Thad E. Wilson and Kristen Metzler-Wilson
Thermoregulation is a key physiologic homeostatic process and is subdivided into autonomic, behavioral, and adaptive divisions. Autonomic thermoregulation is a neural process related to the sympathetic and parasympathetic nervous systems. Autonomic thermoregulation is controlled at the subcortical level to alter physiologic processes of heat production and loss to maintain internal temperature. Mammalian, including human, autonomic responses to acute heat or cold stresses are dependent on environmental conditions and species genotype and phenotype, but many similarities exist. Responses to an acute heat stress begin with the sensation of heat, leading to central processing of the information and sympathetic responses via end organs, which can include sweat glands, vasculature, and airway and cardiac tissues. Responses to an acute cold stress begin with the sensation of cold, which leads to central processing of the information and sympathetic responses via end organs, which can include skeletal and piloerector muscles, brown adipose tissue, vasculature, and cardiac tissue. These autonomic responses allow homeostasis of internal temperature to be maintained across a wide range of external temperatures for most mammals, including humans. At times, uncompensable thermal challenges occur that can be maintained for only limited periods of time before leading to pathophysiologic states of hyperthermia or hypothermia.
Natalia Duque-Wilckens and Brian C. Trainor
Aggressive behavior plays an essential role in survival and reproduction across animal species—it has been observed in insects, fish, reptiles, and mammals including humans. Even though specific aggressive behaviors are quite heterogeneous across species, many of the underlying mechanisms modulating aggression are highly conserved. For example, in a variety of species arginine vasopressin (AVP) and its homologue vasotocin in the hypothalamus, play an important role in regulating aggressive behaviorssuch as territorial and inter male aggression. Similarly in the medial amygdala, activation of a subpopulation of GABAergic neurons promotes aggression, while the prefrontal cortex exerts inhibitory control over aggressive behaviors. An important caveat in the aggression literature is that it is focused primarily on males, probably because in most species males are more aggressive than females. However, female aggression is also highly prevalent in many contexts, as it can affect access to resources such as mates, food, and offspring survival. Although it is likely that many underlying mechanisms are shared between sexes, there is sex specific variation in aggression, type, magnitude, and contexts, which suggests that there are important sex differences in how aggression is regulated. For example, while AVP acts to modulate aggression in both male and female hamsters, it increases male aggression but decreases female aggression. These differences can occur at the extent of neurotransmitter or hormones release, sensitivity (i.e., receptor expression), and/or molecular responses.
In response to changes in metabolic demand, the cardiovascular and respiratory systems are regulated in a highly coordinated fashion, such that both ventilation and cardiac output increase in a parallel fashion, thus maintaining a relatively constant level of arterial blood PO2, PCO2, and pH. In addition, external alerting stimuli that trigger defensive or orienting behavioral responses also trigger coordinated cardiorespiratory changes that are appropriate for the particular behavior. Furthermore, environmental challenges such as hypoxia or submersion evoke complex cardiovascular and respiratory response that have the effect of increasing oxygen uptake and/or conserving the available oxygen.
The brain mechanisms that are responsible for generating coordinated cardiorespiratory responses can be divided into reflex mechanisms and feedforward (central command) mechanisms. Reflexes that regulate cardiorespiratory function arise from a wide variety of internal receptors, and include those that signal changes in blood pressure, the level of blood oxygenation, respiratory activity, and metabolic activity. In most cases more than one reflex is activated, so that the ultimate cardiorespiratory response depends upon the interaction between different reflexes. The essential central pathways that subserve these reflexes are largely located within the brainstem and spinal cord, although they can be powerfully modulated by descending inputs arising from higher levels of the brain. The brain defense mechanisms that regulate the cardiorespiratory responses to external threatening stimuli (e.g., the sight, sound, or odor of a predator) are highly complex, and include both subcortical and cortical systems. The subcortical system, which includes the basal ganglia and midbrain colliculi as essential components, is phylogenetically ancient and generates immediate coordinated cardiorespiratory and motor responses to external stimuli. In contrast, the defense system that includes the cortex, hypothalamus, and limbic system evolved at a later time, and is better adapted to generating coordinated responses to external stimuli that involve cognitive appraisal.
Jeremy C. Borniger and Luis de Lecea
The hypocretins (also known as orexins) are selectively expressed in a subset of lateral hypothalamic neurons. Since the reports of their discovery in 1998, they have been intensely investigated in relation to their role in sleep/wake transitions, feeding, reward, drug abuse, and motivated behavior. This research has cemented their role as a subcortical relay optimized to tune arousal in response to various salient stimuli. This article reviews their discovery, physiological modulation, circuitry, and integrative functionality contributing to vigilance state transitions and stability. Specific emphasis is placed on humoral and neural inputs regulating hcrt neural function and new evidence for an autoimmune basis of the sleep disorder narcolepsy. Future directions for this field involve dissection of the heterogeneity of this neural population using single-cell transcriptomics, optogenetic, and chemogenetics, as well as monitoring population and single cell activity. Computational models of the hypocretin network, using the “flip-flop” or “integrator neuron” frameworks, provide a fundamental understanding of how this neural population influences brain-wide activity and behavior.
Brian P. Kenealy and Ei Terasawa
Female reproduction is an interplay between the hypothalamus, pituitary, and ovaries. While the gonadotropin releasing hormone (GnRH) neuron in the hypothalamus regulates gonadal function through the pituitary, GnRH neuronal activity is also profoundly influenced by ovarian steroid hormones. GnRH is released from GnRH neurons in a pulsatile manner after integration of a diverse array of internal and external milieus. Since the discovery of the mammalian GnRH molecule, over a dozen GnRH forms have been identified in the animal kingdom, and large numbers of publications in various lab animal and human studies suggest that GnRH neurons are regulated by multiple neuromodulators in the brain, such as kisspeptin, neurokinin B, β-dynorphin, neuropeptide Y, GnIH, GABA, glutamate, and glial factors. A recent emerging concept is that steroids synthesized locally in the hypothalamus, namely, neuroestradiol and neuroprogesterone, also contribute to the regulation of GnRH neuronal activity, and hence female reproduction. Together with modulation by various inputs and ovarian steroid feedback, GnRH neurons are responsible for puberty, cyclic ovulation, and menopause.
D. Grahame Hardie and A. Mark Evans
This is an advance summary of a forthcoming article in the Oxford Research Encyclopedia of Neuroscience. Please check back later for the full article.
AMP-activated protein kinase (AMPK) is a sensor of energy status expressed in almost all eukaryotic cells, including neurons. It senses the levels of cellular AMP and ADP relative to ATP. If increases in AMP:ATP and/or ADP:ATP ratios are detected (indicating a reduction in cellular energy status), then AMPK is activated by a mechanism involving both allosteric activation and enhanced net phosphorylation at Thr172 on the catalytic subunit by the upstream kinase LKB1. Once activated, AMPK phosphorylates dozens of downstream targets, thus switching on catabolic pathways that generate ATP and switching off anabolic pathways and other energy-consuming processes. AMPK can also be activated by an alternate, non-canonical mechanism triggered by increases in intracellular Ca2+; this activates the calmodulin-dependent kinase CaMKK2, which can phosphorylate Thr172 in the absence of any changes in adenine nucleotide ratios. AMPK is also activated by glucose starvation by a non-canonical mechanism that is dependent upon LKB1 but is independent of changes in adenine nucleotides.
AMPK occurs in essentially all eukaryotes in the form of heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits. In vertebrates, each of the three subunits is encoded by two or three genes, generating up to twelve heterotrimeric combinations displaying subtle variations in tissue distribution and regulation. The α subunits contain the kinase domain with Thr172 in the “activation loop” and regulatory regions that interact with the other two subunits. The β subunits contain a domain that, with the small lobe of the kinase domain on the α subunit, forms the “ADaM” site, the binding site for synthetic drugs that are potent allosteric activators of AMPK. It is not yet clear whether there are endogenous ligand(s) that bind to this site. The γ subunits contain three binding sites for the regulatory nucleotides, AMP, ADP, and ATP.
Consistent with its role as an ancient sensor of nutrient starvation, AMPK in specific neurons of the hypothalamus is involved in the regulation of appetite and feeding behavior, being activated by orexigenic hormones like ghrelin that act via the Ca2+-CaMKK2 pathway, and inhibited by anorexigenic hormones such as leptin, possibly via release of opioids that inhibit AMPK.
A special feature of AMPK in excitable cells is its ability to phosphorylate and modulate the function of ion channels, especially K+ channels. For example, in central neurons phosphorylation of the C-terminal tail of the delayed rectifier K+ channel Kv2.1 hyper-polarizes the plasma membrane and reduces the firing of action potentials, thus potentially conserving energy.
Lily Yan, Laura Smale, and Antonio A. Nunez
Circadian rhythms are endogenous daily rhythms evident in behavior and physiology. In mammals, these rhythms are controlled by a hierarchical network of oscillators showing a coherent circadian coordination or coupling. The hypothalamic suprachiasmatic nucleus (SCN) sits on top of the hierarchy and coordinates the phase of oscillators in other brain regions and in peripheral organs, including endocrine glands. The phase of the SCN oscillator, in reference to the daily light-dark cycle, is identical across mammalian species regardless of whether they are most active during the day or night, that is, diurnal or nocturnal. However, the extra-SCN or peripheral oscillators are out of phase and are often reversed by 180° across diurnal and nocturnal mammals. In the endocrine system, with the notable exception of the pattern of pineal melatonin secretion, which features elevated levels at night regardless of the activity profile of the species, most endocrine rhythms show a 180° reversal when diurnal and nocturnal species are compared. There is also evidence of differences between nocturnal and diurnal species with respect to their rhythms in sensitivity or responsiveness to hormonal stimulation. One of the major unanswered questions in the field of comparative endocrinology relates to the mechanism responsible for the differential coupling in diurnal and nocturnal mammals of extra-SCN oscillators and overt circadian rhythms with the SCN oscillator and the light dark cycle. Viable hypotheses include species-specific switches from excitation to inhibition at key nodes between the SCN and its targets, the presence of extra-SCN signals that converge on SCN targets and reverse the outcome of SCN signals, and changes in oscillatory parameters between the oscillator of the SCN and those outside the SCN resulting in an anti-phase coupling among key oscillators.
Gretchen N. Neigh, Mandakh Bekhbat, and Sydney A. Rowson
Bidirectional interactions between the immune system and central nervous system have been acknowledged for centuries. Over the past 100 years, pioneering studies in both animal models and humans have delineated the behavioral consequences of neuroimmune activation, including the different facets of sickness behavior. Rodent studies have uncovered multiple neural pathways and mechanisms that mediate anorexia, fever, sleep alterations, and social withdrawal following immune activation. Furthermore, work conducted in human patients receiving interferon treatment has elucidated some of the mechanisms underlying immune-induced behavioral changes such as malaise, depressive symptoms, and cognitive deficits.
These findings have provided the foundation for development of treatment interventions for conditions in which dysfunction of immune-brain interactions leads to behavioral pathology. Rodent models of neuroimmune activation frequently utilize endotoxins and cytokines to directly stimulate the immune system. In the absence of pathogen-induced inflammation, a variety of environmental stressors, including psychosocial stressors, also lead to neuroimmune alterations and concurrent behavioral changes. These behavioral alterations can be assessed using a battery of behavioral paradigms while distinguishing acute sickness behavior from the type of behavioral outcome being assessed. Animal studies have also been useful in delineating the role of microglia, the neuroendocrine system, neurotransmitters, and neurotrophins in mediating the behavioral implications of altered neuroimmune activity. Furthermore, the timing and duration of neuroimmune challenge as well as the sex of the organism can impact the behavioral manifestations of altered neuroimmune activity. Finally, neuroimmune modulation through pharmacological or psychosocial approaches has potential for modulating behavior.
Robert S. Bridges
Prolactin (PRL) is a protein hormone with a molecular weight of approximately 23 KD, although variants in size exist. It binds to receptor dimers on the cytoplasmic surface of its target cells and acts primarily through the activation of the STAT5 pathway, which in turn alters gene activity. Pituitary prolactin, while being the main, but not only, source of PRL, is primarily under inhibitory control by hypothalamic dopaminergic neurons. Release of dopamine (DA) into the hypothalamo-hypophyseal portal system binds on DA D2 receptors on PRL-producing lactotrophs within the anterior pituitary gland. Prolactin’s functions include the regulation of behaviors that include maternal care, anxiety, and feeding as well as lactogenesis, hepatic bile formation, immune function, corpora lutea function, and more generally cell proliferation and differentiation. Dysfunctional conditions related to prolactin’s actions include its role in erectile dysfunction and male infertility, mood disorders such as depression during the postpartum period, possible roles in breast and hepatic cancer, prostate hyperplasia, galactorrhea, obesity, immune function, and diabetes. Future studies will further elucidate both the underlying mechanisms of prolactin action together with prolactin’s involvement in these clinical disorders.
Sabra L. Klein and Jaclyn M. Schwarz
Sex is a biological variable that affects immune responses to both self and foreign antigens (e.g., microbial infections) in the central nervous system (CNS) as well as in peripheral organs. The sex of an individual is defined by the differential determination of the sex chromosomes, the organization of the reproductive organs, and the subsequent sex steroid hormone levels in males and females. Sex is distinct from gender, which includes self-identification as being a male or female as well as behaviors and activities that are determined by society or culture in humans. Male and female differences in immunological responses may be influenced by both sex and gender, with sex contributing to the physiological and anatomical differences that influence exposure, recognition, clearance, and even transmission of microbes in males and females. By contrast, gender may reflect behaviors that influence exposure to microbes, access to health care, or health-seeking behaviors that indirectly affect the course of infection in males and females. Though both sex and gender influence the immune response, the focus of this article is the biological factors that influence immunological differences between the sexes in both the CNS and peripheral tissues to alter the course of diseases across the life span.
Understanding of the brain mechanisms regulating reproductive behaviors in female laboratory animals has been aided greatly by our knowledge of estrogen receptors in the brain. Hypothalamic neurons that express the gene for estrogen receptor-alpha regulate activity in the neural circuit for the simplest female reproductive response, lordosis behavior. In turn, many of the neurotransmitter inputs to the critical hypothalamic neurons have been studied using electrophysiological and neurochemical techniques. The upshot of all of these studies is that lordosis behavior presents the best understood set of mechanisms for any mammalian behavior.
Jacques Balthazart and Gregory F. Ball
It is well established that testosterone from testicular origin plays a critical role in the activation of male sexual behavior in most, if not all, vertebrate species. These effects take place to a large extent in the preoptic area although other brain sites are obviously also implicated. In its target areas, testosterone is actively metabolized either into estrogenic and androgenic steroids that have specific behavioral effects or into inactive metabolites. These transformations either amplify the behavioral activity of testosterone or, alternatively, metabolism to an inactive compound dissipates any biological effect. Androgens and estrogens then bind to nuclear receptors that modulate the transcription of specific genes. This process is controlled by a variety of co-activators and co-repressors that, respectively, enhance or inhibit these transcriptional processes. In addition, recent work has shown that the production of estrogens by brain aromatase can be modulated within minutes by changes in neural activity and that these rapid changes in neuroestrogen production impact sexual behavior, in particular sexual motivation within the same time frame. Estrogens thus affect specific aspects of male sexual behavior in two different time frames via two types of mechanisms that are completely different. Multiple questions remain open concerning the cellular brain mechanisms that mediate testosterone action on male sexual behavior.
Alyssa L. Pedersen and Colin J. Saldanha
Given the profound influence of steroids on the organization and activation of the vertebrate central nervous system (CNS), it is perhaps not surprising that these molecules are involved in processes that restructure the cytoarchitecture of the brain. This includes processes such as neurogenesis and the connectivity of neural circuits. In the last 30 years or so, we have learned that the adult vertebrate brain is far from static; it responds to changes in androgens and estrogens, with dramatic alterations in structure and function. Some of these changes have been directly linked to behavior, including sex, social dominance, communication, and memory. Perhaps the most dramatic levels of neuroplasticity are observed in teleosts, where circulating and centrally derived steroids can affect several end points, including cell proliferation, migration, and behavior. Similarly, in passerine songbirds and mammals, testosterone and estradiol are important modulators of adult neuroplasticity, with documented effects on areas of the brain necessary for complex behaviors, including social communication, reproduction, and learning. Given that many of the cellular processes that underlie neuroplasticity are often energetically demanding and temporally protracted, it is somewhat surprising that steroids can affect physiological and behavioral end points quite rapidly. This includes recent demonstrations of extremely rapid effects of estradiol on synaptic neurotransmission and behavior in songbirds and mammals. Indeed, we are only beginning to appreciate the role of temporally and spatially constrained neurosteroidogenesis, like estradiol and testosterone being made in the brain, on the rapid regulation of complex behaviors.
We live in an approximately 24-hour world and circadian rhythms have evolved to adapt organisms to the opportunities presented by Earth’s 24-hour cycle of light and dark. A “master clock” located in the suprachiasmatic nucleus (SCN) of the brain orchestrates daily rhythms in all manner of behavioral, endocrine, metabolic, autonomic, and homeostatic systems in our bodies. The SCN is comprised of about 20,000 neurons and about one third as many astroglia. How can so few neurons and astroglia guide so many rhythms? How do neurons time out an interval as long as a day? The answers are a case study in understanding how genes within cells, and cells within circuits, function together to perform complex activities and optimize bodily functions. While individual clock cells are found in virtually all bodily tissues, the unique connectome of the SCN, its specialized afferent inputs from the retinohypothalamic tract, and its neural and humoral outputs enable its “babel” of neuronal types to synchronize their activity and signal time to the rest of the body.
At the molecular-cellular level, circadian rhythms are regulated by a 24-hour transcriptional–translational feedback loop. At the SCN tissue level, individual SCN neurons coordinate their gene expression and electrical activity, working together in circuits that sustain coherent rhythms. The SCN has many distinct cell types based on their neurotransmitters, neuropeptides, and afferent and efferent connections. There has been much progress in unraveling the dynamic network organization that underlies the SCN network’s communications. Though the precise anatomical connections underlying interneuronal communication in the SCN are not completely understood, key signaling mechanisms that sustain the SCN’s intrinsic rhythmicity have been tackled using intersectional genomic tools. Transgenic animals that permit the visualization of clock gene–protein expression have enabled analysis of SCN network activity over time. Availability of animals bearing mutations in clock genes or proteins enable the determination of changes within neurons, among neurons in networks, and their impact on behavior. The use of continuous readouts of circadian activity that track behavior, or clock gene expression, or electrical activity changes over time, within an SCN or a single neuron, leads the way to unraveling mechanisms sustaining the circadian timing system. Because the results of circadian studies generate huge amounts of data, the entry of mathematical modelers and statisticians into the field has begun to yield useful and testable predictions on how these multiplexed systems work to adapt to our 24-hour world.