A Cyfip2-Dependent Excitatory Interneuron Pathway Establishes the Innate Startle Threshold

Marsden, Kurt C.; Jain, Roshan A.; Wolman, Marc A.; Nelson, Jessica C.; Hayer, Katharina E.; Miltenberg, Ben; Pereda, Alberto E.; Granato, Michael

doi:10.1016/j.celrep.2018.03.095

Cited by 49 publications

(99 citation statements)

References 61 publications

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“…Behavioral switching from SLC to LLC during conditioning or habituation is associated with reduced excitability of the M-cell [Takahashi et al, 2017, Marsden and Granato, 2015]. Furthermore, forward genetic screens have shown that mutants of altered SLC-LLC reaction balance are associated with altered M-cell excitability [Marsden et al, 2018, Jain et al, 2018].…”

Section: Discussionmentioning

confidence: 99%

Early-life social experience shapes social avoidance reactions in larval zebrafish

Groneberg

Marques

Martins

et al. 2020

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Highlights:• Larval zebrafish raised in isolation show enhanced social avoidance reactions • Enhanced avoidance is composed of increased avoidance distances and usage of high acceleration escape swims• The lateral line sensory organ is necessary and sufficient for the increased usage of high acceleration escape swims Summary Social experiences greatly define successive social behavior. Lack of such experiences, especially during critical phases of development, can severely impede the ability to behave adequately in social contexts. To date it is not well characterized how early-life social isolation leads to social deficits and impacts development. In many model species, it is challenging to fully control social experiences, because they depend on parental care. Moreover, complex social behaviors involve multiple sensory modalities, contexts, and actions. Hence, when studying social isolation effects, it is particularly important to parse apart social deficits from general developmental effects, such as abnormal motor learning. Here, we characterized how social experiences during early development of zebrafish larvae modulate their social behavior, at one week of age, when social avoidance reactions can be measured as discrete swim events. We show that raising larvae in social isolation leads to enhanced social avoidance, in terms of reaction distance and reaction strength. Specifically, larvae raised in isolation use a high-acceleration escape swim bout, the short latency C-start, more frequently during social interactions. These behavioral differences are absent in non-social contexts. By ablating the lateral line and presenting the fish with local water vibrations, we show that lateral line inputs are both necessary and sufficient to drive enhanced social avoidance reactions. Taken together, our results show that social experience during development is a critical factor in shaping mechanosensory avoidance reactions in larval zebrafish.An important aspect of behavior is that it is adaptive and can change according to previous 2 outcomes of the actions of the self or others. During early development, as the nervous sys-3 tem builds and refines its connections, an animal is particularly sensitive to external sensory 4 input, or lack thereof (e.g. reviewed by Andersen [2003]). Social experiences during early 5 development can have long lasting effects on social and other behaviors, as shown by the dev-6

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Section: Discussionmentioning

confidence: 99%

Early-life social experience shapes social avoidance reactions in larval zebrafish

Groneberg

Marques

Martins

et al. 2020

Preprint

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“…To identify the gene disrupted in slow learner p174 mutants, we took a previously described whole genome sequencing (WGS) approach followed by homozygosity mapping 29,32,33 . This uncovered a premature stop codon (Y211*) in the huntingtin interacting protein 14 (hip14) gene, encoding a palmitoyltransferase (PAT) which catalyzes the addition of palmitate moieties to cysteine residues of 5 substrate proteins 34 .…”

Section: The Palmitoyltransferase Hip14 Regulates Habituation Learninmentioning

confidence: 99%

“…I-sceI transgenesis was performed as previously described 78 in 1-cell stage embryos from hip14+/-incrosses. Transgenic lines were identified as previously described 33 . Briefly, 24 hpf F1 offspring of G0-injected fish were placed into Eppendorf tubes and incubated at 37°C for 30 min, recovered in petri dishes for 60 min, and screened for mKate with a fluorescent stereomicroscope (Olympus MVX10).…”

Section: Zebrafish Husbandry Mutagenesis Transgenesis and Genotypingmentioning

confidence: 99%

Acute regulation of habituation learning via posttranslational palmitoylation

Nelson

Witze

et al. 2019

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Habituation is an adaptive learning process that enables animals to adjust innate behaviors to changes in the environment. Despite its well documented implications for a wide diversity of behaviors, the molecular and cellular basis of habituation learning is not well understood. Using whole genome sequencing of zebrafish mutants isolated in an unbiased genetic screen, we identified the palmitoyltransferase Hip14 as a critical regulator of habituation learning. We demonstrate that Hip14 regulates depression of sensory inputs onto an identified neuron and provide compelling evidence that Hip14 palmitoylates the Shaker-like channel subunit Kv1.1, thereby regulating Kv1.1 subcellular localization. Furthermore, we show that loss of either Kv1.1 or Hip14 leads to habituation deficits, and that Hip14 is dispensable in development and instead acts acutely to promote habituation. Combined, our results uncover a previously unappreciated role for acute post-translational palmitoylation at defined circuit components to regulate learning.3 Introduction:

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“…We previously performed a forward genetic screen for regulators of the acoustic startle response [23][24][25][26]. In brief, using a high-speed camera and automatic tracking, individual F3 larvae were exposed to a series of startling stimuli (for details on mutagenesis and the breeding scheme to obtain F3 larvae see [23]).…”

Section: A Forward Genetic Screen For Regulators Of the Larval Startlmentioning

confidence: 99%

“…We previously performed a forward genetic approach to identify functional regulators of the acoustic startle response. This approach identified a distinct sets of genes with previously unrecognized roles critical for startle habituation [23,24], startle sensitivity [25], and sensorimotor decision making [26]. Here, we describe kinematic mutants identified from this screen that display defects in executing swim movements of the startle response.…”

Section: Introductionmentioning

confidence: 99%

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

Meserve

Nelson

Marsden

et al. 2020

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The acoustic startle response is an evolutionary conserved avoidance behavior. Disruptions in startle behavior, in particular startle magnitude, are a hallmark of several human neurological disorders. While the neural circuitry underlying startle behavior has been studied extensively, the repertoire of genes and genetic pathways that regulate this locomotor behavior has not been explored using an unbiased genetic approach. To identify such genes, we took advantage of the stereotypic startle behavior in zebrafish larvae and performed a forward genetic screen coupled with whole genome analysis. This identified mutants in eight genes critical for startle behavior, including two genes encoding proteins associated with human neurological disorders, Dolichol kinase (Dolk), a broadly expressed regulator of the glycoprotein biosynthesis pathway, and the potassium Shaker-like channel subunit Kv1.1. We demonstrate that Kv1.1 acts independently of supraspinal inputs to regulate locomotion, suggesting its site of action is within spinal circuitry.Moreover, we show that Kv1.1 protein is mis-localized in dolk mutants, suggesting they act in a common genetic pathway to regulate movement magnitude. Combined, our results identify a diverse set of eight genes all associated with human disorders that regulate zebrafish startle behavior and reveal a previously unappreciated role for Dolk and Kv1.1 in regulating movement magnitude via a common genetic pathway. Author summaryUnderlying all animal behaviors are neural circuits, which are controlled by numerous molecular pathways that direct neuron development and activity. To identify and study these molecular pathways that control behavior, we use a simple vertebrate behavior, the acoustic startle response, in the larval zebrafish. In response to an intense noise, larval zebrafish will quickly turn 3 and swim away to escape. From a genetic screen, we have identified a number of mutants that behave in abnormal ways in response to an acoustic stimulus. We cloned these mutants and identified eight genes that regulate startle behavior. All eight genes are associated with human disorders, and here we focus on two genes, dolk and kcna1a, encoding Dolk, a key regulator of protein glycosylation, and the potassium channel Kv1.1, respectively. We demonstrate that loss of dolk or kcna1a causes larval zebrafish to perform exaggerated swim movements and that Dolk is required for Kv1.1 protein localization to axons of neurons throughout the nervous system, providing strong evidence that dolk and kcna1a act in a common molecular pathway. Combined, our studies provide new insights into the genetic regulation of startle behavior.

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A Cyfip2-Dependent Excitatory Interneuron Pathway Establishes the Innate Startle Threshold

Cited by 49 publications

References 61 publications

Early-life social experience shapes social avoidance reactions in larval zebrafish

Early-life social experience shapes social avoidance reactions in larval zebrafish

Acute regulation of habituation learning via posttranslational palmitoylation

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

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