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Amnesiac


Gene name - amnesiac Synonyms - Cytological map position - 19A1 Function - "memory" neuropeptide Keywords - neural, brain, memory, hormones




Amnesiac



Symbol - amn FlyBase ID: FBgn0086782 Genetic map position - 1-[64] Classification - secreted neuropeptide Cellular location - secreted NCBI link: Entrez Gene amnesiac orthologs: BiolitmineRecent literatureRouse, J., Watkinson, K. and Bretman, A. (2018). Flexible memory controls sperm competition responses in male Drosophila melanogaster. Proc Biol Sci 285(1879). Pubmed ID: 29848652 Summary: Males of many species use social cues to predict sperm competition (SC) and tailor their reproductive strategies, such as ejaculate or behavioural investment, accordingly. While these plastic strategies are widespread, the underlying mechanisms remain largely unknown. Plastic behaviour requires individuals to learn and memorize cues associated with environmental change before using this experience to modify behaviour. Drosophila melanogaster respond to an increase in SC threat by extending mating duration after exposure to a rival male. This behaviour shows lag times between environmental change and behavioural response suggestive of acquisition and loss of memory. Considering olfaction is important for a male's ability to assess the SC environment, it is hypothesized that an olfactory learning and memory pathway may play a key role in controlling this plastic behaviour. The role were assessed of genes and brain structures known to be involved in learning and memory. SC responses depend on anaesthesia-sensitive memory, specifically the genes rut and amn. The gamma lobes of the mushroom bodies are integral to the control of plastic mating behaviour. These results reveal the genetic and neural properties required for reacting to changes in the SC environment. Turrel, O., Goguel, V. and Preat, T. (2018). Amnesiac is required in the adult mushroom body for memory formation. J Neurosci. PubMed ID: 30201766Summary: It was proposed that the Drosophila amnesiac gene (amn) is required for consolidation of aversive memory in the dorsal paired medial (DPM) neurons, a pair of large neurons that broadly innervate the mushroom bodies (MB), the fly center for olfactory learning and memory. Yet, a previous conditional analysis suggested that amn might be involved in the development of brain structures that normally promote adult olfactory memory. To further investigate temporal and spatial requirements of Amnesiac in memory, RNA interference was used in combination with conditional drivers. The data show that acute modulation of amn expression in adult DPM neurons does not impact memory and that amn expression is required for normal development of DPM neurons. Detailed enhancer trap analyses suggest that an amn transcription unit contains two distinct enhancers, one specific of DPM neurons, and the other specific of alpha/beta MB neurons. This prompted an investigation of the role of Amnesiac in the adult MB. These results demonstrate that amn is acutely required in adult alpha/beta MB neurons for middle-term and long-term memory. The data thus establish that amn plays two distinct roles. Its expression is required in DPM neurons for their development, and in adult MB for olfactory memory.BIOLOGICAL OVERVIEW Memory in both vertebrates and invertebrates involves increasing the efficiency of the synaptic function, otherwise known as long term potentiation. Efficiency is increased as a result of synaptic changes wrought by repeated firing of the synapse. What are the biological meditors of this synaptic change? dunce and rutabaga are involved in what has become known as the memory pathway, also known biochemically as the adenylate cyclase second messenger pathway, which is activated by synaptic activity. What are the biological activators of the memory pathway? One way to find genes that are functionally related in a linear pathway is to isolate the suppressors of these genes. amnesiac was isolated as a suppressor of dunce mutant phenotype (Quinn, 1979). Behavioral tests indicate that amnesiac mutants are defective in tests of associative learning (Tully, 1990). Evolutionary homologies of Amnesiac provide clues as to its function. PACAP (pituitary adenylate cyclase-activating polypeptide) and GHRH (growth hormone releasing hormone) are vertebrate peptides able to activate the adenylate cyclase pathway, acting through G-protein coupled receptors. Two potential peptides of Amnesiac are homologous to PACAP and GHRH (Feany, 1995). Thus Amnesiac is a peptide that has the potential to be secreted by neurons in the memory pathway, thereby activating the adenyl cyclase second messenger pathway.PACAP-like activity has been detected in larvae and neuromuscular junctions that function in the adenylyl cyclase second messenger system. The vertebrate PACAP38 triggers two muscular responses in Drosophila: an immediate depolarization and a late enhancement (Zhong, 1995b). Antibody to vertebrate PACAP-38 stains segmentally repeated larval CNS neurons as well as motor nerve terminals (Zhong, 1996). It has long been thought that the neuromuscular synapse may be a good model for the synaptic basis of learning. Amnesiac and the PACAP-like activity demonstrated by Zhong could be functioning through a similar mechanism. Binding of a PACAP-like peptide to its receptors leads to activation of Rutabaga-adenylyl cyclase by the Galpha subunit and of Ras1/Raf by the Gbeta-gamma complex: the pathways then converge to modulate potassium ion-channel activity (Zhong, 1995a and Zhong, 1996). Memory survives metamorphosis. Larvae taught to avoid an odor retain the ability to avoid the odor as adults, 8 days later. Training of amnesiac mutant larvae failed to establish any detectable learning in larvae or memory retention as adults (Tully, 1994).Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathwayUpon exposure to ethanol, adult Drosophila display behaviors that are similar to acute ethanol intoxication in rodents and humans. Within minutes of exposure to ethanol vapor, flies first become hyperactive and disoriented and then uncoordinated and sedated. After approximately 20 min of exposure they become immobile, but nevertheless recover 5-10 min after ethanol is withdrawn. cheapdate, a mutant with enhanced sensitivity to ethanol, has been identified as a contributory factor, using an inebriometer to measure ethanol-induced loss of postural control. An inebriometer is a device that allows a quantitative assessment of ethanol-induced loss of postural control. The inebriometer is an approximately 4 ft long glass column containing multiple oblique mesh baffles through which ethanol vapor is circulated. To begin a "run," about 100 flies are introduced into the top of the inebriometer. With time, flies lose their ability to stand on the baffles and gradually tumble downward. As they fall out of the bottom of the inebriometer, a fraction collector is used to gather them at 3 min intervals, at which point they are counted. The elution profile of wild-type control flies follows a normal distribution; the mean elution time (MET), approximately 20 min at a standard ethanol vapor concentration, is inversely proportional to their sensitivity to ethanol (Moore, 1998). A genetic screen was carried out to isolate P element-induced mutants with altered sensitivity to ethanol intoxication using the inebriometer as the behavioral assay. One X-linked mutation isolated in this screen was named cheapdate (chpd) to reflect the increased ethanol sensitivity displayed by hemizygous mutant male flies. chpd males elute from the inebriometer with a MET of 15 min compared with 20 min for the wild-type controls. This increased ethanol sensitivity of chpd males was observed at all ethanol vapor concentrations tested. Genetic and molecular analyses reveals that cheapdate is an allele of the memory mutant amnesiac. amnesiac has been postulated to encode a neuropeptide that activates the cAMP pathway. Consistent with this, it has been found that the enhanced ethanol sensitivity of cheapdate can be reversed by treatment with agents that increase cAMP levels or PKA activity. Conversely, genetic or pharmacological reduction in PKA activity results in increased sensitivity to ethanol (Moore, 1998). Flies carrying mutations in three molecules involved in cAMP signaling were tested for response to ethanol: (1) rutabaga (rut), encoding the Ca2+-calmodulin-sensitive AC; (2) dunce (dnc), encoding the major cAMP-phosphodiesterase (PDE), and (3) DCO, encoding the major catalytic subunit of cAMP-dependent protein kinase (PKA-C1). Males hemizygous for rut mutations display an ethanol-sensitive phenotype similar to that of amn mutants. Flies heterozygous for the loss-of-function DCO alleles, which show reduced cAMP-stimulated PKA activity, also display increased ethanol sensitivity (homozygotes cannot be tested because they die as embryos). Ethanol sensitivity of males hemizygous for dnc mutations, however, are nearly normal. These data show that flies unable to increase cAMP levels normally (such as rut and possibly amn) or to respond properly to increased cAMP levels (such as DCO/+) are more sensitive to ethanol-induced loss of postural control. The converse, however, is not observed; dnc flies, whose cAMP levels are several times higher than wild type, display nearly normal ethanol sensitivity, a phenotype that is also observed in males doubly mutant for dnc and amn. Unexpectedly, whereas both rut and amn are ethanol sensitive, males doubly mutant for rut and amn are not significantly different from control (Moore, 1998). To further investigate the relationship between cAMP signaling and ethanol sensitivity, the adenylyl cyclase (AC) activator forskolin was used to manipulate cAMP levels in adult flies. Control and amnchpd males were fed a 10 µM forskolin solution for 2 or 4 hr prior to assaying their ethanol sensitivity in the inebriometer. Whereas forskolin treatment has no effect on the behavior of control flies, the ethanol sensitivity defect of amnchpd flies is reversed by a 2 hr forskolin treatment. Likewise, treatment of rut1 males with forskolin for 2 hr leads to normal ethanol sensitivity, a result likely due to the activation of another AC. Interestingly, a 4 hr forskolin treatment of amnchpd males further reduces ethanol sensitivity, suggesting that one or more components of the cAMP pathway may have undergone compensatory up-regulation in amnchpd mutants, thereby increasing the system's ability to respond to pharmacologically induced increases in cAMP levels. Taken together, these data indicate that the effects of amn and rut on ethanol sensitivity are directly related to their ability to modulate cAMP levels (Moore, 1998). A reduction of PKA-C1 function, as observed in males heterozygous for DCO alleles, leads to increased ethanol sensitivity. To corroborate a role for PKA in ethanol sensitivity, adult control and amnchpd males were fed solutions containing 200 µM Rp-cAMPS or Sp-cAMPS for 2 hr prior to their assay in the inebriometer. Rp-cAMPS is a competitive antagonist of cAMP that binds the regulatory subunit of PKA without releasing the catalytic subunit; Sp-cAMPS is an analog of cAMP that activates PKA. Sp-cAMPS treatment of control males does not alter ethanol sensitivity. This treatment, however, completely reverses the enhanced ethanol sensitivity of amnchpd. In contrast, feeding Rp-cAMPS to control males results in increased ethanol sensitivity. Rp-cAMPS treatment has the opposite effect on amnchpd males, partially reversing their increased ethanol sensitivity. While unexpected, this last observation is consistent with the finding that flies doubly mutant for rut and amn do not (unlike single mutants) display increased ethanol sensitivity. Treatment of control flies with the PKA inhibitor Rp-cAMPS for only 2 hr leads to an ethanol-sensitive phenotype similar to that of amn, rut, and DCO/+ flies. This argues that even a relatively short-term inhibition of the cAMP pathway is sufficient to increase ethanol sensitivity (Moore, 1998). In mammalian cells and tissues, ethanol potentiates receptor-mediated cAMP signal transduction; the mechanisms underlying this effect, however, remain poorly understood. While a direct link between cAMP signaling and ethanol-induced behaviors has not been established in mammals, the responses to acute ethanol are thought to be mediated by alterations in the function of various ligand-gated ion channels. Certain subtypes of GABAA and NMDA receptors are potentiated and inhibited by ethanol, respectively, and both these channels can be phosphorylated by PKA in cells, tissues, or heterologous expression systems. It is tempting to speculate that PKA phosphorylation of neurotransmitter receptors is altered by ethanol and that this contributes to the behavior of the inebriated animal (Moore, 1998 and references).Induction of cAMP response element-binding protein-dependent medium-term memory by appetitive gustatory reinforcement in Drosophila larvae: larval memory depends on both amnesiac and CREB Drosophila has been successfully used as a model animal for the study of the genetic and molecular mechanisms of learning and memory. Although most of the Drosophila learning studies have used the adult fly, the relative complexity of its neural network hinders cellular and molecular studies at high resolution. In contrast, the Drosophila larva has a simple brain with uniquely identifiable neural networks, providing an opportunity of an attractive alternative system for elucidation of underlying mechanisms involved in learning and memory. This paper describes a novel paradigm of larval associative learning with a single odor and a positive gustatory reinforcer, sucrose. Mutant analyses have suggested importance of cAMP signaling and potassium channel activities in larval learning as has been demonstrated with the adult fly. Intriguingly, larval memory produced by the appetitive conditioning lasts medium term and depends on both amnesiac and cAMP response element-binding protein (CREB). A significant part of memory was disrupted at very early phase by CREB blockade without affecting immediate learning performance. Moreover, synaptic output of larval mushroom body neurons is required for retrieval but not for acquisition and retention of the larval memory, including the CREB-dependent component (Honjo, 2005). The larval olfactory system is significantly simpler than the adult system with only 21 odorant receptor neurons. To find chemicals that are suitable for larval learning assays, 30 odorants were examined for naive larval chemotactic behavior and they were classified into four groups based on their attractiveness. 19 moderate attractants were examined for their effectiveness on larval appetitive olfactory conditioning. Larvae were exposed to an odor for 30 min in association with 1 M sucrose spread on agar. After conditioning, larvae were gently rinsed with distilled water to remove sucrose and tested for olfactory response on the test plate. For 10 of the 19 odorants, animals that received the odor with 1 M sucrose showed enhanced migration to the conditioned odor with significantly higher RI than control larvae, which had been exposed to the same odor but in conjunction with distilled water. Among the odorants examined, linalool (LIN), Pentyl acetate (PA), and gamma-valerolactone (GVA), which gave the largest RI increments in LIN/SUC conditioning, were chosen (Honjo, 2005). To examine whether the increase of response index after conditioning is attributable to associative learning, a set of control experiments were performed. Significant response index increase was observed only when larvae were trained with LIN in association with SUC (LIN/SUC); response index did not change significantly from naive larvae when larvae are trained with LIN in association with distilled water (LIN) or sucrose alone (SUC). Notably, neither LIN nor sucrose alone resulted in habituation of larval olfactory responses compared with naive animals. Similar results were obtained with PA, except that conditioning with PA in association with distilled water led to slight desensitization. In contrast, conditioning with GVA in association with distilled water led to strong desensitization. However, the associative conditioning with GVA/SUC overcame the suppression (Honjo, 2005). It was then asked whether the enhancement of larval response requires simultaneous exposure to both the odor and the reinforcer. As a temporal dissociation control, larvae were successively exposed first to sucrose and then to LIN or vise versa. Whereas simultaneous exposure to both LIN and sucrose (conditioning 1) resulted in enhanced olfactory response, the dissociation control, in which larvae were first exposed to sucrose and then to LIN, led to no enhancement compared with the odor alone control (conditioning 2). The requirement of temporal association between odor exposure and sucrose reinforcement was further confirmed in another set of dissociation controls. Exposure to LIN (conditioning 5) led to slightly higher larval response than conditioning 2, which seems a nonassociative effect caused by the delay attributable to the 30 min mock treatment (for delayed nonassociative effects). Nonetheless, simultaneous exposure to LIN and 1 M sucrose (conditioning 4) led to additional response index increment reproducing associative odor learning. In contrast, separate exposures to LIN and then 1 M SUC (conditioning 6) failed to do so (Honjo, 2005). It was next asked whether the increased larval olfactory response was specific to the exposed odor. To address this question, larval olfactory responses were tested using odorants other than the one used for conditioning. When larvae were trained with LIN/SUC, PA/SUC, or GVA/SUC, only those trained with LIN/SUC showed significant response index increment in the olfactory test with LIN. Similarly, only larvae trained with PA/SUC showed significant response index increment in the olfactory test with PA. These results thus demonstrate that the enhanced larval response with sucrose is specific to the conditioned odor and suggest that Drosophila larvae discriminate the three odors despite their limited olfactory system (Honjo, 2005). Whereas the above data emphasizes the importance of sucrose as a positive reinforcer, it is not clear whether response index stimulation is attributable to gustatory stimuli or attributable to higher osmotic pressure of 1 M sucrose than that of distilled water. To clarify this point, larvae were trained with LIN in association with 1 MD-sorbitol, a sugar that is tasteless to the flies. Conditioning with LIN in association with D-sorbitol failed to stimulate larval response index compared with the control, in which larvae were exposed to LIN in association with distilled water (Honjo, 2005). Most studies on Drosophila associative learning have used reciprocal and symmetrical experimental paradigms with two odors. In contrast, the paradigm here uses only a single odor for conditioning and test. Consequently, this asymmetr


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