A Drosophila model for alcohol reward

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287

Drosophila melanogaster can acquire a stable appetitive olfactory memory when the presentation of a sugar reward and an odor are paired. However, the neuronal mechanisms by which a single training induces long-term memory are poorly understood. Here we show that two distinct subsets of dopamine neurons in the fly brain signal reward for short-term (STM) and long-term memories (LTM). One subset induces memory that decays within several hours, whereas the other induces memory that gradually develops after training. They convey reward signals to spatially segregated synaptic domains of the mushroom body (MB), a potential site for convergence. Furthermore, we identified a single type of dopamine neuron that conveys the reward signal to restricted subdomains of the mushroom body lobes and induces long-term memory. Constant appetitive memory retention after a single training session thus comprises two memory components triggered by distinct dopamine neurons.dopamine | learning and memory | Drosophila | mushroom body M emory of a momentous event persists for a long time.Whereas some forms of long-term memory (LTM) require repetitive training (1-3), a highly relevant stimulus such as food or poison is sufficient to induce LTM in a single training session (4-7). Recent studies have revealed aspects of the molecular and cellular mechanisms of LTM formation induced by repetitive training (8-11), but how a single training induces a stable LTM is poorly understood (12).Appetitive olfactory learning in fruit flies is suited to address the question, as a presentation of a sugar reward paired with odor induces robust short-term memory (STM) and LTM (6, 7). Odor is represented by a sparse ensemble of the 2,000 intrinsic neurons, the Kenyon cells (13). A current working model suggests that concomitant reward signals from sugar ingestion cause associative plasticity in Kenyon cells that might underlie memory formation (14-20). A single activation session of a specific cluster of dopamine neurons (PAM neurons) by sugar ingestion can induce appetitive memory that is stable over 24 h (19), underscoring the importance of sugar reward to the fly.The mushroom body (MB) is composed of the three different cell types, α/β, α′/β′, and γ, which have distinct roles in different phases of appetitive memories (11,(21)(22)(23)(24)(25). Similar to midbrain dopamine neurons in mammals (26,27), the structure and function of PAM cluster neurons are heterogeneous, and distinct dopamine neurons intersect unique segments of the MB lobes (19,(28)(29)(30)(31)(32)(33)(34). Further circuit dissection is thus crucial to identify candidate synapses that undergo associative modulation.By activating distinct subsets of PAM neurons for reward signaling, we found that short-and long-term memories are independently formed by two complementary subsets of PAM cluster dopamine neurons. Conditioning flies with nutritious and nonnutritious sugars revealed that the two subsets could represent different reinforcing properties: sweet taste and nutritional value of sugar....

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct dopamine neurons mediate reward signals for short- and long-term memories

Yamagata

Ichinose

Aso

et al. 2014

230

287

“…In this context, it is said that such an experience is rewarding or positively reinforcing to the fly. By using such conditioned odor preference assays (6,7), it has been shown that flies perceive sucrose (6), water (8), alcohol intoxication (9), and mating (10) as rewarding, while noxious stimuli, such as electric shock, are perceived as aversive (6,7). These findings parallel those in mammalian systems, underscoring the relevance of reward perception and processing in flies to our general understanding of reward (11)(12)(13)(14).…”

mentioning

confidence: 90%

Dissection of theDrosophilaneuropeptide F circuit using a high-throughput two-choice assay

Shao

Saver

Chung

et al. 2017

Self Cite

In their classic experiments, Olds and Milner showed that rats learn to lever press to receive an electric stimulus in specific brain regions. This led to the identification of mammalian reward centers. Our interest in defining the neuronal substrates of reward perception in the fruit fly Drosophila melanogaster prompted us to develop a simpler experimental approach wherein flies could implement behavior that induces self-stimulation of specific neurons in their brains. The high-throughput assay employs optogenetic activation of neurons when the fly occupies a specific area of a behavioral chamber, and the flies' preferential occupation of this area reflects their choosing to experience optogenetic stimulation. Flies in which neuropeptide F (NPF) neurons are activated display preference for the illuminated side of the chamber. We show that optogenetic activation of NPF neuron is rewarding in olfactory conditioning experiments and that the preference for NPF neuron activation is dependent on NPF signaling. Finally, we identify a small subset of NPF-expressing neurons located in the dorsomedial posterior brain that are sufficient to elicit preference in our assay. This assay provides the means for carrying out unbiased screens to map reward neurons in flies.reward circuit | high-throughput two-choice assay | optogenetics | neuropeptide F | Drosophila

“…Model organisms, including selectively bred lines (8)(9)(10), offer a potentially powerful framework for genomic analyses to identify genes and their functional variants that contribute to complex disorders. The selective breeding process reduces genetic heterogeneity and enriches to high frequency variants that influence the targeted phenotype.…”

Section: Gene Identification | Selectively Bred Linesmentioning

confidence: 99%

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Zhou¹,

Karlsson

Liang³

et al. 2013

107

116

Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 −/− mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target. gene identification | selectively bred linesA lcoholism is a moderately to highly heritable disease (1, 2).The search for genetic variation influencing this complex disorder has yielded limited success. In human populations, candidate gene analyses have established roles for polymorphisms of ADH1B and ALDH2, both enzymes involved in alcohol metabolism (3). Genome-wide association studies (4-7) have implicated several genomic regions. However, the genes and functional variants that account for the genetic association signals remain largely unknown. Complex behavioral disorders may be influenced by many different genes. Most functional alleles are rare or uncommon, also contributing to genetic heterogeneity that hampers locus identification in population samples. Individual variants influencing alcoholism are also likely to be probabilistic in their actions, with limited effect sizes on risk of the disease itself. All of these factors pose significant challenges for identification of genes and functional variants contributing to alcoholism by population-based analyses in people.Model organisms, including selectively bred lines (8-10), offer a potentially powerful framework for genomic analyses to identify genes and their functional variants that contribute to complex disorders. The selective breeding process reduces genetic heterogeneity and enriches to high frequency variants that influence the targeted phenotype. Alcohol-preferring (P) and nonpreferring (NP) rats, a seminal rat model of alcoholism, were bred from Wistar rats by 30-70 generations of bidirectional selection for alcohol preference. These rats model human alcoholism in several ways. They voluntarily consume excessive amounts of alcohol with sustained high blood alcohol concentrations, consume alcohol fo...