Annual Review of Neuroscience

Spitzer, Nicholas C.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031204pmid: 28301776

Neurotransmitter switching is the gain of one neurotransmitter and the loss of another in the same neuron in response to chronic stimulation. Neurotransmitter receptors on postsynaptic cells change to match the identity of the newly expressed neurotransmitter. Neurotransmitter switching often appears to change the sign of the synapse from excitatory to inhibitory or from inhibitory to excitatory. In these cases, neurotransmitter switching and receptor matching thus change the polarity of the circuit in which they take place. Neurotransmitter switching produces up or down reversals of behavior. It is also observed in response to disease. These findings raise the possibility that neurotransmitter switching contributes to depression, schizophrenia, and other illnesses. Many early discoveries of the single gain or loss of a neurotransmitter may have been harbingers of neurotransmitter switching.

Vuong, Helen E.; Yano, Jessica M.; Fung, Thomas C.; Hsiao, Elaine Y.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031347pmid: 28301775

The microbiota is increasingly recognized for its ability to influence the development and function of the nervous system and several complex host behaviors. In this review, we discuss emerging roles for the gut microbiota in modulating host social and communicative behavior, stressor-induced behavior, and performance in learning and memory tasks. We summarize effects of the microbiota on host neurophysiology, including brain microstructure, gene expression, and neurochemical metabolism across regions of the amygdala, hippocampus, frontal cortex, and hypothalamus. We further assess evidence linking dysbiosis of the gut microbiota to neurobehavioral diseases, such as autism spectrum disorder and major depression, drawing upon findings from animal models and human trials. Finally, based on increasing associations between the microbiota, neurophysiology, and behavior, we consider whether investigating mechanisms underlying the microbiota-gut-brain axis could lead to novel approaches for treating particular neurological conditions.

Asahina, Kenta

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031240pmid: 28375770

In this review, I discuss current knowledge and outstanding questions on the neuromodulators that influence aggressive behavior of the fruit fly Drosophila melanogaster. I first present evidence that Drosophila exchange information during an agonistic interaction and choose appropriate actions based on this information. I then discuss the influence of several biogenic amines and neuropeptides on aggressive behavior. One striking characteristic of neuromodulation is that it can configure a neural circuit dynamically, enabling one circuit to generate multiple outcomes. I suggest a consensus effect of each neuromodulatory molecule on Drosophila aggression, as well as effects of receptor proteins where relevant data are available. Lastly, I consider neuromodulation in the context of strategic action choices during agonistic interactions. Genetic components of neuromodulatory systems are highly conserved across animals, suggesting that molecular and cellular mechanisms controlling Drosophila aggression can shed light on neural principles governing action choice during social interactions.

Peters, Andrew J.; Liu, Haixin; Komiyama, Takaki

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031407pmid: 28375768

The motor cortex is far from a stable conduit for motor commands and instead undergoes significant changes during learning. An understanding of motor cortex plasticity has been advanced greatly using rodents as experimental animals. Two major focuses of this research have been on the connectivity and activity of the motor cortex. The motor cortex exhibits structural changes in response to learning, and substantial evidence has implicated the local formation and maintenance of new synapses as crucial substrates of motor learning. This synaptic reorganization translates into changes in spiking activity, which appear to result in a modification and refinement of the relationship between motor cortical activity and movement. This review presents the progress that has been made using rodents to establish the motor cortex as an adaptive structure that supports motor learning.

Shenhav, Amitai; Musslick, Sebastian; Lieder, Falk; Kool, Wouter; Griffiths, Thomas L.; Cohen, Jonathan D.; Botvinick, Matthew M.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031526pmid: 28375769

In spite of its familiar phenomenology, the mechanistic basis for mental effort remains poorly understood. Although most researchers agree that mental effort is aversive and stems from limitations in our capacity to exercise cognitive control, it is unclear what gives rise to those limitations and why they result in an experience of control as costly. The presence of these control costs also raises further questions regarding how best to allocate mental effort to minimize those costs and maximize the attendant benefits. This review explores recent advances in computational modeling and empirical research aimed at addressing these questions at the level of psychological process and neural mechanism, examining both the limitations to mental effort exertion and how we manage those limited cognitive resources. We conclude by identifying remaining challenges for theoretical accounts of mental effort as well as possible applications of the available findings to understanding the causes of and potential solutions for apparent failures to exert the mental effort required of us.

Orger, Michael B.; de Polavieja, Gonzalo G.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-071714-033857pmid: 28375767

A great challenge in neuroscience is understanding how activity in the brain gives rise to behavior. The zebrafish is an ideal vertebrate model to address this challenge, thanks to the capacity, at the larval stage, for precise behavioral measurements, genetic manipulations, and recording and manipulation of neural activity noninvasively and at single-neuron resolution throughout the whole brain. These techniques are being further developed for application in freely moving animals and juvenile stages to study more complex behaviors including learning, decision making, and social interactions. We review some of the approaches that have been used to study the behavior of zebrafish and point to opportunities and challenges that lie ahead.

Howard, MacKenzie A.; Baraban, Scott C.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031250pmid: 28772100

The tragedy of epilepsy emerges from the combination of its high prevalence, impact upon sufferers and their families, and unpredictability. Childhood epilepsies are frequently severe, presenting in infancy with pharmaco-resistant seizures; are often accompanied by debilitating neuropsychiatric and systemic comorbidities; and carry a grave risk of mortality. Here, we review the most current basic science and translational research findings on several of the most catastrophic forms of pediatric epilepsy. We focus largely on genetic epilepsies and the research that is discovering the mechanisms linking disease genes to epilepsy syndromes. We also describe the strides made toward developing novel pharmacological and interventional treatment strategies to treat these disorders. The research reviewed provides hope for a complete understanding of, and eventual cure for, these childhood epilepsy syndromes.

Geuter, Stephan; Koban, Leonie; Wager, Tor D.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031132pmid: 28399689

Placebos have been used ubiquitously throughout the history of medicine. Expectations and associative learning processes are important psychological determinants of placebo effects, but their underlying brain mechanisms are only beginning to be understood. We examine the brain systems underlying placebo effects on pain, autonomic, and immune responses. The ventromedial prefrontal cortex (vmPFC), insula, amygdala, hypothalamus, and periaqueductal gray emerge as central brain structures underlying placebo effects. We argue that the vmPFC is a core element of a network that represents structured relationships among concepts, providing a substrate for expectations and a conception of the situationthe self in contextthat is crucial for placebo effects. Such situational representations enable multidimensional predictions, or priors, that are combined with incoming sensory information to construct percepts and shape motivated behavior. They influence experience and physiology via descending pathways to physiological effector systems, including the spinal cord and other peripheral organs.

Goedert, Michel; Eisenberg, David S.; Crowther, R. Anthony

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031153pmid: 28772101

A pathway from the natively unfolded microtubule-associated protein Tau to a highly structured amyloid fibril underlies human Tauopathies. This ordered assembly causes disease and represents the gain of toxic function. In recent years, evidence has accumulated to suggest that Tau inclusions form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of pathology is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighboring cells. In mice, the intracerebral injection of Tau inclusions induces the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Conformational differences between Tau aggregates from transgenic mouse brain and in vitro assembled recombinant protein account for the greater seeding potency of brain aggregates. Short fibrils constitute the major species of seed-competent Tau in the brains of transgenic mice. The existence of multiple human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist.

Mauss, Alex S.; Vlasits, Anna; Borst, Alexander; Feller, Marla

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031335pmid: 28418757

Images projected onto the retina of an animal eye are rarely still. Instead, they usually contain motion signals originating either from moving objects or from retinal slip caused by self-motion. Accordingly, motion signals tell the animal in which direction a predator, prey, or the animal itself is moving. At the neural level, visual motion detection has been proposed to extract directional information by a delay-and-compare mechanism, representing a classic example of neural computation. Neurons responding selectively to motion in one but not in the other direction have been identified in many systems, most prominently in the mammalian retina and the fly optic lobe. Technological advances have now allowed researchers to characterize these neurons upstream circuits in exquisite detail. Focusing on these upstream circuits, we review and compare recent progress in understanding the mechanisms that generate direction selectivity in the early visual system of mammals and flies.

Clites, Benjamin L.; Pierce, Jonathan T.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031312pmid: 28772099

Diverse animals ranging from worms and insects to birds and turtles perform impressive journeys using the magnetic field of the earth as a cue. Although major cellular and molecular mechanisms for sensing mechanical and chemical cues have been elucidated over the past three decades, the mechanisms that animals use to sense magnetic fields remain largely mysterious. Here we survey progress on the search for magnetosensory neurons and magnetosensitive molecules important for animal behaviors. Emphasis is placed on magnetosensation in insects and birds, as well as on the magnetosensitive neuron pair AFD in the nematode Caenorhabditis elegans. We also review conventional criteria used to define animal magnetoreceptors and suggest how approaches used to identify receptors for other sensory modalities may be adapted for magnetoreceptors. Finally, we discuss prospects for underutilized and novel approaches to identify the elusive magnetoreceptors in animals.

Fan, Xuelai; Wheatley, Elizabeth G.; Villeda, Saul A.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031357pmid: 28441118

The past two decades have seen remarkable progress in our understanding of the multifactorial drivers of hippocampal aging and cognitive decline. Recent findings have also raised the possibility of functional rejuvenation in the aged hippocampus. In this review, we aim to synthesize the mechanisms that drive hippocampal aging and evaluate critically the potential for rejuvenation. We discuss the functional changes in synaptic plasticity and regenerative potential of the aged hippocampus, followed by mechanisms of microglia aging, and assess the cross talk between these proaging processes. We then examine proyouth interventions that demonstrate significant promise in reversing age-related impairments in the hippocampus and, finally, attempt to look ahead toward novel therapeutics for brain aging.

Zilkha, Noga; Scott, Niv; Kimchi, Tali

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031447pmid: 28441117

Parental care is found in species across the animal kingdom, from small insects to large mammals, with a conserved purpose of increasing offspring survival. Yet enormous variability exists between different species and between the sexes in the pattern and level of parental investment. Here, we review the literature on the neurobiological mechanisms underlying maternal and paternal care, especially in rodents, and discuss the relationship between sex differences in behavior and sexual dimorphism in the brain. We argue that although several brain regions and circuits regulating parental care are shared by both sexes, some of the fundamental components comprising the maternal brain are innate and sex specific. Moreover, we suggest that a more comprehensive understanding of the underlying mechanisms can be achieved by expanding the methodological toolbox, applying ethologically relevant approaches such as nontraditional wild-derived animal models and complex seminatural experimental set-ups.

Denk, Franziska; Bennett, David L.; McMahon, Stephen B.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031121pmid: 28441116

Nerve growth factor (NGF) antagonism is on the verge of becoming a powerful analgesic treatment for numerous conditions, including osteoarthritis and lower back pain. This review summarizes the historical research, both fundamental and clinical, that led to our current understanding of NGF biology. We also discuss the surprising number of questions that remain about NGF expression patterns and NGF's various functions and interaction partners in relation to persistent pain and the potential side effects of anti-NGF therapy.

Kim, Susy M.; Su, Chih-Ying; Wang, Jing W.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031558pmid: 28441115

Animals are born with a rich repertoire of robust behaviors that are critical for their survival. However, innate behaviors are also highly adaptable to an animal's internal state and external environment. Neuromodulators, including biogenic amines, neuropeptides, and hormones, are released to signal changes in animals circumstances and serve to reconfigure neural circuits. This circuit flexibility allows animals to modify their behavioral responses according to environmental cues, metabolic demands, and physiological states. Aided by powerful genetic tools, researchers have made remarkable progress in Drosophila melanogaster to address how a myriad of contextual information influences the input-output relationship of hardwired circuits that support a complex behavioral repertoire. Here we highlight recent advances in understanding neuromodulation of Drosophila innate behaviors, with a special focus on feeding, courtship, aggression, and postmating behaviors.

Huk, Alexander C.; Katz, Leor N.; Yates, Jacob L.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031508pmid: 28772104

Over the past two decades, neurophysiological responses in the lateral intraparietal area (LIP) have received extensive study for insight into decision making. In a parallel manner, inferred cognitive processes have enriched interpretations of LIP activity. Because of this bidirectional interplay between physiology and cognition, LIP has served as fertile ground for developing quantitative models that link neural activity with decision making. These models stand as some of the most important frameworks for linking brain and mind, and they are now mature enough to be evaluated in finer detail and integrated with other lines of investigation of LIP function. Here, we focus on the relationship between LIP responses and known sensory and motor events in perceptual decision-making tasks, as assessed by correlative and causal methods. The resulting sensorimotor-focused approach offers an account of LIP activity as a multiplexed amalgam of sensory, cognitive, and motor-related activity, with a complex and often indirect relationship to decision processes. Our data-driven focus on multiplexing (and de-multiplexing) of various response components can complement decision-focused models and provides more detailed insight into how neural signals might relate to cognitive processes such as decision making.

Watabe-Uchida, Mitsuko; Eshel, Neir; Uchida, Naoshige

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031109pmid: 28441114

Dopamine neurons facilitate learning by calculating reward prediction error, or the difference between expected and actual reward. Despite two decades of research, it remains unclear how dopamine neurons make this calculation. Here we review studies that tackle this problem from a diverse set of approaches, from anatomy to electrophysiology to computational modeling and behavior. Several patterns emerge from this synthesis: that dopamine neurons themselves calculate reward prediction error, rather than inherit it passively from upstream regions; that they combine multiple separate and redundant inputs, which are themselves interconnected in a dense recurrent network; and that despite the complexity of inputs, the output from dopamine neurons is remarkably homogeneous and robust. The more we study this simple arithmetic computation, the knottier it appears to be, suggesting a daunting (but stimulating) path ahead for neuroscience more generally.

Zhang, Chi; Kolodkin, Alex L.; Wong, Rachel O.; James, Rebecca E.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031607pmid: 28460185

The retina is a tremendously complex image processor, containing numerous cell types that form microcircuits encoding different aspects of the visual scene. Each microcircuit exhibits a distinct pattern of synaptic connectivity. The developmental mechanisms responsible for this patterning are just beginning to be revealed. Furthermore, signals processed by different retinal circuits are relayed to specific, often distinct, brain regions. Thus, much work has focused on understanding the mechanisms that wire retinal axonal projections to their appropriate central targets. Here, we highlight recently discovered cellular and molecular mechanisms that together shape stereotypic wiring patterns along the visual pathway, from within the retina to the brain. Although some mechanisms are common across circuits, others play unconventional and circuit-specific roles. Indeed, the highly organized connectivity of the visual system has greatly facilitated the discovery of novel mechanisms that establish precise synaptic connections within the nervous system.

Angelucci, Alessandra; Bijanzadeh, Maryam; Nurminen, Lauri; Federer, Frederick; Merlin, Sam; Bressloff, Paul C.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031418pmid: 28471714

Surround modulation (SM) is a fundamental property of sensory neurons in many species and sensory modalities. SM is the ability of stimuli in the surround of a neuron's receptive field (RF) to modulate (typically suppress) the neuron's response to stimuli simultaneously presented inside the RF, a property thought to underlie optimal coding of sensory information and important perceptual functions. Understanding the circuit and mechanisms for SM can reveal fundamental principles of computations in sensory cortices, from mouse to human. Current debate is centered over whether feedforward or intracortical circuits generate SM, and whether this results from increased inhibition or reduced excitation. Here we present a working hypothesis, based on theoretical and experimental evidence, that SM results from feedforward, horizontal, and feedback interactions with local recurrent connections, via synaptic mechanisms involving both increased inhibition and reduced recurrent excitation. In particular, strong and balanced recurrent excitatory and inhibitory circuits play a crucial role in the computation of SM.

Lozano, Andres M.; Hutchison, William D.; Kalia, Suneil K.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-070815-013906pmid: 28772097

Modern functional neurosurgery for movement disorders such as Parkinson's disease, tremor, and dystonia involves the placement of focal lesions or the application of deep brain stimulation (DBS) within circuits that modulate motor function. Precise targeting of these motor structures can be further refined by the use of electrophysiological approaches. In particular, microelectrode recordings enable the delineation of neuroanatomic structures. In the course of these operations, there is an opportunity not only to map basal ganglia structures but also to gain insights into how disturbances in neural activity produce movement disorders. In this review, we aim to highlight what the field has uncovered thus far about movement disorders through DBS. The work to date lays the foundation for future studies that will shed further light on dysfunctional circuits mediating diseases of the nervous system and how we might modulate these circuits therapeutically.

Dhawale, Ashesh K.; Smith, Maurice A.; lveczky, Bence P.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031548pmid: 28489490

Trial-to-trial variability in the execution of movements and motor skills is ubiquitous and widely considered to be the unwanted consequence of a noisy nervous system. However, recent studies have suggested that motor variability may also be a feature of how sensorimotor systems operate and learn. This view, rooted in reinforcement learning theory, equates motor variability with purposeful exploration of motor space that, when coupled with reinforcement, can drive motor learning. Here we review studies that explore the relationship between motor variability and motor learning in both humans and animal models. We discuss neural circuit mechanisms that underlie the generation and regulation of motor variability and consider the implications that this work has for our understanding of motor learning.

Seabrook, Tania A.; Burbridge, Timothy J.; Crair, Michael C.; Huberman, Andrew D.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-071714-033842pmid: 28772103

Vision is the sense humans rely on most to navigate the world, make decisions, and perform complex tasks. Understanding how humans see thus represents one of the most fundamental and important goals of neuroscience. The use of the mouse as a model for parsing how vision works at a fundamental level started approximately a decade ago, ushered in by the mouse's convenient size, relatively low cost, and, above all, amenability to genetic perturbations. In the course of that effort, a large cadre of new and powerful tools for in vivo labeling, monitoring, and manipulation of neurons were applied to this species. As a consequence, a significant body of work now exists on the architecture, function, and development of mouse central visual pathways. Excitingly, much of that work includes causal testing of the role of specific cell types and circuits in visual perception and behaviorsomething rare to find in studies of the visual system of other species. Indeed, one could argue that more information is now available about the mouse visual system than any other sensory system, in any species, including humans. As such, the mouse visual system has become a platform for multilevel analysis of the mammalian central nervous system generally. Here we review the mouse visual system structure, function, and development literature and comment on the similarities and differences between the visual system of this and other model species. We also make it a point to highlight the aspects of mouse visual circuitry that remain opaque and that are in need of additional experimentation to enrich our understanding of how vision works on a broad scale.

Lazzerini Ospri, Lorenzo; Prusky, Glen; Hattar, Samer

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031324pmid: 28525301

The discovery of a third type of photoreceptors in the mammalian retina, intrinsically photosensitive retinal ganglion cells (ipRGCs), has had a revolutionary impact on chronobiology. We can now properly account for numerous non-vision-related functions of light, including its effect on the circadian system. Here, we give an overview of ipRGCs and their function as it relates specifically to mood and biological rhythms. Although circadian disruptions have been traditionally hypothesized to be the mediators of light's effects on mood, here we present an alternative model that dispenses with assumptions of causality between the two phenomena and explains mood regulation by light via another ipRGC-dependent mechanism.

Hennequin, Guillaume; Agnes, Everton J.; Vogels, Tim P.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031005pmid: 28598717

Inhibitory neurons, although relatively few in number, exert powerful control over brain circuits. They stabilize network activity in the face of strong feedback excitation and actively engage in computations. Recent studies reveal the importance of a precise balance of excitation and inhibition in neural circuits, which often requires exquisite fine-tuning of inhibitory connections. We review inhibitory synaptic plasticity and its roles in shaping both feedforward and feedback control. We discuss the necessity of complex, codependent plasticity mechanisms to build nontrivial, functioning networks, and we end by summarizing experimental evidence of such interactions.

Foster, David J.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-072116-031538pmid: 28772098

Hippocampal place cells take part in sequenced patterns of reactivation after behavioral experience, known as replay. Since replay was first reported, nearly 20 years ago, many new results have been found, necessitating revision of the original interpretations. We review some of these results with a focus on the phenomenology of replay.

Zylberberg, Joel; Strowbridge, Ben W.

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-070815-014006pmid: 28772102

A commonly observed neural correlate of working memory is firing that persists after the triggering stimulus disappears. Substantial effort has been devoted to understanding the many potential mechanisms that may underlie memory-associated persistent activity. These rely either on the intrinsic properties of individual neurons or on the connectivity within neural circuits to maintain the persistent activity. Nevertheless, it remains unclear which mechanisms are at play in the many brain areas involved in working memory. Herein, we first summarize the palette of different mechanisms that can generate persistent activity. We then discuss recent work that asks which mechanisms underlie persistent activity in different brain areas. Finally, we discuss future studies that might tackle this question further. Our goal is to bridge between the communities of researchers who study either single-neuron biophysical, or neural circuit, mechanisms that can generate the persistent activity that underlies working memory.

Lein, Ed S.; Belgard, T. Grant; Hawrylycz, Michael; Molnr, Zoltn

2017 Annual Review of Neuroscience

doi: 10.1146/annurev-neuro-070815-013858pmid: 28661727

The cerebral cortex is the source of our most complex cognitive capabilities and a vulnerable target of many neurological and neuropsychiatric disorders. Transcriptomics offers a new approach to understanding the cortex at the level of its underlying genetic code, and rapid technological advances have propelled this field to the high-throughput study of the complete set of transcribed genes at increasingly fine resolution to the level of individual cells. These tools have revealed features of the genetic architecture of adult cortical areas, layers, and cell types, as well as spatiotemporal patterning during development. This has allowed a fresh look at comparative anatomy as well, illustrating surprisingly large differences between mammals while at the same time revealing conservation of some features from avians to mammals. Finally, transcriptomics is fueling progress in understanding the causes of neurodevelopmental diseases such as autism, linking genetic association studies to specific molecular pathways and affected brain regions.