Gustatory habituation in <i>Drosophila</i> relies on <i>rutabaga</i> (adenylate cyclase)-dependent plasticity of GABAergic inhibitory neurons

Paranjpe, Pushkar; Rodrigues, Veronica; VijayRaghavan, K.; Ramaswami, Mani

doi:10.1101/lm.026641.112

Cited by 39 publications

(62 citation statements)

References 67 publications

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“…Previous studies indicated that rut , an adenylyl cyclase gene, affects various neuronal and behavioral plasticities, such as learning and memory associated with environmental cues, including visual, caloric, chemical stimuli, and mechanical stimuli [22]–[26]. We next examined whether rut is also involved in the behavioral change induced by continuous fly courtship songs observed in our experimental condition.…”

Section: Resultsmentioning

confidence: 94%

Selectivity and Plasticity in a Sound-Evoked Male-Male Interaction in Drosophila

et al. 2013

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During courtship, many animals, including insects, birds, fish, and mammals, utilize acoustic signals to transmit information about species identity. Although auditory communication is crucial across phyla, the neuronal and physiologic processes are poorly understood. Sound-evoked chaining behavior, a display of homosexual courtship behavior in Drosophila males, has long been used as an excellent model for analyzing auditory behavior responses, outcomes of acoustic perception and higher-order brain functions. Here we developed a new method, termed ChaIN (Chain Index Numerator), in which we use a computer-based auto detection system for chaining behavior. The ChaIN system can systematically detect the chaining behavior induced by a series of modified courtship song playbacks. Two evolutionarily related Drosophila species, Drosophila melanogaster and Drosophila simulans, exhibited dramatic selective increases in chaining behavior when exposed to specific auditory cues, suggesting that auditory discrimination processes are involved in the acceleration of chaining behavior. Prolonged monotonous pulse sounds containing courtship song components also induced high intense chaining behavior. Interestingly, the chaining behavior was gradually suppressed over time when song playback continued. This behavioral change is likely to be a plastic behavior and not a simple sensory adaptation or fatigue, because the suppression was released by applying a different pulse pattern. This behavioral plasticity is not a form of habituation because different modality stimuli did not recover the behavioral suppression. Intriguingly, this plastic behavior partially depended on the cAMP signaling pathway controlled by the rutabaga adenylyl cyclase gene that is important for learning and memory. Taken together, this study demonstrates the selectivity and behavioral kinetics of the sound-induced interacting behavior of Drosophila males, and provides a basis for the systematic analysis of genes and neural circuits underlying complex acoustic behavior.

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Section: Resultsmentioning

confidence: 94%

Selectivity and Plasticity in a Sound-Evoked Male-Male Interaction in Drosophila

et al. 2013

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“…Because of the recently established role of GABAergic neurons in Drosophila olfactory and proboscis extension reflex habituation (29, 60, 61) and the emerging importance of GABA inhibition in autism (62), we next targeted GABA neurons using the Gad1-Gal4 driver and the same toolbox. This consistently induced habituation deficits in all tested conditions ( Figure 6B) .…”

Section: Resultsmentioning

confidence: 99%

“…The commonly accepted view regards synaptic depression in excitatory neurons, induced by repetitive stimulation, as the underlying mechanism (46, 65). This has recently been challenged by Ramaswami and colleagues who showed that plasticity of inhibitory, GABAergic neurons drives two non-startle types of habituation (60, 61). We found that increased activity of our identified key pathway, Ras-MAPK, in GABAergic but not in cholinergic neurons causes deficits in light-off jump habituation.…”

Section: Discussionmentioning

confidence: 99%

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

Fencková

Asztalos

Cizek

et al. 2018

Preprint

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60Background: Although habituation is one of the most ancient and fundamental forms of learning, its 61 regulators and relevance for human disease are poorly understood. 62Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or 63 without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested 64 these models in light-off jump habituation. We dissected neuronal substrates underlying the 65 identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and 66 interaction networks to determine the clinical features and molecular processes that are associated 67 with habituation deficits. 68Results: We identified more than 100 genes required for habituation learning. For the vast majority 69 of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize 70 ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the 71 Simons Simplex Collection (SSC) carrying damaging de novo mutations in these genes exhibit 72 increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular 73 level, ID genes required for normal habituation are enriched in synaptic function and converge on 74Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK 75 signaling in cholinergic neurons specifically inhibit the adaptive habituation response. 76Conclusions: Our work supports the relevance of habituation learning to autism, identifies an 77 unprecedented number of novel habituation players, supports an emerging role for inhibitory 78 neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK 79 signaling. This establishes habituation as a possible, widely applicable functional readout and target 80 for pharmacologic intervention in ID/ASD. 81 82 described in a fraction of ASD individuals (9-11), but has not been connected yet to specific genetic 96 defects, with a single exception. Recently, two independent studies demonstrated habituation 97 deficits in patients with Fragile X syndrome, the most common monogenic cause of intellectual 98 disability (ID) and ASD (12, 13), confirming previously reported habituation deficits in Fmr1 KO mice 99 (14, 15). Habituation deficits have also been reported in a limited number of other ID or ASD 100 (ID/ASD) disease models (16)(17)(18)(19). 101Because assessing human gene function in habituation is challenging, we utilized a cross-102 species approach. We apply light-off jump habituation in Drosophila to increase our knowledge on 103 the genetic control of habituation and, at the same time, to address the relevance of decreased 104 habituation in ID and in comorbid ASD disorders. Since ID is present in 70% of individuals with ASD 105 (20), monogenic causes of ID provide a unique molecular windows to ASD pathology (21). Drosophila 106 is a powerful, well-established model for ID (22)(23)(24) and offers genome-wide resources to st...

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“…Potentiation of inhibitory synapses is implicated in habituation of the Aplysia siphon withdrawal reflex (Bristol and Carew, 2005; Fischer et al, 1997), the crayfish escape response (Krasne and Teshiba, 1995; Shirinyan et al, 2006), and the Drosophila proboscis extension response to sweet stimulation (Paranjpe et al, 2012). Similarly, decreased startle responsiveness during a conditioning program similar to habituation is mediated by inhibitory long-term potentiation (iLTP) in the adult goldfish M-cell (Oda et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Ca2+ Imaging Reveals that Decreased Dendritic Excitability Drives Startle Habituation

Marsden

Granato

2015

Cell Reports

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Summary Exposure to repetitive startling stimuli induces habitation, a simple form of learning. Despite its simplicity, the precise cellular mechanisms by which repeated stimulation converts a robust behavioral response to behavioral indifference are unclear. Here, we use head-restrained zebrafish larvae to monitor subcellular Ca2+ dynamics in Mauthner neurons, the startle command neurons, during startle habituation in vivo. Using the Ca2+ reporter GCaMP6s we find that the amplitude of Ca2+ signals in the lateral dendrite of the Mauthner neuron determines startle probability and that depression of this dendritic activity rather than downstream inhibition mediates short-term habituation mediates glycine and N-methyl-D-aspartate (NMDA) receptor dependent short-term habituation. Combined, our results suggest a model for habituation learning in which increased inhibitory drive from feedforward inhibitory neurons combined with decreased excitatory input from auditory afferents decreases dendritic and Mauthner neuron excitability.

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Gustatory habituation in Drosophila relies on rutabaga (adenylate cyclase)-dependent plasticity of GABAergic inhibitory neurons

Cited by 39 publications

References 67 publications

Selectivity and Plasticity in a Sound-Evoked Male-Male Interaction in Drosophila

Selectivity and Plasticity in a Sound-Evoked Male-Male Interaction in Drosophila

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

In Vivo Ca2+ Imaging Reveals that Decreased Dendritic Excitability Drives Startle Habituation

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