Genes interact with the environment, experience, and biology of the brain to shape an animal’s behavior. This latest volume in Advances in Genetics, organized according to the most widely used model organisms, describes the latest genetic discoveries in relation to neural circuit development and activity. Explores the latest topics in neural circuits and behavior research in zebrafish, drosophila, C.elegans, and mouse models Includes methods for testing with ethical, legal, and social implications Critically analyzes future prospects

This book offers representative examples from fly and mouse models to illustrate the ongoing success of the synergistic, state-of-the-art strategy, focusing on the ways it enhances our understanding of sensory processing. The authors focus on sensory systems (vision, olfaction), which are particularly powerful models for probing the development, connectivity, and function of neural circuits, to answer this question: How do individual nerve cells functionally cooperate to guide behavioral responses? Two genetically tractable species, mice and flies, together significantly further our understanding of these processes. Current efforts focus on integrating knowledge gained from three interrelated fields of research: (1) understanding how the fates of different cell types are specified during development, (2) revealing the synaptic connections between identified cell types (“connectomics”) using high-resolution three-dimensional circuit anatomy, and (3) causal testing of how iden tified circuit elements contribute to visual perception and behavior.

In neuroscience, methodological advancements bring about new discoveries, while unanswered questions prompt technical innovations. My thesis involves both aspects, contributing to the genetic toolkit in fruit flies as well as our understanding of olfactory behavior. Innate olfactory attraction and aversion are observed throughout the animal kingdom, but it is not well understood how such valences are encoded by the sensory circuits, how the relevant behaviors are implemented, or, more fundementally, to what extent attraction and aversion share principles of information processing. Using state-of-the-art genetic tools, I demonstrate that aversion is much more robust than attraction against blockade of the sensory circuits (Chapter 2), and that aversion engages specific kinematic and motor-related neurons (Chapter 3). Aversion and attraction are thus likely processed by distinct circuits and principles throughout the sensory-motor transformation. In addition, Chapter 4 not only provides another case where attraction but not averson was affected by a genetic perturbation, but may also link a circuit for specific behavior to a gene necessary for the function of the circuit. To further our ability to explore neural circuits, I developed a transcriptional reporter of intracellular calcium (TRIC, Chapter 5). TRIC signals in the sensory systems depend on neuronal activity, and it sucessfully quantified neuronal responses that change slowly, such as those of neuropeptide F-expressing neurons to sexual deprivation and neuroendocrine pars intercerebralis cells to food and arousal. In the last case, I also demonstrate that TRIC can be used for circuit manipulation. TRIC can thus monitor neuromodulatory circuits whose activity varies slowly with the physiological states of the animal, and its modular design will facilitate future optimizations for even broader applications.

Visual perception is a creative process. An elaborate hierarchy of interconnected areas processes visual information, while incorporating predictions about the visual scene. How the brain creates the perceptually stable images, is a central question in the field of Neuroscience. This thesis was aimed at addressing fundamental questions on the organizational and computational principles of the visual cortex. We utilized a range of genetic tools, physiological recording techniques, computational procedures, and psychophysics methods to measure and manipulate neuronal activity in behaving mice. A long-standing argument questioning the transferability of research insights from the mouse to human vision has been that the mouse retina lacks a fovea. We demonstrated that the representation of space in mouse visual cortex resembles that in humans in a previously unforeseen manner. We measured cortex-wide population receptive-fields (pRFs) and discovered a region directly in front of, and slightly above the mouse with considerably smaller pRFs, called the ‘focea’. The decrease in pRF size in the focea was not caused by smaller receptive fields (RF) of individual neurons. Instead, a more orderly representation of space and an over-representation of binocular regions cause reduced pRF sizes in the focea. Using behavioral paradigms, we showed that mice have improved visual resolution in the focea and that mice make compensatory eye movements to stabilize this region. These experiments advance our knowledge about organizational principles of the mouse visual system and have important implications for the translatability of research on mouse vision. After examining organizational principles of the visual system, we explored functional properties of the visual cortex, investigating the neural circuits underlying perceptual organization.

Proper wiring of the nervous system is crucial for behavior, and defects in nervous system connectivity have been associated with cognitive impairment and neurological disease. How do neurons acquire their diverse morphologies, and how do they interact during development to form the intricate "maps" and circuits of the nervous system? While neural circuit assembly requires the intricate choreography of diverse processes, the specific placement of axons and dendrites is particularly important in determining how circuits process information. Using two well-characterized model circuits in Drosophila and mouse, I will discuss the genetic and molecular mechanisms that regulate how axons find their targets, and how dendrites adopt specific morphologies. The Drosophila olfactory system is an excellent model of wiring specificity, with stereotyped 1:1 connectivity between 50 classes of peripheral olfactory receptor neurons (ORNs) and 50 classes of central projection neurons (PNs). While studying how this connectivity pattern emerges during development, I discovered that a family of guidance factors called semaphorins regulates axon and dendrite development through multiple mechanisms. Specifically, secreted Semaphorin-2b acts both cell-autonomously and non-autonomously to specify developing axon trajectory. Indeed, secreted semaphorins mediate both axon-axon interactions and axon-target interactions. Furthermore, Sema-2b is negatively regulated by the Notch pathway during ORN development, and thus inextricably links cell fate determination to axon trajectory choice. Developmental trajectory defects have devastating consequences for the final targeting of ORN axons. Together, these findings reveal how reiterative use of the same molecules can seamlessly pattern neural circuits during successive developmental stages, and highlight novel mechanisms of semaphorin signaling. To study dendrite morphogenesis, I turned to the mouse cerebellum, another well-characterized neural circuit. This project arose as part of a larger effort to explore how neurotrophins regulate central brain development. Neurotrophins are well known for their roles in regulating the survival, differentiation, and plasticity of central and peripheral neurons. However, their functions in neural circuit assembly remain mysterious. Using a sparse mosaic genetic technique, I discovered that the neurotrophin receptor TrkC is specifically required for cerebellar Purkinje cell dendrite arborization. TrkC mutant Purkinje cells exhibited stunted dendritic trees with decreased complexity and length. Interestingly, removing TrkC from all Purkinje cells did not cause dendrite defects, raising the possibility of a competitive mechanism. Indeed, a series of conditional knockout and virus-based experiments suggest that TrkC and its ligand NT-3 drive competitive interactions between Purkinje cells. As functionally important NT-3 comes from the presynaptic partners of Purkinje cells, such "dendritic competition" contrasts with the classic target-derived "neurotrophic hypothesis." Together, these studies highlight the usefulness of mosaic genetic approaches in revealing the cellular mechanisms of neural circuit assembly. They also uncover surprising new roles for two historic signaling systems, and demonstrate how cells integrate both cell-intrinsic and environmental cues to establish the exquisite architecture of the nervous system.