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Octopamine Integrates Internal Energy Status into Formation of Food-Related Memories in Drosophila


Core Concepts
The duration of starvation determines whether Drosophila forms appetitive short-term or longer-lasting intermediate memories. Insulin-like signaling in octopaminergic reward neurons integrates internal energy storage into memory formation, with octopamine acting as a negative regulator of memory.
Abstract
The study investigates how the internal energy status of Drosophila melanogaster influences the formation and stability of food-related memories. Key highlights: Prolonged starvation leads to the formation of more stable, anesthesia-resistant intermediate and long-term memories, while mild starvation results in short-term memory. The neurotransmitter octopamine acts as a negative regulator of long-term memory formation. Blocking octopamine function in control flies or feeding octopamine to octopamine-deficient mutants enhances or suppresses long-term memory, respectively. Insulin receptor signaling in octopaminergic reward neurons integrates the internal energy status into memory formation. Reducing insulin receptor function in these neurons restores short-term memory in octopamine-deficient mutants. The internal glycogen levels in the muscles and fat bodies influence the strength of short-term memory. Decreasing glycogen levels enhances short-term memory, while increasing glycogen levels reduces it. Octopamine-deficient mutants show reduced sucrose preference and intake when mildly starved, but overconsume sucrose after prolonged starvation, correlating with their altered memory performance. The results demonstrate that the internal energy status, as reflected by glycogen levels, is integrated into the reward system via insulin-octopamine signaling to regulate the formation and stability of food-related memories, which in turn influences feeding behavior.
Stats
Flies starved for 16 h showed short-term memory, while flies starved for 40 h formed more stable, anesthesia-resistant intermediate and long-term memories. Octopamine-deficient TβhnM18 mutants starved for 16 h did not form short-term memory, but developed long-term memory, which became anesthesia-resistant after 40 h of starvation. Reducing glycogen levels in the muscles or both muscles and fat bodies enhanced short-term memory, while increasing glycogen levels reduced it. Octopamine-deficient mutants showed reduced sucrose intake when mildly starved, but overconsumption after prolonged starvation.
Quotes
"Prolonged starvation results in anesthesia-resistant ITM (Figure 2D). In contrast, mildly starved TβhnM18 mutants form a long-term memory that is sensitive to anesthesia-sensitive and detectable 24 h after the training. Prolonged starvation in TβhnM18 mutants leads to anesthesia-resistant long-term memory." "Feeding 3 mM of the octopamine receptor antagonist epinastine for 1 h after training resulted in memory 6 h later in w1118 flies. Feeding 3 mM octopamine for 6 h after training suppresses LTM in TβhnM18." "Blocking InR signaling in Tdc2-Gal4-targeted octopaminergic neurons in TβhnM18 mutants significantly increased 5% sucrose consumption."

Deeper Inquiries

How might the regulation of food-related memories and feeding behavior by the octopamine system be conserved across species, including in vertebrates?

The regulation of food-related memories and feeding behavior by the octopamine system may be conserved across species, including in vertebrates, through the evolutionary conservation of neurotransmitter systems and neural circuits. Octopamine, the invertebrate counterpart of noradrenaline in vertebrates, plays a crucial role in modulating feeding behavior and memory formation. In vertebrates, noradrenaline is involved in similar functions, such as regulating energy homeostasis, reward processing, and memory formation. The basic principles of how neurotransmitters like octopamine and noradrenaline influence neural circuits to integrate internal energy status with memory and feeding behavior are likely to be conserved across species. Additionally, the downstream signaling pathways and mechanisms through which octopamine influences memory and feeding behavior may share commonalities with those in vertebrates, indicating a level of conservation in the regulatory mechanisms.

What other neural mechanisms, beyond insulin-octopamine signaling, might integrate internal energy status information to influence memory formation and feeding?

In addition to insulin-octopamine signaling, several other neural mechanisms may integrate internal energy status information to influence memory formation and feeding behavior. One such mechanism could involve the interaction between the hypothalamus and the mesolimbic reward system. The hypothalamus plays a crucial role in regulating energy balance and metabolism, while the mesolimbic reward system is involved in processing reward-related information. The communication between these two brain regions could allow for the integration of internal energy status with reward processing and memory formation. Additionally, neurotransmitters like dopamine, serotonin, and neuropeptides such as orexin and ghrelin may also play a role in integrating internal energy status information to influence memory and feeding behavior. These neural systems are known to be involved in regulating appetite, motivation, and cognitive functions, making them potential candidates for integrating energy status information with memory formation and feeding behavior.

Could dysregulation of the octopamine system contribute to the development of metabolic disorders like obesity and diabetes, and if so, what therapeutic interventions might target this system?

Dysregulation of the octopamine system could potentially contribute to the development of metabolic disorders like obesity and diabetes. For example, alterations in octopamine signaling that disrupt the integration of internal energy status with memory formation and feeding behavior may lead to imbalanced energy intake and expenditure, contributing to weight gain and metabolic dysfunction. In the context of obesity, dysregulation of the octopamine system could result in an increased preference for high-calorie foods, reduced satiety signaling, and altered energy metabolism, all of which are factors associated with obesity development. Similarly, in diabetes, dysregulation of octopamine signaling could impact glucose homeostasis, insulin sensitivity, and energy utilization, potentially exacerbating the progression of the disease. Therapeutic interventions targeting the octopamine system to address metabolic disorders could involve modulating octopamine receptor activity, enhancing octopamine release, or regulating downstream signaling pathways. For example, pharmacological agents that target octopamine receptors to restore normal signaling levels could help rebalance energy homeostasis and improve metabolic outcomes. Additionally, lifestyle interventions such as dietary modifications, exercise, and stress management techniques could also influence octopamine system function and contribute to the management of metabolic disorders. Further research into the specific mechanisms through which octopamine influences metabolic health could provide valuable insights for developing targeted therapeutic strategies.
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