Neural basis of behavioral choice and sequences – DECISIONSEQ

The complexity of the interactions between an organism and its environment creates a variety of behavioral choices. It is essential for survival across the animal kingdom to make appropriate choices depending on the environmental context and the internal state and this process often goes awry in human neuropshychiatric disorders. Despite the importance of this brain function, how decision-making is implemented in the nervous system by specific circuits remains a significant gap in our knowledge. Many actions are physically mutually exclusive so competitive interactions must exist to enable the selection of one behavior and concomitant full suppression of all alternatives. Often, behaviors are not single actions but multiple actions organized into sequences that allow the animals to achieve their goals. Therefore mechanisms must be in place to regulate the transition between different behaviors in a sequence. Here again the network architecture underlying the generation of action sequences is not known with synaptic resolution, despite the relevance of this process human health. The difficulty in determining the detailed network architectures underlying computations involved in decision-making and sequence generation is primarily due to the challenges in mapping connectivity between neurons with synaptic resolution and establishing causality between neurons and behaviors with cellular resolution with the approaches and model systems used.
We propose to study circuit mechanisms of selection, repression and transitions between actions and fill the above described knowledge gap. Our multidisciplinary approach will combine neural manipulation during behavior, electron microscopy (EM) reconstruction of neuronal connectivity with synaptic resolution and recording of neuronal activity in the tractable model system, the Drosophila larva. These questions will be addressed comprehensively by studying the circuitry underlying larval behavioral response to mechanical stimuli in a variety of contexts and across the entire nervous system. We will investigate 1) how the sensory context and internal state of the animal modulate behavioral choice 2) how competitive interactions between opposing options are implemented across the nervous system and 3) how transitions between actions are controlled to generate flexible behavioral sequences. We aim at determining with unprecedented resolution the network architectures and circuit mechanisms underlying competitive interactions and sequence transitions. The identification of circuit motifs and basic principles of behavioral choice and sequence implementation in the tractable genetic model system will lay the basis for future investigations in larger, more complex systems. Identifying the circuit mechanisms underlying decision-making and sequence generation will provide the groundwork for developing treatments for disease in which these processes are impaired, that are circuit-specific and thus with fewer side effects. It will also provide the basis for studying the roles of genes in identified circuit elements in the future and thus extending these studies to understanding the genetic basis of decision-making and the generation of sequences and potentially the genes that could cause circuit defects that give rise to impairment of decision-making and sequence generation in disease.