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Evan E Eichler - One of the best experts on this subject based on the ideXlab platform.
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Habituation learning is a widely affected mechanism in drosophila models of intellectual disability and autism spectrum disorders
Biological Psychiatry, 2019Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, David P Goodman, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E EichlerAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype–phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified >100 genes required for Habituation learning. For 93 of these genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to ASD, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish Habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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a hundred genes implicated in intellectual disability and autism regulate Habituation learning and reveal an opposing role for ras mapk signaling in inhibitory and excitatory neurons
bioRxiv, 2019Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, David P Goodman, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E EichlerAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection (SSC) carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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integrative cross species analyses suggest deficits in Habituation learning as a widely affected mechanism in intellectual disability and autism spectrum disorders
bioRxiv, 2018Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E Eichler, Raphael BernierAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable biomarker and target for pharmacologic intervention in ID/ASD.
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integrative cross species analyses identify deficits in Habituation learning as a widely affected mechanism in autism
bioRxiv, 2018Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E Eichler, Raphael BernierAbstract:Background: Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results: We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions: Our work demonstrates the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.
Michaela Fenckova - One of the best experts on this subject based on the ideXlab platform.
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Habituation learning is a widely affected mechanism in drosophila models of intellectual disability and autism spectrum disorders
Biological Psychiatry, 2019Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, David P Goodman, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E EichlerAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype–phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified >100 genes required for Habituation learning. For 93 of these genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to ASD, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish Habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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a hundred genes implicated in intellectual disability and autism regulate Habituation learning and reveal an opposing role for ras mapk signaling in inhibitory and excitatory neurons
bioRxiv, 2019Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, David P Goodman, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E EichlerAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection (SSC) carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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integrative cross species analyses suggest deficits in Habituation learning as a widely affected mechanism in intellectual disability and autism spectrum disorders
bioRxiv, 2018Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E Eichler, Raphael BernierAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable biomarker and target for pharmacologic intervention in ID/ASD.
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integrative cross species analyses identify deficits in Habituation learning as a widely affected mechanism in autism
bioRxiv, 2018Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E Eichler, Raphael BernierAbstract:Background: Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results: We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions: Our work demonstrates the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.
Catharine H. Rankin - One of the best experts on this subject based on the ideXlab platform.
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Habituation mechanisms and their importance for cognitive function
Frontiers in Integrative Neuroscience, 2015Co-Authors: Susanne Schmid, Donald A. Wilson, Catharine H. RankinAbstract:How does our brain form and store memories? One way to approach this mystery is to study a very basic form of learning—Habituation—in a relatively simple nervous system. Habituation describes the progressive decrease of the amplitude or frequency of a motor response to repeated sensory stimulation that is not caused by sensory receptor adaptation or motor fatigue. A multitude of different organisms, behaviors, and experimental approaches have been used to study Habituation, but still surprisingly little is known about the underlying mechanisms. A theoretical framework of the concept of Habituation has been laid by Thompson and Spencer (1966), and by the dual process theory of Groves and Thompson (1970), which describes Habituation and sensitization as two independent processes that interact to yield the final behavioral outcome. In a symposium in 2009, the original concept was revisited and the definitions of Habituation (and disHabituation) were slightly revised for clarity; however, remarkably there were only few changes to the defining characteristics (Rankin et al., 2009). It is becoming evident that behavioral Habituation is caused by different mechanisms depending on time frame of stimulation, type of sensory pathway studied, and hierarchical level of signal processing. On the other hand, Habituation mechanisms seem to be highly conserved, underlining the importance of Habituation for the survival of a species (see Schmid et al., 2010). The scope of this Frontiers Research Topic is to give an overview over the concept of Habituation, the different animal and behavioral models used for studying Habituation mechanisms, as well as the different synaptic and molecular processes suggested to play a role in behavioral Habituation. Fischer et al. (2014) studied short-term Habituation of the gill-withdrawal reflex in Aplysia. In accordance with the notion of different mechanisms mediating Habituation in different time frames and different pathways, they report an intrinsic mechanism that is specific for short-term Habituation at short training intervals of 1s. Typlt et al. (2013b) investigated the role of a voltage-and calcium activated potassium channel (BK channel) in short- and long-term Habituation of an elicited behavior (acoustic startle) versus a motivated exploratory behavior using transgenic mice, and further confirm disparate, yet evolutionary highly conserved Habituation mechanisms. Pilz et al. (2014) tackled a contentious issue of whether long-term Habituation of acoustic startle in mice is context specific. They report that long-term Habituation is stimulus-modality specific, but not context specific, confirming it as a non-associative form of learning. Dutta and Gutfreund (2014) review data from barn owls and primates on computation of saliency in the optic tectum/superior colliculus and how this is linked to Habituation and neural adaptation. Perez-Gonzalez and Malmierca (2014) review different forms of spike adaptation in auditory neurons of different levels of auditory processing hierarchy. These mechanisms lead to sensory filtering and Habituation of perception. Manella et al. (2013) studied how the modulatory norepinephrine system in the brain influences odor Habituation and odor memory in rats. Besides the importance of understanding the underlying mechanisms of Habituation as a basic form of learning or sensory filtering, some articles go beyond understanding mechanisms of Habituation and explore how its disruption impacts other cognitive domains and higher cognitive function. Typlt et al. (2013a) link Habituation deficits to impairments in spatial learning. The Mini Review of De Luca (2014) sheds light on the mechanism of the Habituation phenomenon of mesolimbic and mesocortical dopamine transmission in response to taste stimuli, and its putative role as a marker of cortical dysfunction in specific conditions such as addiction. Related to this topic, Lloyd et al. (2014) review the Habituation of reinforcer effectiveness and the role of dopamine neurotransmission in Habituation to the reinforcer. They indicate that behavioral disorders such as obesity or attention deficit hyperactivity disorder (ADHD) may be caused by abnormal Habituation to the reinforcer due to genetic or environmental factors. Interestingly, studying the electrodermal orienting reflex in humans, Steiner and Barry (2014) argue against the dual-process theory's explanation that disHabituation is caused by sensitization, and instead suggest that disHabituation is a disruption of the Habituation process, with its magnitude determined by the corresponding arousal level. It is certainly debatable to what extent this can be generalized to other modalities and pathways. In a theoretical essay Cevik (2014) argues that the impact of a stimulus on behavior and its potential to modulate the effects of other stimuli increase as its distance from the body decreases, an interesting and certainly also debatable concept. In summary, this research topic contains original research articles, reviews, and theoretical essays that provide an updated view on different models for studying Habituation, its underlying mechanisms, and its importance as prerequisite for higher cognitive function. The number and high quality of the papers on this topic provide support for the notion that Habituation is a rich area of study, touching on a number of important questions related to behavioral plasticity.
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Habituation revisited an updated and revised description of the behavioral characteristics of Habituation
Neurobiology of Learning and Memory, 2009Co-Authors: Catharine H. Rankin, Mark A. Geyer, David F. Clayton, Thomas W Abrams, Robert J Barry, Seema Bhatnagar, John Colombo, Gianluca Coppola, David L Glanzman, Stephen MarslandAbstract:In the 20th century, great progress was made in understanding the behavioral characteristics of Habituation. A landmark paper published by Thompson and Spencer in 1966 clarified the definition of Habituation, synthesized the research to date and presented a list of nine behavioral characteristics of Habituation that appeared to be common in all organisms studied The history of Habituation and the historical context of Thompson & Spencer's (1966) distillation are reviewed more fully in an article by Thompson (2009) that is included in this issue. This list was repeated and expanded upon by Groves and Thompson in 1970. These two papers are now citation classics and are considered to be the authorities on the characteristics of Habituation. In August 2007, a group of 15 researchers (the authors of this review) who study Habituation in a wide range of species and paradigms met to revisit these characteristics and refine them based on the 40 years of research since Thompson and Spencer 1966. The descriptions and characteristics from 1966 have held up remarkably well, and the revisions we have made to them were often for clarity rather than content. We made substantial changes to only a few of the characteristics, usually to add new information and expand upon the description rather than to substantially alter the original point. We restricted ourselves to an analysis of Habituation; there was insufficient time for detailed discussions of the other form of non-associative learning “sensitization.” Thus this review is restricted to our discussions of Habituation and disHabituation (as it relates directly to Habituation). Many people will be surprised to learn that, although Habituation is termed ”the simplest form of learning” and is well studied behaviorally, remarkably little is known about the neural mechanisms underlying Habituation. Researchers who work on this form of learning believe that because Habituation allows animals to filter out irrelevant stimuli and focus selectively on important stimuli, it is a prerequisite for other forms of learning. Therefore, to fully understand the mechanisms of more complex forms of learning and cognition it is important to understand the basic building blocks of Habituation. The objectives of this special issue are to re-ignite interest in studying the mechanisms of Habituation and thereby to stimulate efforts to further our understanding of the neural basis of Habituation. In this review, we will first define Habituation, then review and revise the nine characteristics of Habituation that were originally determined by Thompson and Spencer in 1966 and that have been seen across all species studied. In addition, we describe a tenth characteristic that was added at the workshop. Finally we present several issues that were discussed extensively at the meeting and highlight how the view of Habituation that arose from our discussions differs from the original characterization by Thompson and Spencer.
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Analyses of Habituation in Caenorhabditis elegans
Learning & Memory, 2001Co-Authors: Jacqueline K. Rose, Catharine H. RankinAbstract:: Although the nonassociative form of learning, Habituation, is often described as the simplest form of learning, remarkably little is known about the cellular processes underlying its behavioral expression. Here, we review research on Habituation in the nematode Caenorhabditis elegans that addresses Habituation at behavioral, neural circuit, and genetic levels. This work highlights the need to understand the dynamics of a behavior before attempting to determine its underlying mechanism. In many cases knowing the characteristics of a behavior can direct or guide a search for underlying cellular mechanisms. We have highlighted the importance of interstimulus interval (ISI) in both short- and long-term Habituation and suggested that different cellular mechanisms might underlie Habituation at different ISIs. Like other organisms, C. elegans shows both accumulation of Habituation with repeated training blocks and long-term retention of spaced or distributed training, but not for massed training. Exposure to heat shock during the interblock intervals eliminates the long-term memory for Habituation but not the accumulation of short-term Habituation over blocks of training. Analyses using laser ablation of identified neurons, and of identified mutants have shown that there are multiple sites of plasticity for the response and that glutamate plays a role in long-term retention of Habituation training.
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Recovery from Habituation in Caenorhabditis elegans is dependent on interstimulus interval and not Habituation kinetics.
Behavioral Neuroscience, 1996Co-Authors: Stephen R. Wicks, Catharine H. RankinAbstract:: The Habituation of the tap withdrawal reflex of Caenorhabditis elegans was assessed to determine whether the kinetics of recovery from Habituation were dependent on the interstimulus interval (ISI) used during Habituation training, or alternately, on the rate and asymptotic level of Habituation produced at a given ISI. Two groups of intact animals were trained at either a 10-s (CON10) or a 60-s (CON60) ISI. Laser ablation was used to alter the Habituation kinetics in one further group of animals (PLM10), independent of ISI. Although the PLM10 animals trained at a 10-s ISI habituated like CON60 worms, the recovery from Habituation of the PLM10 animals very closely resembled the recovery of the CON10 worms. Thus recovery kinetics are dictated by consequences of a given ISI, which do not impact upon Habituation rate and asymptote. This suggests the recruitment of multiple ISI-dependent processes during Habituation in C. elegans.
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Factors affecting Habituation and recovery from Habituation in the nematode Caenorhabditis elegans.
Behavioral Neuroscience, 1992Co-Authors: Catharine H. Rankin, Brett S. BrosterAbstract:: In four experiments, the factors that affect the rate of Habituation, the degree of Habituation, and the rate of recovery from Habituation in a simple reflex circuit in Caenorhabditis elegans were investigated. The results showed that Habituation was more pronounced and faster, and that recovery from Habituation was more rapid, with short interstimulus intervals (ISIs) than with longer ISIs. Rate of recovery differed in animals that had reached asymptotic response levels when compared with animals still in the descending portion of the Habituation curve. Once animals reached asymptotic response levels, rate of recovery appeared to be determined by ISI and not by additional stimuli.
Michael Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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analyzing Habituation responses to novelty in zebrafish danio rerio
Behavioural Brain Research, 2010Co-Authors: Keith Wong, Marco Elegante, Brett Bartels, Salem Elkhayat, David Tien, Jason Goodspeed, Chris Suciu, Chelsea Grimes, Amanda Chung, Michael RosenbergAbstract:Analysis of Habituation is widely used to characterize animal cognitive phenotypes and their modulation. Although zebrafish (Danio rerio) are increasingly utilized in neurobehavioral research, their Habituation responses have not been extensively investigated. Utilizing the novel tank test, we examine intra- and inter-session Habituation and demonstrate robust Habituation responses in adult zebrafish. Analyzing the intra-session Habituation to novelty further, we also show that selected anxiogenic drugs (caffeine, pentylenetetrazole), as well as stress-inducing alarm pheromone, attenuated zebrafish Habituation. Some acute anxiolytic agents, such as morphine and ethanol, while predictably reducing zebrafish anxiety, had no effects on Habituation. Chronic ethanol and fluoxetine treatments improved intra-session Habituation in zebrafish. In general, our study parallels literature on rodent Habituation responses to novelty, and reconfirms zebrafish as a promising model for cognitive neurobehavioral research.
Laura E R Blok - One of the best experts on this subject based on the ideXlab platform.
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Habituation learning is a widely affected mechanism in drosophila models of intellectual disability and autism spectrum disorders
Biological Psychiatry, 2019Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, David P Goodman, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E EichlerAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype–phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified >100 genes required for Habituation learning. For 93 of these genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to ASD, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish Habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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a hundred genes implicated in intellectual disability and autism regulate Habituation learning and reveal an opposing role for ras mapk signaling in inhibitory and excitatory neurons
bioRxiv, 2019Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, David P Goodman, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E EichlerAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection (SSC) carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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integrative cross species analyses suggest deficits in Habituation learning as a widely affected mechanism in intellectual disability and autism spectrum disorders
bioRxiv, 2018Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E Eichler, Raphael BernierAbstract:Abstract Background Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions Our work supports the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable biomarker and target for pharmacologic intervention in ID/ASD.
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integrative cross species analyses identify deficits in Habituation learning as a widely affected mechanism in autism
bioRxiv, 2018Co-Authors: Michaela Fenckova, Laura E R Blok, Lenke Asztalos, Pavel Cizek, Euginia L Singgih, Jeffrey C Glennon, Joanna Inthout, Christiane Zweier, Evan E Eichler, Raphael BernierAbstract:Background: Although Habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood. Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump Habituation. We dissected neuronal substrates underlying the identified Habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with Habituation deficits. Results: We identified more than 100 genes required for Habituation learning. For the vast majority of these, 93 genes, a role in Habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal Habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive Habituation response. Conclusions: Our work demonstrates the relevance of Habituation learning to autism, identifies an unprecedented number of novel Habituation players, supports an emerging role for inhibitory neurons in Habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes Habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.
