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Neuroscience research has exploded, with more than fifty thousand neuroscientists applying increasingly advanced methods. A mountain of new facts and mechanisms has emerged. And yet a principled framework to organize this knowledge has been missing. In this book, Peter Sterling and Simon Laughlin, two leading neuroscientists, strive to fill this gap, outlining a set of organizing principles to explain the whys of neural design that allow the brain to compute so efficiently. Setting out to \"reverse engineer\" the brain -- disassembling it to understand it -- Sterling and Laughlin first consider why an animal should need a brain, tracing computational abilities from bacterium to protozoan to worm. They examine bigger brains and the advantages of \"anticipatory regulation\"; identify constraints on neural design and the need to \"nanofy\"; and demonstrate the routes to efficiency in an integrated molecular system, phototransduction. They show that the principles of neural design at finer scales and lower levels apply at larger scales and higher levels; describe neural wiring efficiency; and discuss learning as a principle of biological design that includes \"save only what is needed.\"Sterling and Laughlin avoid speculation about how the brainmightwork and endeavor to make sense of what is already known. Their distinctive contribution is to gather a coherent set of basic rules and exemplify them across spatial and functional scales.

The exquisite intricacies of neural circuits are fundamental to an animal's diverse and complex repertoire of sensory and motor functions. The ability to precisely map neural circuits and to selectively manipulate neural activity is critical to understanding brain function and has, therefore been a long-standing goal for neuroscientists. The recent development of optogenetic tools, combined with transgenic mouse lines, has endowed us with unprecedented spatiotemporal precision in circuit analysis. These advances greatly expand the scope of tractable experimental investigations. Here, in the first half of the review, we will present applications of optogenetics in identifying connectivity between different local neuronal cell types and of long-range projections with both and methods. We will then discuss how these tools can be used to reveal the functional roles of these cell-type specific connections in governing sensory information processing, and learning and memory in the visual cortex, somatosensory cortex, and motor cortex. Finally, we will discuss the prospect of new optogenetic tools and how their application can further advance modern neuroscience. In summary, this review serves as a primer to exemplify how optogenetics can be used in sophisticated modern circuit analyses at the levels of synapses, cells, network connectivity and behaviors.

Spinal cord injury is linked to the interruption of neural pathways, which results in irreversible neural dysfunction. Neural repair and neuroregeneration are critical goals and issues for rehabilitation in spinal cord injury, which require neural stem cell repair and multimodal neuromodulation techniques involving personalized rehabilitation strategies. Besides the involvement of endogenous stem cells in neurogenesis and neural repair, exogenous neural stem cell transplantation is an emerging effective method for repairing and replacing damaged tissues in central nervous system diseases. However, to ensure that endogenous or exogenous neural stem cells truly participate in neural repair following spinal cord injury, appropriate interventional measures (e.g., neuromodulation) should be adopted. Neuromodulation techniques, such as noninvasive magnetic stimulation and electrical stimulation, have been safely applied in many neuropsychiatric diseases. There is increasing evidence to suggest that neuromagnetic/electrical modulation promotes neuroregeneration and neural repair by affecting signaling in the nervous system; namely, by exciting, inhibiting, or regulating neuronal and neural network activities to improve motor function and motor learning following spinal cord injury. Several studies have indicated that fine motor skill rehabilitation training makes use of residual nerve fibers for collateral growth, encourages the formation of new synaptic connections to promote neural plasticity, and improves motor function recovery in patients with spinal cord injury. With the development of biomaterial technology and biomechanical engineering, several emerging treatments have been developed, such as robots, brain-computer interfaces, and nanomaterials. These treatments have the potential to help millions of patients suffering from motor dysfunction caused by spinal cord injury. However, large-scale clinical trials need to be conducted to validate their efficacy. This review evaluated the efficacy of neural stem cells and magnetic or electrical stimulation combined with rehabilitation training and intelligent therapies for spinal cord injury according to existing evidence, to build up a multimodal treatment strategy of spinal cord injury to enhance nerve repair and regeneration.

Animals rely on highly sensitive thermoreceptors to seek out optimal temperatures, but the molecular mechanisms of thermosensing are not well understood. The Dorsal Organ Cool Cells (DOCCs) of the Drosophila larva are a set of exceptionally thermosensitive neurons critical for larval cool avoidance. Here, we show that DOCC cool-sensing is mediated by Ionotropic Receptors (IRs), a family of sensory receptors widely studied in invertebrate chemical sensing. We find that two IRs, IR21a and IR25a, are required to mediate DOCC responses to cooling and are required for cool avoidance behavior. Furthermore, we find that ectopic expression of IR21a can confer cool-responsiveness in an Ir25a-dependent manner, suggesting an instructive role for IR21a in thermosensing. Together, these data show that IR family receptors can function together to mediate thermosensation of exquisite sensitivity. Animals need to be able to sense temperatures for a number of reasons. For example, this ability allows animals to avoid conditions that are either too hot or too cold, and to maintain an optimal body temperature. Most animals detect temperature via nerve cells called thermoreceptors. These sensors are often extremely sensitive and some can even detect changes in temperature of just a few thousandths of a degree per second. However, it is not clear how thermoreceptors detect temperature with such sensitivity, and many of the key molecules involved in this ability are unknown. In 2015, researchers discovered a class of highly sensitive nerve cells that allow fruit fly larvae to navigate away from unfavorably cool temperatures. Now, Ni, Klein et al. – who include some of the researchers involved in the 2015 work – have determined that these nerves use a combination of two receptors to detect cooling. Unexpectedly, these two receptors – Ionotropic Receptors called IR21a and IR25a – had previously been implicated in the detection of chemicals rather than temperature. IR25a was well-known to combine with other related receptors to detect an array of tastes and smells, while IR21a was thought to act in a similar way but had not been associated with detecting any specific chemicals. These findings demonstrate that the combination of IR21a and IR25a detects temperature instead. Together, these findings reveal a new molecular mechanism that underlies an animal’s ability to sense temperature. These findings also raise the possibility that other “orphan” Ionotropic Receptors, which have not been shown to detect any specific chemicals, might actually contribute to sensing temperature instead. Further work will explore this possibility and attempt to uncover precisely how IR21a and IR25a work to detect cool temperatures.

Previously, we demonstrated that visual and olfactory associative memories of Drosophila share mushroom body (MB) circuits (Vogt et al., 2014 ). Unlike for odor representation, the MB circuit for visual information has not been characterized. Here, we show that a small subset of MB Kenyon cells (KCs) selectively responds to visual but not olfactory stimulation. The dendrites of these atypical KCs form a ventral accessory calyx (vAC), distinct from the main calyx that receives olfactory input. We identified two types of visual projection neurons (VPNs) directly connecting the optic lobes and the vAC. Strikingly, these VPNs are differentially required for visual memories of color and brightness. The segregation of visual and olfactory domains in the MB allows independent processing of distinct sensory memories and may be a conserved form of sensory representations among insects.

In the paper, circuits obtained by superpositions over bases consisting of arbitrary subsets of piecewise-linear functions are studied, and criteria for the expressibility of an arbitrary continuous piecewise-linear function over such bases is proved. Estimates of the linear complexity and nonlinear dependence of the resulting circuits are given.

Peripheral and intraspinal feedback is required to shape and update the output of spinal networks that execute motor behavior. We report that lumbar dI2 spinal interneurons in chicks receive synaptic input from afferents and premotor neurons. These interneurons innervate contralateral premotor networks in the lumbar and brachial spinal cord, and their ascending projections innervate the cerebellum. These findings suggest that dI2 neurons function as interneurons in local lumbar circuits, are involved in lumbo-brachial coupling, and that part of them deliver peripheral and intraspinal feedback to the cerebellum. Silencing of dI2 neurons leads to destabilized stepping in posthatching day 8 hatchlings, with occasional collapses, variable step profiles, and a wide-base walking gait, suggesting that dI2 neurons may contribute to the stabilization of the bipedal gait.

Male sexual function in mammals is controlled by the brain neural circuits and the spinal cord centers located in the lamina X of the lumbar spinal cord (L3–L4). Recently, we reported that hypothalamic oxytocin neurons project to the lumbar spinal cord to activate the neurons located in the dorsal lamina X of the lumbar spinal cord (dXL) via oxytocin receptors, thereby facilitating male sexual activity. Sexual experiences can influence male sexual activity in rats. However, how this experience affects the brain–spinal cord neural circuits underlying male sexual activity remains unknown. Focusing on dXL neurons that are innervated by hypothalamic oxytocinergic neurons controlling male sexual function, we examined whether sexual experience affects such neural circuits. We found that >50% of dXL neurons were activated in the first ejaculation group and ~30% in the control and intromission groups in sexually naïve males. In contrast, in sexually experienced males, ~50% of dXL neurons were activated in both the intromission and ejaculation groups, compared to ~30% in the control group. Furthermore, sexual experience induced expressions of gastrin-releasing peptide and oxytocin receptors in the lumbar spinal cord. This is the first demonstration of the effects of sexual experience on molecular expressions in the neural circuits controlling male sexual activity in the spinal cord.

We identified the neurons comprising the Drosophila mushroom body (MB), an associative center in invertebrate brains, and provide a comprehensive map describing their potential connections. Each of the 21 MB output neuron (MBON) types elaborates segregated dendritic arbors along the parallel axons of ∼2000 Kenyon cells, forming 15 compartments that collectively tile the MB lobes. MBON axons project to five discrete neuropils outside of the MB and three MBON types form a feedforward network in the lobes. Each of the 20 dopaminergic neuron (DAN) types projects axons to one, or at most two, of the MBON compartments. Convergence of DAN axons on compartmentalized Kenyon cell–MBON synapses creates a highly ordered unit that can support learning to impose valence on sensory representations. The elucidation of the complement of neurons of the MB provides a comprehensive anatomical substrate from which one can infer a functional logic of associative olfactory learning and memory. One of the key goals of neuroscience is to understand how specific circuits of brain cells enable animals to respond optimally to the constantly changing world around them. Such processes are more easily studied in simpler brains, and the fruit fly—with its small size, short life cycle, and well-developed genetic toolkit—is widely used to study the genes and circuits that underlie learning and behavior. Fruit flies can learn to approach odors that have previously been paired with food, and also to avoid any odors that have been paired with an electric shock, and a part of the brain called the mushroom body has a central role in this process. When odorant molecules bind to receptors on the fly's antennae, they activate neurons in the antennal lobe of the brain, which in turn activate cells called Kenyon cells within the mushroom body. The Kenyon cells then activate output neurons that convey signals to other parts of the brain. It is known that relatively few Kenyon cells are activated by any given odor. Moreover, it seems that a given odor activates different sets of Kenyon cells in different flies. Because the association between an odor and the Kenyon cells it activates is unique to each fly, each fly needs to learn through its own experiences what a particular pattern of Kenyon cell activation means. Aso et al. have now applied sophisticated molecular genetic and anatomical techniques to thousands of different transgenic flies to identify the neurons of the mushroom body. The resulting map reveals that the mushroom body contains roughly 2200 neurons, including seven types of Kenyon cells and 21 types of output cells, as well as 20 types of neurons that use the neurotransmitter dopamine. Moreover, this map provides insights into the circuits that support odor-based learning. It reveals, for example, that the mushroom body can be divided into 15 anatomical compartments that are each defined by the presence of a specific set of output and dopaminergic neuron cell types. Since the dopaminergic neurons help to shape a fly's response to odors on the basis of previous experience, this organization suggests that these compartments may be semi-autonomous information processing units. In contrast to the rest of the insect brain, the mushroom body has a flexible organization that is similar to that of the mammalian brain. Elucidating the circuits that support associative learning in fruit flies should therefore make it easier to identify the equivalent mechanisms in vertebrate animals.

The Golgi apparatus is a central hub in the intracellular secretory pathway. By positioning in the specific intracellular region and transporting materials to spatially restricted compartments, the Golgi apparatus contributes to the cell polarity establishment and morphological specification in diverse cell types. In neurons, the Golgi apparatus mediates several essential steps of initial neural circuit formation during early brain development, such as axon-dendrite polarization, neuronal migration, primary dendrite specification, and dendritic arbor elaboration. Moreover, neuronal activity-dependent remodeling of the Golgi structure enables morphological changes in neurons, which provides the cellular basis of circuit reorganization during postnatal critical period. In this review, I summarize recent findings illustrating the unique Golgi positioning and its developmental dynamics in various types of neurons. I also discuss the upstream regulators for the Golgi positioning in neurons, and functional roles of the Golgi in neural circuit formation and reorganization. Elucidating how Golgi apparatus sculpts neuronal connectivity would deepen our understanding of the cellular/molecular basis of neural circuit development and plasticity.