Characterization of aminergic neurons controlling behavioral persistence and motivation in Drosophila melanogaster

Deprivation is at odds with survival. To obliterate their condition of hunger animals engage in costly foraging behavior. This conundrum demands unceasing integration of external sensory processing and internal metabolic monitors. Unsurprisingly, such critical behaviors are translated to strong impulses. If unchecked, however, impulsivity can trap animals in unfavorable behavioral states and prevent them from exploiting other valuable opportunities. Categorically, motivational mechanisms have been proposed as the conduit to comply with or decline a response to a strong impulse. Thus, motivation emerges as a critical determinant for observed animal behavioral variability at a given time. Although neuronal circuit diagrams may be deceptively static, neuromodulation can implement behavioral variability in the nervous systems. Bioamines, such as dopamine and norepinephrine, mediate modulatory impact on intrinsic motivational circuits that govern feeding and reward. Across model organisms, however, how animals integrate and update decision-making based on the current motivational and internal states are still poorly understood at the molecular and circuitry levels. Due to its extensive toolbox and amenable miniature nervous systems, Drosophila melanogaster is poised to enrich the current perspective for these concepts. For Drosophila melanogaster, certain odors are salient cues for long distance foraging events. To explore how starved flies make goal-directed decisions, I developed a novel spherical treadmill paradigm. Through the utilization of high-resolution behavioral analyses and tight control of, otherwise highly turbulent, odor delivery, I found that food-deprived flies tracked vinegar persistently even in the repeated absence of a food reward. Combining this behavioral paradigm with immediate neuronal manipulations revealed that this innate persistence recruited circuits that are traditionally linked with learning and memory in an internal state-dependent manner. TH+ cluster dopaminergic neurons, operators of punishment learning, and Dop1R2 signaling enabled this olfactory-driven persistence. Downstream of these dopaminergic neurons, a single mushroom body output neuron, MVP2 was crucial for persistence. MVP2 was necessary and sufficient to integrate hunger state as the underlying motivational drive for food-seeking persistence. Furthermore, I investigated how this strong impulse is counteracted when a fly reaches its goal, nutritious food. A change from odor tracking to food consumption demands the coordination of different sensory systems and motor control subunits. Norepinephrine is implemented in such global switches; such as fight or flight transitions. Using optogenetic manipulation, I demonstrated that the food-seeking drive was suppressed by, an insect norepinephrine analog, octopaminergic input, via VPM4 neurons. Being connected to MVP2 synaptically, which we showed using high-resolution tracing techniques, and a surrogate for feeding at the neuronal level, VPM4 neurons acted as the inhibitory brake on persistent odor tracking to allow feeding related behavior. As a culmination of novel paradigm development, thermo/optogenetic neuronal manipulations and connectomics, this work presents a neuronal microcircuit that recapitulates the alterations of animal behavior faithfully from odor tracking to olfactory suppression during feeding. Specific subsets of dopaminergic and octopaminergic neurons are found to be mediators of motivationally driven events. My findings provide fresh mechanistic insights on how multimodal integration can occur in the brain, how such systems are prone to the internal states, and offers several plausible explanations on how persistence emerges. Finally, this work might serve as a template to better understand the roles and the functional diversity of mammalian aminergic neurons

Characterization of aminergic neurons controlling behavioral persistence and motivation in Drosophila melanogaster

Deprivation is at odds with survival. To obliterate their condition of hunger animals engage in costly foraging behavior. This conundrum demands unceasing integration of external sensory processing and internal metabolic monitors. Unsurprisingly, such critical behaviors are translated to strong impulses. If unchecked, however, impulsivity can trap animals in unfavorable behavioral states and prevent them from exploiting other valuable opportunities. Categorically, motivational mechanisms have been proposed as the conduit to comply with or decline a response to a strong impulse. Thus, motivation emerges as a critical determinant for observed animal behavioral variability at a given time. Although neuronal circuit diagrams may be deceptively static, neuromodulation can implement behavioral variability in the nervous systems. Bioamines, such as dopamine and norepinephrine, mediate modulatory impact on intrinsic motivational circuits that govern feeding and reward. Across model organisms, however, how animals integrate and update decision-making based on the current motivational and internal states are still poorly understood at the molecular and circuitry levels. Due to its extensive toolbox and amenable miniature nervous systems, Drosophila melanogaster is poised to enrich the current perspective for these concepts. For Drosophila melanogaster, certain odors are salient cues for long distance foraging events. To explore how starved flies make goal-directed decisions, I developed a novel spherical treadmill paradigm. Through the utilization of high-resolution behavioral analyses and tight control of, otherwise highly turbulent, odor delivery, I found that food-deprived flies tracked vinegar persistently even in the repeated absence of a food reward. Combining this behavioral paradigm with immediate neuronal manipulations revealed that this innate persistence recruited circuits that are traditionally linked with learning and memory in an internal state-dependent manner. TH+ cluster dopaminergic neurons, operators of punishment learning, and Dop1R2 signaling enabled this olfactory-driven persistence. Downstream of these dopaminergic neurons, a single mushroom body output neuron, MVP2 was crucial for persistence. MVP2 was necessary and sufficient to integrate hunger state as the underlying motivational drive for food-seeking persistence. Furthermore, I investigated how this strong impulse is counteracted when a fly reaches its goal, nutritious food. A change from odor tracking to food consumption demands the coordination of different sensory systems and motor control subunits. Norepinephrine is implemented in such global switches; such as fight or flight transitions. Using optogenetic manipulation, I demonstrated that the food-seeking drive was suppressed by, an insect norepinephrine analog, octopaminergic input, via VPM4 neurons. Being connected to MVP2 synaptically, which we showed using high-resolution tracing techniques, and a surrogate for feeding at the neuronal level, VPM4 neurons acted as the inhibitory brake on persistent odor tracking to allow feeding related behavior. As a culmination of novel paradigm development, thermo/optogenetic neuronal manipulations and connectomics, this work presents a neuronal microcircuit that recapitulates the alterations of animal behavior faithfully from odor tracking to olfactory suppression during feeding. Specific subsets of dopaminergic and octopaminergic neurons are found to be mediators of motivationally driven events. My findings provide fresh mechanistic insights on how multimodal integration can occur in the brain, how such systems are prone to the internal states, and offers several plausible explanations on how persistence emerges. Finally, this work might serve as a template to better understand the roles and the functional diversity of mammalian aminergic neurons

A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila.

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive

Two interesting cases of coronary artery fistulas treated by coil embolization

13th International Congress of Update in Cardiology and Cardiovascular Surgery (UCCVS) -- MAR 23-26, 2017 -- Cesme, TURKE

Estimation of forensic age using substages of ossification of the medial clavicle in living individuals

Forensic age estimation based on staging of ossification of the medial clavicular bone is one of the methods recommended by the Study Group on Forensic Age Diagnostics of the German Association of Forensic Medicine. In the present study, we analyzed the stages of ossification of the medial clavicular epiphyses on thin-sliced (1 mm) computed tomography (CT) images using the substages defined within stages 2 and 3. The retrospective CT analysis involved 193 subjects (129 males, 64 females) ranging in age from 13 to 28 years. Spearman's correlation analysis revealed a positive correlation between age and ossification stage in both male and female subjects. Stage 3c was first observed at 19 years of age in both sexes and may thus serve as a valuable forensic marker for determining an age of 18 years. Although further research is needed on the ossification stages of the medial clavicular epiphyses, the present findings could contribute to existing reports on observers' experiences using CT analysis of ossification combined with analysis of substages

Internal State Dependent Odor Processing and Perception—The Role of Neuromodulation in the Fly Olfactory System

Animals rely heavily on their sense of olfaction to perform various vital interactions with an ever-in-flux environment. The turbulent and combinatorial nature of air-borne odorant cues demands the employment of various coding strategies, which allow the animal to attune to its internal needs and past or present experiences. Furthermore, these internal needs can be dependent on internal states such as hunger, reproductive state and sickness. Neuromodulation is a key component providing flexibility under such conditions. Understanding the contributions of neuromodulation, such as sensory neuron sensitization and choice bias requires manipulation of neuronal activity on a local and global scale. With Drosophila's genetic toolset, these manipulations are feasible and even allow a detailed look on the functional role of classical neuromodulators such as dopamine, octopamine and neuropeptides. The past years unraveled various mechanisms adapting chemosensory processing and perception to internal states such as hunger and reproductive state. However, future research should also investigate the mechanisms underlying other internal states including the modulatory influence of endogenous microbiota on Drosophila behavior. Furthermore, sickness induced by pathogenic infection could lead to novel insights as to the neuromodulators of circuits that integrate such a negative postingestive signal within the circuits governing olfactory behavior and learning. The enriched emporium of tools Drosophila provides will help to build a concrete picture of the influence of neuromodulation on olfaction and metabolism, adaptive behavior and our overall understanding of how a brain works

Internal State Dependent Odor Processing and Perception—The Role of Neuromodulation in the Fly Olfactory System

Animals rely heavily on their sense of olfaction to perform various vital interactions with an ever-in-flux environment. The turbulent and combinatorial nature of air-borne odorant cues demands the employment of various coding strategies, which allow the animal to attune to its internal needs and past or present experiences. Furthermore, these internal needs can be dependent on internal states such as hunger, reproductive state and sickness. Neuromodulation is a key component providing flexibility under such conditions. Understanding the contributions of neuromodulation, such as sensory neuron sensitization and choice bias requires manipulation of neuronal activity on a local and global scale. With Drosophila's genetic toolset, these manipulations are feasible and even allow a detailed look on the functional role of classical neuromodulators such as dopamine, octopamine and neuropeptides. The past years unraveled various mechanisms adapting chemosensory processing and perception to internal states such as hunger and reproductive state. However, future research should also investigate the mechanisms underlying other internal states including the modulatory influence of endogenous microbiota on Drosophila behavior. Furthermore, sickness induced by pathogenic infection could lead to novel insights as to the neuromodulators of circuits that integrate such a negative postingestive signal within the circuits governing olfactory behavior and learning. The enriched emporium of tools Drosophila provides will help to build a concrete picture of the influence of neuromodulation on olfaction and metabolism, adaptive behavior and our overall understanding of how a brain works

A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.publishe