Tyramine and its Amtyr1 receptor modulate attention in honey bees (Apis mellifera)
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eLife assessment:
This article reports the fundamental discovery that interfering with the function of the tyramine receptor causes a rapid decline in responses to olfactory stimuli in the honey bee. While tyramine signaling might specifically control the process of latent inhibition without affecting appetitive conditioning, the present analysis is incomplete in terms of ruling out the possibility that tyramine affects other functions of the antennal lobe. Nonetheless, compelling data highlight the role of one of the most highly expressed biogenic amine receptors in the insect olfactory system.
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Abstract
Animals must learn to ignore stimuli that are irrelevant to survival and attend to ones that enhance survival. When a stimulus regularly fails to be associated with an important consequence, subsequent excitatory learning about that stimulus can be delayed, which is a form of nonassociative conditioning called ‘latent inhibition’. Honey bees show latent inhibition toward an odor they have experienced without association with food reinforcement. Moreover, individual honey bees from the same colony differ in the degree to which they show latent inhibition, and these individual differences have a genetic basis. To investigate the mechanisms that underly individual differences in latent inhibition, we selected two honey bee lines for high and low latent inhibition, respectively. We crossed those lines and mapped a Quantitative Trait Locus for latent inhibition to a region of the genome that contains the tyramine receptor gene Amtyr1 [We use Amtyr1 to denote the gene and AmTYR1 the receptor throughout the text.]. We then show that disruption of Amtyr1 signaling either pharmacologically or through RNAi qualitatively changes the expression of latent inhibition but has little or slight effects on appetitive conditioning, and these results suggest that AmTYR1 modulates inhibitory processing in the CNS. Electrophysiological recordings from the brain during pharmacological blockade are consistent with a model that AmTYR1 indirectly regulates at inhibitory synapses in the CNS. Our results therefore identify a distinct Amtyr1 -based modulatory pathway for this type of nonassociative learning, and we propose a model for how Amtyr1 acts as a gain control to modulate hebbian plasticity at defined synapses in the CNS. We have shown elsewhere how this modulation also underlies potentially adaptive intracolonial learning differences among individuals that benefit colony survival. Finally, our neural model suggests a mechanism for the broad pleiotropy this gene has on several different behaviors.
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eLife assessment:
This article reports the fundamental discovery that interfering with the function of the tyramine receptor causes a rapid decline in responses to olfactory stimuli in the honey bee. While tyramine signaling might specifically control the process of latent inhibition without affecting appetitive conditioning, the present analysis is incomplete in terms of ruling out the possibility that tyramine affects other functions of the antennal lobe. Nonetheless, compelling data highlight the role of one of the most highly expressed biogenic amine receptors in the insect olfactory system.
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Reviewer #1 (Public Review):
Latshaw and colleagues show that interfering with the function of the tyramine receptor, AmTYR1, causes a precipitous decline in responses to olfactory stimuli, a decline consistent with AmTYR1's proposed involvement in the regulation of inhibitory networks within the antennal lobes (primary olfactory centres) of the honey bee brain. Interestingly, impacts on odour learning of disrupting AmTYR1 function are enhanced by repeatedly exposing bees to an odour without reinforcement ('familiarization'). The authors argue that disruption of AmTYR1 signalling increases the expression of latent inhibition without affecting appetitive conditioning. The results do not, in my view, support this claim. Nevertheless, the disruption of tyramine signalling in the bee brain clearly packs a powerful punch.
Strengths:
Repeated …Reviewer #1 (Public Review):
Latshaw and colleagues show that interfering with the function of the tyramine receptor, AmTYR1, causes a precipitous decline in responses to olfactory stimuli, a decline consistent with AmTYR1's proposed involvement in the regulation of inhibitory networks within the antennal lobes (primary olfactory centres) of the honey bee brain. Interestingly, impacts on odour learning of disrupting AmTYR1 function are enhanced by repeatedly exposing bees to an odour without reinforcement ('familiarization'). The authors argue that disruption of AmTYR1 signalling increases the expression of latent inhibition without affecting appetitive conditioning. The results do not, in my view, support this claim. Nevertheless, the disruption of tyramine signalling in the bee brain clearly packs a powerful punch.
Strengths:
Repeated presentation of an odour without reinforcement slows subsequent learning of an association between the odour in question and food reward (latent inhibition). This study's aim was to investigate the mechanisms that underlie individual differences in this trait.The authors select honey bee lines showing high and low levels of latent inhibition and use QTL mapping to identify genes potentially responsible for this trait. Amtyr1 is identified, a gene that encodes a tyramine receptor the authors have shown elsewhere is expressed in the brain, including on presynaptic terminals of olfactory sensory neurons in the antennal lobes (primary olfactory centres of the brain). Using the tyramine receptor blocker, yohimbine, and Amtyr1 knockdown with dsiRNA, Latshaw et al. show that disruption of tyramine signalling via AmTYR1 receptors inhibits dramatically the magnitude of responses to odour signals at the level of the antennal lobes. Odour learning appears to remain largely intact unless, prior to conditioning, bees are exposed repeatedly to puffs of odour without reinforcement (a situation expected to induce latent inhibition). As a result of familiarization, learning not only of the familiarized odour, but also of novel odours declines dramatically. These findings are fascinating and consistent with the hypothesis that AmTYR1 is involved in regulating inhibitory networks within the AL.
Weaknesses:
The authors argue that disruption of AmTYR1 signalling increases the expression of latent inhibition without affecting appetitive conditioning. The results, in my view, do not support this conclusion. Electrophysiological recordings from the AL show that blocking AmTYR1 function causes significant non-odour-specific suppression of responses at the level of the antennal lobes, a result that would be predicted if inhibiting AmTYR1 function increased lateral inhibition (as opposed to latent inhibition) globally in the antennal lobe.Under these conditions, the consequences of odour familiarization would, I believe, be predicted by current models of inhibitory networks in antennal lobes. A schematic of olfactory circuits within the antennal lobes, and the location of AmTYR1 receptors within this network, would assist in enabling readers to navigate these complex networks and interpret the interesting findings presented in this study. While the stated aim was to investigate the mechanisms that underlie individual differences in latent inhibition, this goal seems to be lost along the way.
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Reviewer #2 (Public Review):
The aim of the present work was to find physiological mechanisms for the phenomenon of "latent inhibition" in honey bees. To achieve this goal, the authors have very successfully combined different population genetic, behavioral pharmacological, and electrophysiological methods. From my point of view, the experiments were mostly carried out accurately, but some aspects of the methods used should be described more fully and/or justified. With the identification of the tyramine receptor AmTYR1 as an important mediator of latent inhibition, the goal was achieved. In any case, the work should stimulate investigation of whether the orthologous receptor of the fruit fly Drosophila has comparable functions in this model organism. Thus, in the future, the more powerful genetic tools of this alternative model …
Reviewer #2 (Public Review):
The aim of the present work was to find physiological mechanisms for the phenomenon of "latent inhibition" in honey bees. To achieve this goal, the authors have very successfully combined different population genetic, behavioral pharmacological, and electrophysiological methods. From my point of view, the experiments were mostly carried out accurately, but some aspects of the methods used should be described more fully and/or justified. With the identification of the tyramine receptor AmTYR1 as an important mediator of latent inhibition, the goal was achieved. In any case, the work should stimulate investigation of whether the orthologous receptor of the fruit fly Drosophila has comparable functions in this model organism. Thus, in the future, the more powerful genetic tools of this alternative model organism could be used. So far, only dopamine receptor pathways have been associated with latent inhibition in Drosophila. Comparisons with the mechanisms of latent inhibition in vertebrates are now also possible.
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Reviewer #3 (Public Review):
The findings by Latshaw et al. identify Amtyr1 as a major regulator of latent inhibition - a neurological mechanism whereby non-productive stimuli are down-ranked in reward:stimuli association - in honeybees. The authors utilize intracolony variation in exhibited latent inhibition in male honey bees to map Quantitative Trait Loci associated with this phenotype, then use the identified regulatory regions (associated with Amtyr1) to target Amtyr1 using several perturbation methods to demonstrate the centrality of this locus to latent inhibition, and neurophysiology methods to assess the neuronal effect. Overall their results are convincing and approaches appear rigorous.
Overall I found this paper to be relatively easy or hard to review, depending on how you rate reviewing a paper that does many of the things …
Reviewer #3 (Public Review):
The findings by Latshaw et al. identify Amtyr1 as a major regulator of latent inhibition - a neurological mechanism whereby non-productive stimuli are down-ranked in reward:stimuli association - in honeybees. The authors utilize intracolony variation in exhibited latent inhibition in male honey bees to map Quantitative Trait Loci associated with this phenotype, then use the identified regulatory regions (associated with Amtyr1) to target Amtyr1 using several perturbation methods to demonstrate the centrality of this locus to latent inhibition, and neurophysiology methods to assess the neuronal effect. Overall their results are convincing and approaches appear rigorous.
Overall I found this paper to be relatively easy or hard to review, depending on how you rate reviewing a paper that does many of the things you would have suggested to assess the functional centrality of a target gene to an observed phenotype.
I really do not have many criticisms of the approach, findings, or rigor of major note. I would appreciate it if the authors noted (acceptable as supplementary) the other QTL loci identified (lines 123-124), as the text implies other genes may have been identified in their QTL mapping. If so, this may be of interest to the general community.
I also personally prefer exact p-values reported (e.g., line 253) instead of the "<<0.01" or (line 257) "<0.01".
Honestly, I'm a little disappointed in how little I could criticize, which is only partially related to my not being an expert in the field. The paper was clear, well written, rigorous (as far as I could tell), validates findings via multiple routes, and extends their locus-focused (lol) results into neurotransmitter differences, empirically determined.
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