The glucocorticoid hormones cortisol and corticosterone coordinate circadian events and are master regulators of the stress response. These actions of the glucocorticoids are mediated by mineralocorticoid receptors (NR3C2, or MRs) and glucocorticoid receptors (NR3C1, or GRs). MRs bind the natural glucocorticoids cortisol and corticosterone with a 10-fold higher affinity than GRs. The glucocorticoids are inactivated only in the nucleus tractus solitarii (NTS), rendering the NTS-localized MRs aldosterone-selective and involved in regulation of salt appetite. Everywhere else in the brain MRs are glucocorticoid-preferring. MR and GR are transcription factors involved in gene regulation but recently were also found to mediate rapid non-genomic actions. Genomic MRs, with a predominant localization in limbic circuits, are important for the threshold and sensitivity of the stress response system. Non-genomic MRs promote appraisal processes, memory retrieval, and selection of coping style. Activation of GRs makes energy substrates available and dampens initial defense reactions. In the brain, GR activation enhances appetitive- and fear-motivated behavior and promotes memory storage of the selected coping style in preparation of the future. Thus, MRs and GRs complement each other in glucocorticoid control of the initiation and termination of the stress response, suggesting that the balance in MR- and GR-mediated actions is crucial for homeostasis and health.
Mineralocorticoid Receptors and Glucocorticoid Receptors in HPA Stress Responses During Coping and Adaptation
Edo Ronald de Kloet and Marian Joëls
Developmental Neurobiology of Anxiety and Related Disorders
Emily M. Cohodes and Dylan G. Gee
The majority of anxiety disorders emerge during childhood and adolescence, a developmental period characterized by dynamic changes in frontolimbic circuitry. Frontolimbic circuitry plays a key role in fear learning and has been a focus of recent efforts to understand the neurobiological correlates of anxiety disorders across development. Although less is known about the neurobiological underpinnings of anxiety disorders in youth than in adults, studies of pediatric anxiety have revealed alterations in both the structure and function of frontolimbic circuitry. The amygdala, prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampus contribute to fear conditioning and extinction, and interactions between these regions have been implicated in anxiety during development. Specifically, children and adolescents with anxiety disorders show altered amygdala volumes and exhibit heightened amygdala activation in response to neutral and fearful stimuli, with the magnitude of signal change in amygdala reactivity corresponding to the severity of symptomatology. Abnormalities in the PFC and ACC and their connections with the amygdala may reflect weakened top-down control or compensatory efforts to regulate heightened amygdala reactivity associated with anxiety. Taken together, alterations in frontolimbic connectivity are likely to play a central role in the etiology and maintenance of anxiety disorders. Future studies should aim to translate the emerging understanding of the neurobiological bases of pediatric anxiety disorders to optimize clinical interventions for youth.
Xenacoelomorpha Nervous Systems
Pedro Martínez, Volker Hartenstein, and Simon G. Sprecher
The emergence and diversification of bilateral animals are among the most important transitions in the history of life on our planet. A proper understanding of the evolutionary process will derive from answering such key questions as, how did complex body plans arise in evolutionary time, and how are complex body plans “encoded” in the genome? the first step is focusing on the earliest stages in bilaterian evolution, probing the most elusive organization of the genomes and microscopic anatomy in basally branching taxa, which are currently assembled in a clade named Xenacoelomorpha. This enigmatic phylum is composed of three major taxa: acoel flatworms, nemertodermatids, and xenoturbellids. Interestingly, the constituent species of this clade have an enormously varied set of morphologies; not just the obvious external features but also their tissues present a high degree of constructional variation. This interesting diversity of morphologies (a clear example being the nervous system, with animals showing different degrees of compaction) provides a unique system in which to address outstanding questions regarding the parallel evolution of genomes and the many morphological characters encoded by them. A systematic exploration of the anatomy of members of these three taxa, employing immunohistochemistry, in situ hybridization, and high-throughput transmission electron microscopy, will provide the reference framework necessary to understand the changing roles of genes and gene networks during the evolution of xenacoelomorph morphologies and, in particular, of their nervous systems.
Axon Regeneration in Peripheral Nerves
Despite the intrinsically greater capacity for axons to regenerate in injured peripheral nerves than after injury to the central nervous system, functional recovery after most nerve injuries is very poor. A need for novel treatments that will enhance axon regeneration and improve recovery is substantial. Several such experimental treatments have been studied, each based on part of the stereotypical cellular responses that follow a nerve injury. Genetic manipulations of Schwann cells that have transformed from a myelinating to a repair phenotype that either increase their production of axon growth-promoting molecules, decrease production of inhibitors, or both result in enhanced regeneration. Local or systemic application of these molecules or small molecule mimetics of them also will promote regeneration. The success of treatments that stimulate axonal protein synthesis at the site of the nerve injury and in the growing axons, an early and important response to axon injury, is significant, as is that of manipulations of the types of immune cells that migrate into the injury site or peripheral ganglia. Modifications of the extracellular matrix through which the regenerating axons course, including the stimulation of new blood vessel formation, promotes the navigation of nascent regenerating neurites past the injury site, resulting in greater axon regeneration. Experimental induction of expression of regeneration associated gene activity in the cell bodies of the injured neurons is especially useful when regenerating axons must regenerate over long distances to reinnervate targets. The consistently most effective experimental approach to improving axon regeneration in peripheral nerves has been to increase the activity of the injured neurons, either through electrical, optical, or chemogenetic stimulation or through exercise. These activity-dependent experimental therapies show greatest promise for translation to use in patients.
Neuroendocrine and Neuroimmune Mechanisms Regulating the Blood-Brain Barrier
Divine C. Nwafor, Allison L. Brichacek, Sreeparna Chakraborty, Catheryne A. Gambill, Stanley A. Benkovic, and Candice M. Brown
The blood-brain barrier (BBB) is a dynamic structural interface between the brain and periphery that plays a critical function in maintaining cerebral homeostasis. Over the past two decades, technological advances have improved our understanding of the neuroimmune and neuroendocrine mechanisms that regulate a healthy BBB. The combination of biological sex, sex steroids, age, coupled with innate and adaptive immune components orchestrates the crosstalk between the BBB and the periphery. Likewise, the BBB also serves as a nexus within the hypothalamic-pituitary-adrenal (HPA) and gut-brain-microbiota axes. Compromised BBB integrity permits the entry of bioactive molecules, immune cells, microbes, and other components that migrate into the brain parenchyma and compromise neuronal function. A paramount understanding of the mechanisms that determine the bidirectional crosstalk between the BBB and immune and endocrine pathways has become increasingly important for implementation of therapeutic strategies to treat a number of neurological disorders that are significantly impacted by the BBB. Examples of these disorders include multiple sclerosis, Alzheimer’s disease, stroke, epilepsy, and traumatic brain injury.
BDNF-Induced Plasticity of Spinal Circuits Underlying Pain and Learning
Sandra M. Garraway
Understanding of the various types of plasticity that occur in the spinal cord, as well as understanding of spinal cord functions, has vastly improved over the past 50 years, mainly due to an increase in the number of research studies and review articles on the subject. It is now understood that the spinal cord is not merely a passive conduit of neural impulses. Instead, the spinal cord can independently execute complex functions. Numerous experimental approaches have been utilized for more targeted exploration of spinal cord functions. For example, isolating the spinal cord from supraspinal influences has been used to demonstrate that simple forms of learning can be performed by spinal neuronal networks. Moreover, reduced preparations, such as acute spinal cord slices, have been used to show that spinal neurons undergo different types of modulation, including activity-dependent synaptic modification. Most spinal cord processes, ranging from integration of incoming sensory input to execution of locomotor outputs, involve plasticity. Nociceptive processing that leads to pain and spinal learning is an example of plasticity that is well-studied in the spinal cord. At the neural level, both processes involve an interplay of cellular mediators, which include glutamate receptors, protein kinases, and growth factors. The neurotrophin brain-derived neurotrophic factor (BDNF) has also been implicated in these processes, specifically as a promoter of both pro-nociception and spinal learning mechanisms. Interestingly, the role of BDNF in mediating spinal plasticity can be altered by injury. The literature spanning approximately 5 decades is reviewed and the role of BDNF is discussed in mediating cellular plasticity underlying pain processing and learning within the spinal cord.
Insect Navigation: Neural Basis to Behavior
Navigation is the ability of animals to move through their environment in a planned manner. Different from directed but reflex-driven movements, it involves the comparison of the animal’s current heading with its intended heading (i.e., the goal direction). When the two angles don’t match, a compensatory steering movement must be initiated. This basic scenario can be described as an elementary navigational decision. Many elementary decisions chained together in specific ways form a coherent navigational strategy. With respect to navigational goals, there are four main forms of navigation: explorative navigation (exploring the environment for food, mates, shelter, etc.); homing (returning to a nest); straight-line orientation (getting away from a central place in a straight line); and long-distance migration (seasonal long-range movements to a location such as an overwintering place). The homing behavior of ants and bees has been examined in the most detail. These insects use several strategies to return to their nest after foraging, including path integration, route following, and, potentially, even exploit internal maps. Independent of the strategy used, insects can use global sensory information (e.g., skylight cues), local cues (e.g., visual panorama), and idiothetic (i.e., internal, self-generated) cues to obtain information about their current and intended headings. How are these processes controlled by the insect brain? While many unanswered questions remain, much progress has been made in recent years in understanding the neural basis of insect navigation. Neural pathways encoding polarized light information (a global navigational cue) target a brain region called the central complex, which is also involved in movement control and steering. Being thus placed at the interface of sensory information processing and motor control, this region has received much attention recently and emerged as the navigational “heart” of the insect brain. It houses an ordered array of head-direction cells that use a wide range of sensory information to encode the current heading of the animal. At the same time, it receives information about the movement speed of the animal and thus is suited to compute the home vector for path integration. With the help of neurons following highly stereotypical projection patterns, the central complex theoretically can perform the comparison of current and intended heading that underlies most navigation processes. Examining the detailed neural circuits responsible for head-direction coding, intended heading representation, and steering initiation in this brain area will likely lead to a solid understanding of the neural basis of insect navigation in the years to come.
Neural Oscillations in Audiovisual Language and Communication
Linda Drijvers and Sara Mazzini
How do neural oscillations support human audiovisual language and communication? Considering the rhythmic nature of audiovisual language, in which stimuli from different sensory modalities unfold over time, neural oscillations represent an ideal candidate to investigate how audiovisual language is processed in the brain. Modulations of oscillatory phase and power are thought to support audiovisual language and communication in multiple ways. Neural oscillations synchronize by tracking external rhythmic stimuli or by re-setting their phase to presentation of relevant stimuli, resulting in perceptual benefits. In particular, synchronized neural oscillations have been shown to subserve the processing and the integration of auditory speech, visual speech, and hand gestures. Furthermore, synchronized oscillatory modulations have been studied and reported between brains during social interaction, suggesting that their contribution to audiovisual communication goes beyond the processing of single stimuli and applies to natural, face-to-face communication. There are still some outstanding questions that need to be answered to reach a better understanding of the neural processes supporting audiovisual language and communication. In particular, it is not entirely clear yet how the multitude of signals encountered during audiovisual communication are combined into a coherent percept and how this is affected during real-world dyadic interactions. In order to address these outstanding questions, it is fundamental to consider language as a multimodal phenomenon, involving the processing of multiple stimuli unfolding at different rhythms over time, and to study language in its natural context: social interaction. Other outstanding questions could be addressed by implementing novel techniques (such as rapid invisible frequency tagging, dual-electroencephalography, or multi-brain stimulation) and analysis methods (e.g., using temporal response functions) to better understand the relationship between oscillatory dynamics and efficient audiovisual communication.
Deep Neural Networks in Computational Neuroscience
Tim C. Kietzmann, Patrick McClure, and Nikolaus Kriegeskorte
The goal of computational neuroscience is to find mechanistic explanations of how the nervous system processes information to give rise to cognitive function and behavior. At the heart of the field are its models, that is, mathematical and computational descriptions of the system being studied, which map sensory stimuli to neural responses and/or neural to behavioral responses. These models range from simple to complex. Recently, deep neural networks (DNNs) have come to dominate several domains of artificial intelligence (AI). As the term “neural network” suggests, these models are inspired by biological brains. However, current DNNs neglect many details of biological neural networks. These simplifications contribute to their computational efficiency, enabling them to perform complex feats of intelligence, ranging from perceptual (e.g., visual object and auditory speech recognition) to cognitive tasks (e.g., machine translation), and on to motor control (e.g., playing computer games or controlling a robot arm). In addition to their ability to model complex intelligent behaviors, DNNs excel at predicting neural responses to novel sensory stimuli with accuracies well beyond any other currently available model type. DNNs can have millions of parameters, which are required to capture the domain knowledge needed for successful task performance. Contrary to the intuition that this renders them into impenetrable black boxes, the computational properties of the network units are the result of four directly manipulable elements: input statistics, network structure, functional objective, and learning algorithm. With full access to the activity and connectivity of all units, advanced visualization techniques, and analytic tools to map network representations to neural data, DNNs represent a powerful framework for building task-performing models and will drive substantial insights in computational neuroscience.
Achieving Adaptive Plasticity in the Spinal Cord
James W. Grau
The traditional view of central nervous system function presumed that learning is the province of the brain. From this perspective, the spinal cord functions primarily as a conduit for incoming/outgoing neural impulses, capable of organizing simple reflexes but incapable of learning. Research has challenged this view, demonstrating that neurons within the spinal cord, isolated from the brain by means of a spinal cut (transection), can encode environmental relations and that this experience can have a lasting effect on function. The exploration of this issue has been informed by work in the learning literature that establishes the behavioral criteria and work within the pain literature that has shed light on the underlying neurobiological mechanisms. Studies have shown that spinal systems can exhibit single stimulus learning (habituation and sensitization) and are sensitive to both stimulus–stimulus (Pavlovian) and response–outcome (instrumental) relations. Regular environmental relations can both bring about an alteration in the performance of a spinally mediated response and impact the capacity to learn in future situations. The latter represents a form of behavioral metaplasticity. At the neurobiological level, neurons within the central gray matter of the spinal cord induce lasting alterations by engaging the NMDA receptor and signal pathways implicated in brain-dependent learning and memory. Of particular clinical importance, uncontrollable/unpredictable pain (nociceptive) input can induce a form of neural over-excitation within the dorsal horn (central sensitization) that impairs adaptive learning. Pain input after a contusion injury can increase tissue loss and undermines long-term recovery.