Insulin signaling is acutely required for long-term memory in Drosophila

Chambers, Daniel B.; Androschuk, Alaura; Rosenfelt, Cory; Langer, Steven; Harding, Mark Geoffrey; Bolduc, François V.

doi:10.3389/fncir.2015.00008

Cited by 41 publications

(43 citation statements)

References 31 publications

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“…First, considering that extirpation of the LLs enhances MIP release by releasing the LGCs from inhibition (Geraerts, 1976a(Geraerts, ,b, 1992Roubos et al, 1980;Geraerts et al, 1992;Smit et al, 1998), they argue for the existence of a causal link between learning and memory performance, somatotropic control and ILP neuroendocrinology in L. stagnalis. As such, our findings echo a growing literature linking somatotropic systems to cognition and other brain functions in both vertebrates and invertebrates (Creyghton et al, 2004;Isgaard et al, 2007;Studzinski et al, 2015;Chambers et al, 2015). Second, as the LLs of L. stagnalis arbitrate in the division of resources between growth and reproduction, which are two of the principal items of organismal resource budgets and two of the most important life history variables, our results implicitly corroborate the existence of trade-offs between reproduction and nervous system function, and, intriguingly, suggest that LLs may be one of the key loci that set the pace of neuronal and cognitive ageing in this model system.…”

Section: Ll Extirpation Improves Ltm Formationsupporting

confidence: 88%

“…The idea that ILPs play important and diverse roles in the fate of the nervous system is supported by various lines of evidence implicating ILPs in aspects of neuronal plasticity and cognitive function in a wide range of invertebrate and vertebrate species, including L. stagnalis (Creyghton et al, 2004;Zhao et al, 2004;Azami et al, 2006;Isgaard et al, 2007;Fernandez and TorresAlemán, 2012;Murakami et al, 2013;Mita et al, 2014;Pirger et al, 2014;Chambers et al, 2015;Kojima et al, 2015;Studzinksi et al, 2015;Akinola, 2016;Tanabe et al, 2017). Moreover, ILPs are also known to be important regulators of adult neurogenesis, angiogenesis and synaptogenesis, and insulin has been shown to affect synapse remodelling through downstream neurotrophic signalling cascades (Granata et al, 2007;Nelson et al, 2008;Åberg, 2010).…”

Section: Ll Extirpation Improves Ltm Formationmentioning

confidence: 99%

“…In recent years, ILPs have been increasingly implicated in brain function. For example, in the mammalian brain, ILPs exert beneficial effects on processes such as growth and development, cell survival, adult neurogenesis, synaptic plasticity and cognition (Isgaard et al, 2007;Åberg, 2010;Fernandez and Torres-Alemán, 2012;Chambers et al, 2015). Lymnaea stagnalis appears to form no exception to this rule; several studies report that MIP genes are upregulated during LTM consolidation and that insulin/MIP signalling is necessary for LTM formation (Azami et al, 2006;Murakami, et al, 2013;Mita et al, 2014;Pirger et al, 2014;Kojima et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Linking the why and how of aging; evidence for somatotropic control of long-term memory function in the pond snail Lymnaea stagnalis

Weerd

Hermann

Wildering

2017

Journal of Experimental Biology

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Organisms live on a budget; hence, they cannot maximize all their activities at the same time. Instead, they must prioritize how they spend limiting resources on the many processes they rely on in their lives. Among others, they are thought to economize on the maintenance and repair processes required for survival in favour of maximizing reproduction, with ageing as a consequence. We investigate the biological mechanisms of neuronal ageing. Using Lymnaea stagnalis, we have previously described various aspects of age-associated neuronal decline and appetitive long-term memory failure. In view of postulated trade-offs between somatic maintenance and reproduction, we tested for interactions between resource allocation mechanisms and brain function. We show that removal of the lateral lobes, which are key regulators of energy balance in L. stagnalis, increases body mass and enhances appetitive learning, raising the possibility that the lateral lobes are one of the sites where the 'why' and 'how' of (neuronal) ageing meet.

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Section: Ll Extirpation Improves Ltm Formationsupporting

confidence: 88%

Section: Ll Extirpation Improves Ltm Formationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Linking the why and how of aging; evidence for somatotropic control of long-term memory function in the pond snail Lymnaea stagnalis

Weerd

Hermann

Wildering

2017

Journal of Experimental Biology

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“…Mutations of Ilps and conditional expression of a dominantnegative transgene of the insulin receptor (InR) affect feeding preference toward nutritive sugars (Stafford et al, 2012). Inhibition of insulin signaling inhibits learning and memory induced by olfactory conditioning (Naganos et al, 2012;Chambers et al, 2015) and reduces sleep (Cong et al, 2015). Considering the significance of IPCs and Ilp/InR signaling for the regulation of innate and learned behaviors, it is likely that Ilps also act as neuromodulators involved in the regulation of female sexual receptivity.…”

mentioning

confidence: 99%

Knockout mutations of insulin-like peptide genes enhance sexual receptivity in <i>Drosophila</i> virgin females

Watanabe

Sakai

2015

Genes Genet. Syst.

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In the fruitfly Drosophila melanogaster, females take the initiative to mate successfully because they decide whether to mate or not. However, little is known about the molecular and neuronal mechanisms regulating sexual receptivity in virgin females. Genetic tools available in Drosophila are useful for identifying molecules and neural circuits involved in the regulation of sexual receptivity. We previously demonstrated that insulin-producing cells (IPCs) in the female brain are critical to the regulation of female sexual receptivity. Ablation and inactivation of IPCs enhance female sexual receptivity, suggesting that neurosecretion from IPCs inhibits female sexual receptivity. IPCs produce and release insulinlike peptides (Ilps) that modulate various biological processes such as metabolism, growth, lifespan and behaviors. Here, we report a novel role of the Ilps in sexual behavior in Drosophila virgin females. Compared with wild-type females, females with knockout mutations of Ilps showed a high mating success rate toward wild-type males, whereas wild-type males courted wild-type and Ilp-knockout females to the same extent. Wild-type receptive females retard their movement during male courtship and this reduced female mobility allows males to copulate. Thus, it was anticipated that knockout mutations of Ilps would reduce general locomotion. However, the locomotor activity in Ilp-knockout females was significantly higher than that in wild-type females. Thus, our findings indicate that the high mating success rate in Ilp-knockout females is caused by their enhanced sexual receptivity, but not by improvement of their sex appeal or by general sluggishness.

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“…Mice with impaired IS exhibit defective short-and long-term memory, while enhancing IS improves these functions. Consistently, IS is required for learning and short-and long-term memory in Drosophila as well [16,17]. A caveat is that most previous studies demonstrate that a reduction in IS leads to deficits in memory or cognitive function, while dfmr1 mutants show increased IS which also appears to disrupt memory.…”

mentioning

confidence: 85%

A New Link Between Insulin Signaling and Fragile X Syndrome

Zhang

2016

Neurosci. Bull.

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Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the most common known genetic cause of autism or autism spectrum disorders. FXS is caused by silencing or mutation of the fragile X mental retardation gene (FMR1), a known RNA-binding protein that acts as a negative regulator of translation [1,2]. FXS patients demonstrate a myriad of symptoms that can vary widely between individuals, including impaired cognition, physical abnormalities, sleep problems, hyperarousal to sensory stimuli, increased anxiety, obsessive compulsive disorder-like behavior, attention-deficit hyperactive disorder symptoms, self-injurious behavior, aggression, and increased risk of seizures [3]. The molecular mechanisms underlying FXS are not clear, and currently there is no ideal treatment.The Drosophila homolog of mammalian FMR1, dFMR1, contains several highly conserved domains that are also found in human FMR1 [1]. Loss of dFMR1 or expressing a mutant that carries deletions or point mutations in the coding region can lead to several behavioral and anatomical defects in the fly, including defects in learning and memory, social interaction, circadian rhythm, and sleep [2,[4][5][6][7], many of which are similar to those seen in FXS patients. The conservation of FMR1 protein between Drosophila and human, as well as the similarity in phenotypes when the gene is disrupted makes it possible to use fruit fly, this powerful, fast, and cost-effective genetic model, to investigate the molecular mechanism underlying FXS and facilitate drug development.In a recent paper published in Molecular Psychiatry [8], researchers from the University of Pennsylvania uncovered misregulated insulin signaling (IS), which contributes to circadian and memory deficits in the Drosophila FXS model. Expression of dfmr1 in the insulin-producing cells of the brain is sufficient to rescue the memory deficits and restore normal circadian behavior in dfmr1 mutant flies. Moreover, the protein level of insulin-like peptide DILP2 is elevated in dfmr1 mutant flies. What is the consequence of increased DILP2 in the brain? A GFP-pleckstrin homology (PH) domain reporter was used by the authors to monitor the activation of phosphoinositide 3-kinase (PI3K), and increased membrane localization of the reporter was detected in dfmr1 mutant brains, indicating stronger PI3K activation. As PI3K is known to phosphorylate Akt at S505, the authors next examined phosphorylation at this particular site. Consistently, an enhanced p-S505-Akt signal was detected at the plasma membrane of dfmr1 mutants, further validating elevated PI3K signaling in these flies. Moreover, rescuing dfmr1 significantly decreased DILP2, membrane GFP-PH, and p-S505-Akt levels, indicating that the increased IS observed is indeed due to a lack of dFMR1. Does elevated IS lead to the circadian and cognitive phenotypes? To address this, the authors expressed a dominant-negative form of the 110-kDa catalytic subunit of PI3K (DP110 DN ) which reduces its activity, or the phosphatase and ...

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Insulin signaling is acutely required for long-term memory in Drosophila

Cited by 41 publications

References 31 publications

Linking the why and how of aging; evidence for somatotropic control of long-term memory function in the pond snail Lymnaea stagnalis

Linking the why and how of aging; evidence for somatotropic control of long-term memory function in the pond snail Lymnaea stagnalis

Knockout mutations of insulin-like peptide genes enhance sexual receptivity in <i>Drosophila</i> virgin females

A New Link Between Insulin Signaling and Fragile X Syndrome

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