetite modulators (Jordi et al, 2018)] in neurodegenerative diseases research and the enhanced development of whole animal models of AD by transplanting human iPSC neurons into the macque monkey, which leads to plaque and tangle development, as well as cognitive impairment. A marmoset model of AD is also under development at RIKEN using CRISPR to insert mutations of the gene PSEN1 into fertilized eggs.…”

Section: Of 28mentioning

confidence: 99%

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

Mullane

Williams

2019

CP Pharmacology

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The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40‐year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease‐associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs—including their bioavailability and toxicity—the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged‐related dementias. © 2019 by John Wiley & Sons, Inc.

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High-throughput screening for selective appetite modulators: A multibehavioral and translational drug discovery strategy

Abstract: Large-scale chemical and multibehavioral profiling identifies previously unknown potent and specific appetite modulators.

Cited by 49 publications

References 58 publications

A Bidirectional Network for Appetite Control in Larval Zebrafish

A Bidirectional Network for Appetite Control in Larval Zebrafish

Probabilistic Models of Larval Zebrafish Behavior: Structure on Many Scales

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

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