Evolution and function in serotonergic systems

Serotonergic systems of invertebrate and vertebrate centralnervous systems (CNS) are functionally similar in multiple characters.Serotonin (5-HT) neurons dispersed throughout the CNS of lophotrochozoaninvertebrates (molluscs and leeches) are analogous to vertebrate5-HT neurons concentrated in the raphe nuclei of mid- and hindbrain:they innervate specific central pattern generators and othercircuits of the CNS, receive feedback from them, and supportgeneral behavioral arousal. In both groups 5-HT regulates excitatorygain of CNS circuitry and uses similarly diverse 5-HT receptors.Marked contrast, however, exists for roles of 5-HT in regulationof appetite. Where invertebrate 5-HT neurons promote an appetitivestate, this role is supplanted in the vertebrates by a peptidergicnetwork centered around orexins/hypocretins, to which the roleof 5-HT in arousal is subordinate. In the vertebrates, 5-HThas appetite-suppressant properties. This is paralleled by differingcomplexities of mechanisms that bring about satiety. Lophotrozoansappear to rely on simple stretching of the gut, with no obviousfeedback from true nutrient stores. In contrast, vertebrateappetite is regulated by hypothalamic sensitivity to hormonalsignals reporting separately on the status of fat cells anddigestive activity, and to blood glucose, in addition to gutstretch. The simple satiety mechanism of a mollusc can be usedin value-based foraging decisions that integrate hunger state,taste, and experience (Gillette and others 2000). For vertebrates,where appetite and arousal are regulated by signals from long-livednutrient stores, decisions can be based on resource need goingfar beyond simple gut content, enabling value estimation andrisk assessment in the longer-term. Thus, connection of nutrientstorage depots to CNS circuitry mediating appetite may supplycritical substrate for evolving complexity in brain and behavior.This hypothesis may be tested in expanded comparative studiesof 5-HT and peptidergic functions in appetite and arousal.     

Orexins activate histaminergic neurons via the orexin 2 receptor.

Orexins (orexin A and B) are recently identified neuropeptides implicated in the regulation of vigilance states and energy homeostasis. We have shown here the physiological significance of histaminergic neurons in the orexin-induced arousal responses. Immunohistochemical and electron microscopic techniques revealed direct synaptic interaction between orexin-immunoreactive nerve terminals and histidine decarboxylase-immunoreactive neurons in the TMN. Electrophysiological study revealed that orexins dose-dependently activate histaminergic neurons, which were freshly isolated from rats TMN region. To further evaluate, we examined the effect of pyrilamine, an H(1) receptor antagonist, on orexin-induced arousal response in rats. Simultaneously recordings of electroencephalograph and electromyograph showed that intracerebroventricular infusion of orexin A significantly increased the awake state in the light phase. Central application of pyrilamine significantly inhibited this response. These results strongly suggest that activation of histaminergic neurons by orexins might be important for modulation of the arousal.     

The Critical Roles of Information and Nonequilibrium Thermodynamics in Evolution of Living Systems

Living cells are spatially bounded, low entropy systems that, although far from thermodynamic equilibrium, have persisted for billions of years. Schrödinger, Prigogine, and others explored the physical principles of living systems primarily in terms of the thermodynamics of order, energy, and entropy. This provided valuable insights, but not a comprehensive model. We propose the first principles of living systems must include: (1) Information dynamics, which permits conversion of energy to order through synthesis of specific and reproducible, structurally-ordered components; and (2) Nonequilibrium thermodynamics, which generate Darwinian forces that optimize the system. Living systems are fundamentally unstable because they exist far from thermodynamic equilibrium, but this apparently precarious state allows critical response that includes: (1) Feedback so that loss of order due to environmental perturbations generate information that initiates a corresponding response to restore baseline state. (2) Death due to a return to thermodynamic equilibrium to rapidly eliminate systems that cannot maintain order in local conditions. (3) Mitosis that rewards very successful systems, even when they attain order that is too high to be sustainable by environmental energy, by dividing so that each daughter cell has a much smaller energy requirement. Thus, nonequilibrium thermodynamics are ultimately responsible for Darwinian forces that optimize system dynamics, conferring robustness sufficient to allow continuous existence of living systems over billions of years.     

How generalized CNS arousal strengthens sexual arousal (and vice versa)

Heightened states of generalized CNS arousal are proposed here to facilitate sexual arousal in both males and females. Genetic, pharmacologic and biophysical mechanisms by which this happens are reviewed. Moreover, stimulation of the genital epithelia, as triggers of sex behavior, is hypothesized to lead to a greater generalized arousal in a manner that intensifies sexual motivation. Finally, launched from histochemical studies intended to characterize cells in the genital epithelium, a surprising idea is proposed that links density of innervation with the efficiency of wound healing and with the capacity of that epithelium to stimulate generalized CNS arousal. Thus, bidirectional arousal-related mechanisms that foster sexual behaviors are envisioned as follows: from specific to generalized (as with genital stimulation) and from generalized to specific.     

Dynamic optimization of bioprocesses: efficient and robust numerical strategies

The dynamic optimization (open loop optimal control) of non-linear bioprocesses is considered in this contribution. These processes can be described by sets of non-linear differential and algebraic equations (DAEs), usually subject to constraints in the state and control variables. A review of the available solution techniques for this class of problems is presented, highlighting the numerical difficulties arising from the non-linear, constrained and often discontinuous nature of these systems. In order to surmount these difficulties, we present several alternative stochastic and hybrid techniques based on the control vector parameterization (CVP) approach. The CVP approach is a direct method which transforms the original problem into a non-linear programming (NLP) problem, which must be solved by a suitable (efficient and robust) solver. In particular, a hybrid technique uses a first global optimization phase followed by a fast second phase based on a local deterministic method, so it can handle the nonconvexity of many of these NLPs. The efficiency and robustness of these techniques is illustrated by solving several challenging case studies regarding the optimal control of fed-batch bioreactors and other bioprocesses. In order to fairly evaluate their advantages, a careful and critical comparison with several other direct approaches is provided. The results indicate that the two-phase hybrid approach presents the best compromise between robustness and efficiency.     

Motor learning through the combination of primitives

In this paper we discuss a new perspective on how the central nervous system (CNS) represents and solves some of the most fundamental computational problems of motor control. In particular, we consider the task of transforming a planned limb movement into an adequate set of motor commands. To carry out this task the CNS must solve a complex inverse dynamic problem. This problem involves the transformation from a desired motion to the forces that are needed to drive the limb. The inverse dynamic problem is a hard computational challenge because of the need to coordinate multiple limb segments and because of the continuous changes in the mechanical properties of the limbs and of the environment with which they come in contact. A number of studies of motor learning have provided support for the idea that the CNS creates, updates and exploits internal representations of limb dynamics in order to deal with the complexity of inverse dynamics. Here we discuss how such internal representations are likely to be built by combining the modular primitives in the spinal cord as well as other building blocks found in higher brain structures. Experimental studies on spinalized frogs and rats have led to the conclusion that the premotor circuits within the spinal cord are organized into a set of discrete modules. Each module, when activated, induces a specific force field and the simultaneous activation of multiple modules leads to the vectorial combination of the corresponding fields. We regard these force fields as computational primitives that are used by the CNS for generating a rich grammar of motor behaviours.     

Computation emerges from adaptive synchronization of networking neurons

The activity of networking neurons is largely characterized by the alternation of synchronous and asynchronous spiking sequences. One of the most relevant challenges that scientists are facing today is, then, relating that evidence with the fundamental mechanisms through which the brain computes and processes information, as well as with the arousal (or progress) of a number of neurological illnesses. In other words, the problem is how to associate an organized dynamics of interacting neural assemblies to a computational task. Here we show that computation can be seen as a feature emerging from the collective dynamics of an ensemble of networking neurons, which interact by means of adaptive dynamical connections. Namely, by associating logical states to synchronous neuron's dynamics, we show how the usual Boolean logics can be fully recovered, and a universal Turing machine can be constructed. Furthermore, we show that, besides the static binary gates, a wider class of logical operations can be efficiently constructed as the fundamental computational elements interact within an adaptive network, each operation being represented by a specific motif. Our approach qualitatively differs from the past attempts to encode information and compute with complex systems, where computation was instead the consequence of the application of control loops enforcing a desired state into the specific system's dynamics. Being the result of an emergent process, the computation mechanism here described is not limited to a binary Boolean logic, but it can involve a much larger number of states. As such, our results can enlighten new concepts for the understanding of the real computing processes taking place in the brain.     

A psychophysiological analysis of the efficiency of instructing schoolchildren]

Examination of 163 schoolboys in higher forms has revealed that strength of the nervous system and functional state of the CNS (functional level of the system, level of functional possibilities, arousal and reaction stability) do not differ in schoolchildren with various progress in learning. The school teaching efficiency correlated with parameters of strength of the nervous system only in excellent and good pupils, the functional state of the nervous system being of importance for their teaching, especially its such parameters as arousal, level of functional possibilities and reaction stability. In pupils with poor progress those correlations were absent.     

Drosophila miR-124 regulates neuroblast proliferation through its target anachronism

MicroRNAs (miRNAs) have been implicated as regulators of central nervous system (CNS) development and function. miR-124 is an evolutionarily ancient, CNS-specific miRNA. On the basis of the evolutionary conservation of its expression in the CNS, miR-124 is expected to have an ancient conserved function. Intriguingly, investigation of miR-124 function using antisense-mediated miRNA depletion has produced divergent and in some cases contradictory findings in a variety of model systems. Here we investigated miR-124 function using a targeted knockout mutant and present evidence for a role during central brain neurogenesis in Drosophila melanogaster. miR-124 activity in the larval neuroblast lineage is required to support normal levels of neuronal progenitor proliferation. We identify anachronism (ana), which encodes a secreted inhibitor of neuroblast proliferation, as a functionally important target of miR-124 acting in the neuroblast lineage. ana has previously been thought to be glial specific in its expression and to act from the cortex glia to control the exit of neuroblasts from quiescence into the proliferative phase that generates the neurons of the adult CNS during larval development. We provide evidence that ana is expressed in miR-124-expressing neuroblast lineages and that ana activity must be limited by the action of miR-124 during neuronal progenitor proliferation. We discuss the possibility that the apparent divergence of function of miR-124 in different model systems might reflect functional divergence through target site evolution.     

Numerically evaluated functional equivalence between chaotic dynamics in neural networks and cellular automata under totalistic rules

Chaotic dynamics in a recurrent neural network model and in two-dimensional cellular automata, where both have finite but large degrees of freedom, are investigated from the viewpoint of harnessing chaos and are applied to motion control to indicate that both have potential capabilities for complex function control by simple rule(s). An important point is that chaotic dynamics generated in these two systems give us autonomous complex pattern dynamics itinerating through intermediate state points between embedded patterns (attractors) in high-dimensional state space. An application of these chaotic dynamics to complex controlling is proposed based on an idea that with the use of simple adaptive switching between a weakly chaotic regime and a strongly chaotic regime, complex problems can be solved. As an actual example, a two-dimensional maze, where it should be noted that the spatial structure of the maze is one of typical ill-posed problems, is solved with the use of chaos in both systems. Our computer simulations show that the success rate over 300 trials is much better, at least, than that of a random number generator. Our functional simulations indicate that both systems are almost equivalent from the viewpoint of functional aspects based on our idea, harnessing of chaos.     

Sexual arousal in men: a review and conceptual analysis

Sexual arousal is an emotional/motivational state that can be triggered by internal and external stimuli and that can be inferred from central (including verbal), peripheral (including genital), and behavioral (including action tendencies and motor preparation) responses. This article, while focusing on sexual arousal in men, provides a conceptual analysis of this construct, reviews models of sexual arousal, and discusses the usefulness of perspectives derived from motivation and emotion research in improving our understanding of its determinants and behavioral correlates. In this, it considers the role of genital feedback in men's subjective sexual arousal and the connections between sexual arousal and sexual desire. Future research and definitions may increasingly focus on its central integrative functions (as opposed to its input and output characteristics). Yet, the study of sexual arousal can be expected to continue to benefit from the measurement of its genital, verbal, and behavioral components. Instances of discordance between response components suggest that they are, at least in part, under the control of different mechanisms, and it is proposed that a better understanding of sexual arousal will prove contingent on a better understanding of such mechanisms and the conditions under which they converge and diverge.     

Failure of adaptive self-organized criticality during epileptic seizure attacks

Critical dynamics are assumed to be an attractive mode for normal brain functioning as information processing and computational capabilities are found to be optimal in the critical state. Recent experimental observations of neuronal activity patterns following power-law distributions, a hallmark of systems at a critical state, have led to the hypothesis that human brain dynamics could be poised at a phase transition between ordered and disordered activity. A so far unresolved question concerns the medical significance of critical brain activity and how it relates to pathological conditions. Using data from invasive electroencephalogram recordings from humans we show that during epileptic seizure attacks neuronal activity patterns deviate from the normally observed power-law distribution characterizing critical dynamics. The comparison of these observations to results from a computational model exhibiting self-organized criticality (SOC) based on adaptive networks allows further insights into the underlying dynamics. Together these results suggest that brain dynamics deviates from criticality during seizures caused by the failure of adaptive SOC.     

Comparative physiological and biochemical aspects of hypothermia as a model for hibernation

It is obvious that research is far from the last chapter in developing a model for natural hibernation. The relationships and comparative mechanisms for thermogenesis and survival in hibernation and experimental hypothermia are still unclear. Yet, two primary areas appear to be most promising, namely, the control of thermogenesis via the glucocorticoids and the specific role of the central nervous system (CNS) in survival of hypothermic subjects and arousal of hibernating subjects. Although there have been several approaches to understanding the role of the CNS in terms of circulation, integrity of the blood-brain barrier (BBB) system, and CNS sites of activity, it may appear that more questions have been raised than have been answered. However, a more optimistic view can also be taken. The development of a laboratory model, using experimental hypothermia for natural hibernation, is progressing. This view is justified in terms of results from the use of glucocorticoids in metabolic regulation of available carbohydrates, i.e., available glucose in hypothermia, and the continued promising parallel studies of physiological and biochemical integrity of areas of the CNS in hypothermic and hibernating subjects.     

The role of succinate dehydrogenase and oxaloacetate in metabolic suppression during hibernation and arousal

Hibernation elicits a major reduction in whole-animal O₂ consumption that corresponds with active suppression of liver mitochondrial electron transport capacity at, or downstream of, succinate dehydrogenase (SDH). During arousal from the torpor phase of hibernation this suppression is reversed and metabolic rates rise dramatically. In this study, we used the 13-lined ground squirrel (Ictidomys tridecemlineatus) to assess isolated liver mitochondrial respiration during the torpor phase of hibernation and various stages of arousal to elucidate a potential role of SDH in metabolic suppression. State 3 and state 4 respiration rates were seven- and threefold lower in torpor compared with the summer-active and interbout euthermic states. Respiration rates increased during arousal so that when body temperature reached 30°C in late arousal, state 3 and state 4 respiration were 3.3- and 1.8-fold greater than during torpor, respectively. SDH activity was 72% higher in interbout euthermia than in torpor. Pre-incubating with isocitrate [to alleviate oxaloacetate (OAA) inhibition] increased state 3 respiration rate during torpor by 91%, but this rate was still fourfold lower than that measured in interbout euthermia. Isocitrate pre-incubation also eliminated differences in SDH activity among hibernation bout stages. OAA concentration correlated negatively with both respiration rates and SDH activity. These data suggest that OAA reversibly inhibits SDH in torpor, but cannot fully account for the drastic metabolic suppression observed during this hibernation phase.     

The Histaminergic Tuberomamillary Nucleus Is Involved in Appetite for Sex,Water and Amphetamine

The histaminergic system is one component of the ascending arousal system which is involved in wakefulness, neuroendocrine control, cognition, psychiatric disorders and motivation. During the appetitive phase of motivated behaviors the arousal state rises to an optimal level, thus giving proper intensity to the behavior. Previous studies have demonstrated that the histaminergic neurons show an earlier activation during the appetitive phase of feeding, compared to other ascending arousal system nuclei, paralleled with a high increase in arousal state. Lesions restricted to the histaminergic neurons in rats reduced their motivation to get food even after 24h of food deprivation, compared with intact or sham lesioned rats. Taken together, these findings indicate that the histaminergic system is important for appetitive behavior related to feeding. However, its role in other goal-directed behaviors remains unexplored. In the present work, male rats rendered motivated to obtain water, sex, or amphetamine showed an increase in Fos-ir of histaminergic neurons in appetitive behaviors directed to get those reinforcers. However, during appetitive tests to obtain sex, or drug in amphetamine-conditioned rats, Fos expression increased in most other ascending arousal system nuclei, including the orexin neurons in the lateral hypothalamus, dorsal raphe, locus coeruleus and laterodorsal tegmental neurons, but not in the ventral tegmental area, which showed no Fos-ir increase in any of the 3 conditions. Importantly, all these appetitive behaviors were drastically reduced after histaminergic cell-specific lesion, suggesting a critical contribution of histamine on the intensity component of several appetitive behaviors.     

Key roles of the histaminergic system in sleep-wake regulation

Histamine plays an important role in mediating wakefulness in mammals. Based on the findings from gene-manipulated mice, we provide several lines of evidence showing the roles of the histaminergic system in the somnogenic effects of prostaglandin (PG) D2 and adenosine, and in the arousal effects of PGE2 and orexin. PGD2 activates DP1 receptors (R) to promote sleep by stimulating them to release adenosine. The released adenosine activates adenosine A2AR and subsequently excites the ventrolateral preoptic area (VLPO), one of the sleep centers in the anterior hypothalamus. VLPO neurons then send inhibitory signals to downregulate the histaminergic tuberomammillary nucleus (TMN), which contributes to arousal. A1R is expressed in histaminergic neurons of the rat TMN. Adenosine in the TMN inhibits the histaminergic system via A1R and promotes non–rapid eye movement sleep. Conversely, both endogenous PGE2 and orexin activate the histaminergic system through EP4R and OX-2R, respectively, to promote wakefulness via histamine H1R. Furthermore, the arousal effect of ciproxifan, H3R antagonist, depends on the activation of histaminergic systems. These findings indicate that VLPO and TMN regulate sleep and wakefulness by means of a “flip-flop” mechanism operating in an anti-coincident manner during sleep–wake state transitions.

     

A contextual definition of male sexual arousal

Sexual arousal is a construct without a widely shared definition. Historically, sexual arousal has usually referred to a central physiological state, but there has been much less agreement on its relation to motivation, emotion, and - for males - penile erection and ejaculation. Many behavioral and physiological measures have been used as operational definitions of sexual arousal, but the relation of the measure to arousal is often assumed rather than tested. For men, penile erection in the presence of erotic stimuli has been considered the most reliable and valid indicator of sexual arousal. The adoption of analogous criteria is recommended for research on other male mammals in order to establish a minimal basis for inferring that they are sexually aroused. That is, sexual arousal should be inferred only when penile erection is observed in a sexual context. A sexual context is provisionally defined as an environment that tends in most reproductively active males of the species to provoke further sexual stimulation, e.g., copulation or self-stimulation to ejaculation. Erection occurring outside of a sexual context, as during REM sleep or from injection of drugs, is not grounds for inferring arousal. Conversely, males engaging in behavior directed toward estrous females may be sexually motivated, but in the absence of erection, the males should not be assumed to be sexually aroused. Implications of other erection-context interactions are also considered. Adoption of these more conservative criteria for inferring sexual arousal may promote greater precision in identifying the physiological systems mediating this hypothetical construct.