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Jill E. Schneider
During the evolution of animals, survival and reproduction depended upon mechanisms that maintained internal homeostasis in the face of environmental change. These environmental changes included fluctuations in ambient temperature, food availability, humidity, day length, and population density. Most, if not all, of these variables have effects on the availability of energy, and most vertebrate species have mechanisms that sense energy availability and adjust behavioral priorities accordingly. For example, when the availability of food and potential mating partners is stable and abundant, brain mechanisms often inhibit ingestive behavior, increase energy expenditure, and give priority to courtship and mating. In response to severe energy shortages, brain mechanisms are likely to stimulate foraging, food hoarding, and overeating. These same deficits often delay reproductive development or inhibit adult reproductive behavior. Such adaptations involve the integration of sensory signals with peripheral hormone signals and central effectors, and they are key to understanding health and disease, particularly obesity, eating disorders, and diabetes.
The link between energy balance and reproduction recurs repeatedly, whether in the context of the sensory-somatic system, the autonomic nervous system, or the neuroendocrine cascades. Peripheral signals that are detected by receptors on vagal and splanchnic nerves are relayed to the caudal hindbrain. This brain area contains the effectors for peripheral hormone secretion and for chewing and swallowing, and this same brain area contains receptors for humoral and metabolic signals from peripheral circulation. The caudal hindbrain is therefore a strong candidate for integration of multiple signals that control the initiation of meals, meal size, energy storage, and energy expenditure, including the energy expended on reproduction. There are some differences between the reproductive and ingestive mechanisms, but there are also many striking similarities. There are still gaps in our knowledge about the nature and location of metabolic receptors and the pathways to their effectors. Some of the most promising research is designed to shed light on how hormonal signals might be enhanced or modulated by the peripheral energetic condition (e.g., the level of oxidizable metabolic fuels).
Richard L. Doty
Decreased ability to smell is common in older persons. Some demonstrable smell loss is present in more than 50% of those 65 to 80 years of age, with up to 10% having no smell at all (anosmia). Over the age of 80, 75% exhibit some loss with up to 20% being totally anosmic. The causes of these decrements appear multifactorial and likely include altered intranasal airflow patterns, cumulative damage to the olfactory receptor cells from viruses and other environmental insults, decrements in mucosal metabolizing enzymes, closure of the cribriform plate foramina through which olfactory receptor cells axons project to the brain, loss of selectivity of receptor cells to odorants, and altered neurotransmission, including that exacerbated in some age-related neurodegenerative diseases.
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.
Caleigh Guoynes and Catherine Marler
How hormones and neuromodulators initiate and maintain paternal care is important for understanding the evolution of paternal care and the plasticity of the social brain. The focus here is on mammalian paternal behavior in rodents, non-human primates and humans. Only 5% of mammalian species express paternal care, and many of those species likely evolved the behavior convergently. This means that there is a high degree of variability in how hormones and neuromodulators shape paternal care across species. Important factors to consider include social experience (alloparental care, mating, pair bonding, raising a previous litter), types of care expressed (offspring protection, providing and sharing food, socio-cognitive development), and timing of hormonal changes (after mating, during gestation, after contact with offspring). The presence or absence of infanticide towards offspring prior to mating may also be a contributor, especially in rodents. Taking these important factors into account, we have found some general trends across species. (1) Testosterone and progesterone tend to be negatively correlated with paternal care but promote offspring defense in some species. The most evidence for a positive association between paternal care and testosterone have appeared in rodents. (2) Prolactin, oxytocin, corticosterone, and cortisol tend to be positively correlated. (3) Estradiol and vasopressin are likely nuclei specific—with some areas having a positive correlation with paternal care and others having a negative association. Some mechanisms appear to be coopted from females and others appear to have evolved independently. Overall, the neuroendocrine system seems especially important for mediating environmental influences on paternal behavior.
Romuald Nargeot and Alexis Bédécarrats
Euopisthobranchia (Aplysia), Nudipleura (Tritonia, Hermissenda, Pleurobranchaea), and Panpulmonata (Lymnaea, Helix, Limax) gastropod mollusks exhibit a variety of reflex, rhythmic, and motivated behaviors that can be modified by elementary forms of learning and memory. The relative simplicity of their nervous systems and behavioral repertoires has allowed the uncovering of processes of neuronal and synaptic plasticity underlying non-associative learning, such as habituation, sensitization, and different forms of associative learning, such as classical and operant conditioning. Decades of work on these simpler and accessible animal systems have almost uniquely yielded an understanding into the mechanistic basis of learning and memory spanning behavior, neuronal circuitry, and molecules. Given the conservative nature of evolutionary processes, the mechanisms deciphered have also provided valuable insights into the neural basis of learning and memory in other metazoans, including higher vertebrates.
Paul Benjamin and Michael Crossley
It is conceptually reasonable to explore how the evolution of behavior involves changes in neural circuitry. Progress in determining this evolutionary relationship has been limited in neuroscience because of difficulties in identifying individual neurons that contribute to the evolutionary development of behaviors across species. However, the results from the feeding systems of gastropod mollusks provide evidence for this concept of co-evolution because the evolution of different types of feeding behaviors in this diverse group of mollusks is mirrored by species-specific changes in neural circuitry. The evolution of feeding behaviors involves changes in the motor actions that allow diverse food items to be acquired and ingested. The evolution in neural control accompanies this variation in food and the associated changes in flexibility of feeding behaviors. This is present in components of the feeding network that are involved in decision making, rhythm generation, and behavioral switching but is absent in background mechanisms that are conserved across species, such as those controlling arousal state. These findings show how evolutionary changes, even at the single neuron level, closely reflect the details of behavioral evolution.
Mineralocorticoid Receptors and Glucocorticoid Receptors in HPA Stress Responses During Coping and Adaptation
Edo Ronald de Kloet and Marian Joëls
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.
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.
Eliot A. Brenowitz
Animals produce communication signals to attract mates and deter rivals during their breeding season. The coincidence in timing results from the modulation of signaling behavior and neural activity by sex steroid hormones associated with reproduction. Adrenal steroids can influence signaling for aggressive interactions outside the breeding season. Androgenic and estrogenic hormones act on brain circuits that regulate the motivation to produce and respond to signals, the motor production of signals, and the sensory perception of signals. Signal perception, in turn, can stimulate gonadal development.
Asymmetry of bilateral visual and auditory sensors has functional advantages for depth visual perception and localization of auditory signals, respectively. In order to detect the spatial distribution of an odor, bilateral olfactory organs may compare side differences of odor intensity and timing by using a simultaneous sampling mechanism; alternatively, they may use a sequential sampling mechanism to compare spatial and temporal input detected by one or several chemosensors. Extensive research on strategies and mechanisms necessary for odor source localization has been focused mainly on invertebrates. Several recent studies in mammals such as moles, rodents, and humans suggest that there is an evolutionary advantage in using stereo olfaction for successful navigation towards an odor source. Smelling in stereo or a three-dimensional olfactory space may significantly reduce the time to locate an odor source; this quality provides instantaneous information for both foraging and predator avoidance. However, since mammals are capable of finding odor sources and tracking odor trails with one sensor side blocked, they may use an intriguing temporal mechanism to compare odor concentration from sniff to sniff. A particular focus of this article is attributed to differences between insects and mammals regarding the use of unilateral versus bilateral chemosensors for odor source localization.
Chuan-Chin Chiao and Roger T. Hanlon
Visual camouflage change is a hallmark of octopus, squid, and cuttlefish and serves as their primary defense against predators. They can change their total body appearance in less than a second due to one principal feature: every aspect of this sensorimotor system is neurally refined for speed. Cephalopods live in visually complex environments such as coral reefs and kelp forests and use their visual perception of backgrounds to rapidly decide which camouflage pattern to deploy. Counterintuitively, cuttlefish have evolved a small number of pattern designs to achieve camouflage: Uniform, Mottle, and Disruptive, each with variation. The expression of these body patterns is based on several fundamental scene features. In cuttlefish, there appear to be several “visual assessment shortcuts” that enable camouflage patterning change in as little as 125 milliseconds. Neural control of the dynamic body patterning of cephalopods appears to be organized hierarchically via a set of lobes within the brain, including the optic lobes, the lateral basal lobes, and the anterior/posterior chromatophore lobes. The motor output of the central nervous system (CNS) in terms of the skin patterns that are produced is under sophisticated neural control of chromatophores, iridophores, and three-dimensional skin papillae. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. This coloration system, often referred to as rapid neural polyphenism, is unique in the animal kingdom and can be explained and interpreted in the context of sensory and behavioral ecology.
Corinna Darian-Smith and Karen Fisher
Spinal cord injury (SCI) affects well over a million people in the United States alone, and its personal and societal costs are huge. This article provides a current overview of the organization of somatosensory and motor pathways, in the context of hand/paw function in nonhuman primate and rodent models of SCI. Despite decades of basic research and clinical trials, therapeutic options remain limited. This is largely due to the fact that (i) spinal cord structure and function is very complex and still poorly understood, (ii) there are many species differences which can make translation from the rodent to primate difficult, and (iii) we are still some way from determining the detailed multilevel pathway responses affecting recovery. There has also been little focus, until recently, on the sensory pathways involved in SCI and recovery, which are so critical to hand function and the recovery process. The potential for recovery in any individual depends on many factors, including the location and size of the injury, the extent of sparing of fiber tracts, and the post-injury inflammatory response. There is also a progression of change over the first weeks and months that must be taken into account when assessing recovery. There are currently no good biomarkers of recovery, and while axon terminal sprouting is frequently used in the experimental setting as an indicator of circuit remodeling and “recovery,” the correlation between sprouting and functional recovery deserves scrutiny.
Judith M. Ford, Holly K. Hamilton, and Alison Boos
Auditory verbal hallucinations (AVH), also referred to as “hearing voices,” are vivid perceptions of speech that occur in the absence of any corresponding external stimulus but seem very real to the voice hearer. They are experienced by the majority of people with schizophrenia, less frequently in other psychiatric and neurological conditions, and are relatively rare in the general population. Because antipsychotic medications are not always successful in reducing the severity or frequency of AVH, a better understanding is needed of their neurobiological basis, which may ultimately lead to more precise treatment targets.
What voices say and how the voices sound, or their phenomenology, varies widely within and across groups of people who hear them. In help-seeking populations, such as people with schizophrenia, the voices tend to be threatening and menacing, typically spoken in a non-self-voice, often commenting and sometimes commanding the voice hearers to do things they would not otherwise do. In psychotic populations, voices differ from normal inner speech by being unbidden and unintended, co-opting the voice hearer’s attention. In healthy voice-hearing populations, voices are not typically distressing nor disabling, and are sometimes comforting and reassuring. Regardless of content and valence, voices tend to activate some speech and language areas of the brain. Efforts to silence these brain areas with neurostimulation have had mixed success in reducing the frequency and salience of voices. Progress with this treatment approach would likely benefit from more precise anatomical targets and more precisely dosed neurostimulation.
Neural mechanisms that may underpin the experience of voices are being actively investigated and include mechanisms enabling context-based predictions and distinctions between experiences coming from self and other. Both these mechanisms can be studied in non-human animal “models” and both can provide new anatomical targets for neurostimulation.
Dayna L. Averitt, Rebecca S. Hornung, and Anne Z. Murphy
The modulatory influence of sex hormones on acute pain, chronic pain disorders, and pain management has been reported for over seven decades. The effect of hormones on pain is clearly evidenced by the multitude of chronic pain disorders that are more common in women, such as headache and migraine, temporomandibular joint disorder, irritable bowel syndrome, chronic pelvic pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis. Several of these pain disorders also fluctuate in pain intensity over the menstrual cycle, including headache and migraine and temporomandibular joint disorder. The sex steroid hormones (estrogen, progesterone, and testosterone) as well as some peptide hormones (prolactin, oxytocin, and vasopressin) have been linked to pain by both clinical and preclinical research. Progesterone and testosterone are widely accepted as having protective effects against pain, while the literature on estrogen reports both exacerbation and attenuation of pain. Prolactin is reported to trigger pain, while oxytocin and vasopressin have analgesic properties in both sexes. Only in the last two decades have neuroscientists begun to unravel the complex anatomical and molecular mechanisms underlying the direct effects of sex hormones and mechanisms have been reported in both the central and peripheral nervous systems. Mechanisms include directly or indirectly targeting receptors and ion channels on sensory neurons, activating pain excitatory or pain inhibitory centers in the brain, and reducing inflammatory mediators. Despite recent progress, there remains significant controversy and challenges in the field and the seemingly pleiotropic role estrogen plays on pain remains ambiguous. Current knowledge of the effects of sex hormones on pain has led to the burgeoning of gender-based medicine, and gaining further insight will lead to much needed improvement in pain management in women.
Danielle S. Stolzenberg, Kimberly L. Hernandez-D'Anna, Oliver J. Bosch, and Joseph S. Lonstein
For female mammals, caring for young until weaning or even longer is an extension of the reproductive burden that begins at insemination. Given the high price females potentially pay for failing to transmit genetic material to future generations, a multitude of interacting endocrine, neuroendocrine, and other neurochemical determinants are in place to ensure competent maternal caregiving by the time the offspring are born. Achieving this high maternal competency at parturition seems effortless but is quite a feat given that many nulliparous and parentally inexperienced female mammals are more prone to ignore, if not outright harm, conspecific neonates. There are important roles for ovarian steroids (e.g., estradiol and progesterone), adrenal steroids (e.g., glucocorticoids), and neuropeptide hormones (e.g., prolactin, oxytocin, arginine-vasopressin, and corticotropin-releasing factor) released during pregnancy, parturition, and postpartum in the onset and maintenance of caregiving behaviors in a broad range of commonly studied animals including rats, mice, rabbits, sheep, and primates. It is especially remarkable that the same collection of hormones influences caregiving similarly across these diverse animals, although to varying degrees. In addition to the well-known effects of hormones and neuropeptides on motherhood, more recent research indicates that experience-dependent epigenetic effects are also powerful modulators of the same neural substrates that can influence maternal responding.
Justin D. Lieber and Sliman J. Bensmaia
The ability to identify tactile objects depends in part on the perception of their surface microstructure and material properties. Texture perception can, on a first approximation, be described by a number of nameable perceptual axes, such as rough/smooth, hard/soft, sticky/slippery, and warm/cool, which exist within a complex perceptual space. The perception of texture relies on two different neural streams of information: Coarser features, measured in millimeters, are primarily encoded by spatial patterns of activity across one population of tactile nerve fibers, while finer features, down to the micron level, are encoded by finely timed temporal patterns within two other populations of afferents. These two streams of information ascend the somatosensory neuraxis and are eventually combined and further elaborated in the cortex to yield a high-dimensional representation that accounts for our exquisite and stable perception of texture.
What is a Sequence? The Neural Mechanisms of Perceptual, Motor, and Task Sequences Across Species and Their Interaction with Addiction
Theresa M. Desrochers and Theresa H. McKim
Sequences permeate daily life. They can be defined as a discrete series of items or states that occur in a specific order with a beginning and end. The brain supports the perception and execution of sequences. Perceptual sequences involve tracking regularities in incoming stimuli, such as the series of sounds that make up a word in language. Executed sequences range from the series of muscle activations used by a frog to catch a fly to a chess master mapping her next moves. How the brain controls sequences must therefore scale to multiple levels of control. Investigating how the brain functions to accomplish this task spans from the study of individual cells in the brain to human cognition. Understanding the neural systems that underlie sequential control is necessary to approach the mechanistic underpinnings of complex conditions such as addiction, which may be rooted in difficult-to-extinguish sequential behaviors. Current research focuses on studies in both animal and human models and spans the levels of complexity of sequential control and the brain systems that support it.
Kristina A. Kigerl and Phillip G. Popovich
Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in chronic multi-organ pathology and dysfunction. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. All of these factors likely contribute to the development of gut dysbiosis after SCI—an imbalance in the composition of the gut microbiota that can impact the development and progression of numerous pathological conditions, including SCI. The gut microbiota are the community of microbes (bacteria, viruses, fungi) that live in the GI tract and are critical for nutrient absorption, digestion, and immune system development. These microbes also communicate with the CNS through modulation of the immune system, production of neuroactive metabolites and neurotransmitters, and activation of the vagus nerve.
After SCI, gut dysbiosis develops and persists for more than one year from the time of injury. In experimental models of SCI, gut dysbiosis is correlated with changes in inflammation and functional recovery. Moreover, probiotic treatment can improve locomotor recovery and immune function in the gut-associated lymphoid tissue (GALT). Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) using microbiome sequencing data. As research identifies microbial-derived small molecules and the genes responsible for their production, it is likely that it will become feasible to manipulate these molecules to affect human biology and disease.
Ashlyn Swift-Gallant and S. Marc Breedlove
While prenatal sex hormones guide the development of sex-typical reproductive structures, they also act on the developing brain, resulting in sex differences in brain and behavior in animal models. Stemming from this literature is the prominent hypothesis that prenatal neuroendocrine factors underlie sex differences in human sexual orientation, to explain why most males have a preference for female sexual partners (gynephilia), whereas most females display a preference for male sexual partners (androphilia). Convergent evidence from experiments of nature and indirect markers of prenatal hormones strongly support a role for prenatal androgens in same-same sexual orientations in women, although this finding is specific to a subset of lesbians who are also gender nonconforming (“butch”). More gender-conforming lesbians (“femmes”) do not show evidence of increased prenatal androgens. The literature has been more mixed for male sexual orientation: some report evidence of low prenatal androgen exposure, while others report evidence of high androgen levels and many other studies find no support for a role of prenatal androgen exposure in the development of androphilia in males. Recent evidence suggests there may be subgroups of gay men who owe their sexual orientation to distinct biodevelopmental mechanisms, which could account for these mixed findings. Although this research is young, it is similar to findings from lesbian populations, because gay men who are more gender nonconforming, and report a preference for receptive anal sex, differ on markers of prenatal development from gay men who are more gender conforming and report a preference for insertive anal sex. This chapter concludes with future research avenues including assessing whether multiple biodevelopmental pathways underlie sexual orientation and whether neuroendocrine factors and other biological mechanisms (e.g., immunology, genetics) interact to promote a same-sex sexual orientation.
Elisabetta Tolla, Jonathan H. Pérez, Ian C. Dunn, Simone L. Meddle, and Tyler J. Stevenson
Neuroendocrine mechanisms control the seasonal reproduction in birds and mammals. Seasonal reproduction is ubiquitous across vertebrate and invertebrate species, and its timing is extremely crucial in order to maximize offspring survival. The hypothalamus is the key brain region that integrates environmental cues. An endogenous circannual timer with oscillations that approximate one year is also localized in the hypothalamus. Successful timing of reproduction involves the combination of endogenous internal timers that are entrained by local environmental cues. Photoperiod, or the annual change in day length, is the primary cue most temperate animals use to predict future environmental conditions. Birds are able to detect light through photoreceptors located in the medio-basal hypothalamus. These photoreceptors are localized in neuroendocrine regions and regulate the key reproductive neuropeptide gonadotropin-releasing hormone (GnRH). In mammals, retinal photoreceptors transduce light information the suprachiasmatic nucleus in the hypothalamus, which then modulates the nocturnal duration of melatonin. Melatonin in mammals is crucial, as it regulates the neuroendocrine release of GnRH and downstream transitions across seasonal reproductive states. The tanycyte cells lining the third ventricle (3rdV) of the hypothalamus are the critical node for the integration of internal (i.e., circannual timing) and external (e.g., photoperiod) information necessary for the regulation of seasonal reproduction.