An Operating Principle of the Cerebral Cortex, and a Cellular Mechanism for Attentional Trial-and-Error Pattern Learning and Useful Classification Extraction

A feature of the brains of intelligent animals is the ability to learn to respond to an ensemble of active neuronal inputs with a behaviorally appropriate ensemble of active neuronal outputs. Previously, a hypothesis was proposed on how this mechanism is implemented at the cellular level within the neocortical pyramidal neuron: the apical tuft or perisomatic inputs initiate "guess" neuron firings, while the basal dendrites identify input patterns based on excited synaptic clusters, with the cluster excitation strength adjusted based on reward feedback. This simple mechanism allows neurons to learn to classify their inputs in a surprisingly intelligent manner. Here, we revise and extend this hypothesis. We modify synaptic plasticity rules to align with behavioral time scale synaptic plasticity (BTSP) observed in hippocampal area CA1, making the framework more biophysically and behaviorally plausible. The neurons for the guess firings are selected in a voluntary manner via feedback connections to apical tufts in the neocortical layer 1, leading to dendritic Ca2+ spikes with burst firing, which are postulated to be neural correlates of attentional, aware processing. Once learned, the neuronal input classification is executed without voluntary or conscious control, enabling hierarchical incremental learning of classifications that is effective in our inherently classifiable world. In addition to voluntary, we propose that pyramidal neuron burst firing can be involuntary, also initiated via apical tuft inputs, drawing attention towards important cues such as novelty and noxious stimuli. We classify the excitations of neocortical pyramidal neurons into four categories based on their excitation pathway: attentional versus automatic and voluntary/acquired versus involuntary. Additionally, we hypothesize that dendrites within pyramidal neuron minicolumn bundles are coupled via depolarization...Comment: 20 pages, 13 figure

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

Protein appetite drives macronutrient-related differences in ventral tegmental area neural activity

Acknowledgements: The authors acknowledge the help and support from the staff of the Division of Biomedical Services, Preclinical Research Facility, University of Leicester, for technical support and the care of experimental animals. The authors would like to thank Vaibhav Konanur for developing the analytical method used to correct fluorescence traces, Leon Lagnado for kindly loaning equipment used in initial photometry experiments, and Andrew MacAskill for useful discussions regarding analysis. This work was funded by the Biotechnology and Biological Sciences Research Council [grant #BB/M007391/1 to J.E.M.], the European Commission [grant #GA 631404 to J.E.M.], The Leverhulme Trust [grant #RPG-2017-417 to J.E.M. and J.A-S.], and Tromsø Research Foundation [grant #19-SGJMcC to J. E. M.).Peer reviewedPublisher PD

Neuronal mechanisms underlying innate and learned olfactory processing in Drosophila

Olfaction allows animals to adapt their behavior in response to different chemical cues in their environment. How does the brain efficiently discriminate different odors to drive appropriate behavior, and how does it flexibly assign value to odors to adjust behavior according to experience? This review traces neuronal mechanisms underlying these processes in adult Drosophila melanogaster from olfactory receptors to higher brain centers. We highlight neural circuit principles like lateral inhibition, segregation and integration of olfactory channels, temporal accumulation of sensory evidence, and compartmentalized synaptic plasticity underlying associative memory