Valeri D. Goncharuk

Organization of circadian functions: interaction with the body.

The hypothalamus integrates information from the brain and the body; this activity is essential for survival of the individual (adaptation to the environment) and the species (reproduction). As a result, countless functions are regulated by neuroendocrine and autonomic hypothalamic processes in concert with the appropriate behaviour that is mediated by neuronal influences on other brain areas. In the current chapter attention will be focussed on fundamental hypothalamic systems that control metabolism, circulation and the immune system. Herein a system is defined as a physiological and anatomical functional unit, responsible for the organisation of one of these functions. Interestingly probably because these systems are essential for survival, their function is highly dependent on each others performance and often shares same hypothalamic structures. The functioning of these systems is strongly influenced by (environmental) factors such as the time of the day, stress and sensory autonomic feedback and by circulating hormones. In order to get insight in the mechanisms of hypothalamic integration we have focussed on the influence of the biological clock; the suprachiasmatic nucleus (SCN) on processes that are organized by and in the hypothalamus. The SCN imposes its rhythm onto the body via three different routes of communication: 1.Via the secretion of hormones; 2. via the parasympathetic and 3.via the sympathetic autonomous nervous system. The SCN uses separate connections via either the sympathetic or via the parasympathetic system not only to prepare the body for the coming change in activity cycle but also to prepare the body and its organs for the hormones that are associated with such change. Up till now relatively little attention has been given to the question how peripheral information might be transmitted back to the SCN. Apart from light and melatonin little is known about other systems from the periphery that may provide information to the SCN. In this chapter attention will be paid to e.g. the role of the circumventricular organs in passing info to the SCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted. The ARC is crucial in the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. Receptors for metabolic hormones like insulin, leptin and ghrelin allow the ARC to sense information from the periphery and signal it to the central nervous system. Neuroanatomical tracing studies using injections of a retrograde and anterograde tracer into the ARC and SCN showed a reciprocal connection between the ARC and the SCN which is used to transmit feeding related signals to the SCN. The implications of multiple inputs and outputs of the SCN to the body will be discussed in relation with metabolic functions.

Paraventricular nucleus of the human hypothalamus in primary hypertension: Activation of corticotropin-releasing hormone neurons

By using quantitative immunohistochemical and in situ hybridization techniques, we studied corticotropin‐releasing hormone (CRH) ‐producing neurons of the hypothalamic paraventricular nucleus (PVN) in patients who suffered from primary hypertension and died due to acute cardiac failure. The control group consisted of individuals who had normal blood pressure and died of acute heart failure due to mechanical trauma. Both magno‐ and parvocellular populations of CRH neurons appeared to be more numerous in the PVN of hypertensive patients. Quantitative analysis showed approximately a twofold increase in the total number of CRH neurons and a more than fivefold increase in the amount of CRH mRNA in the hypertensive PVN compared with the control. It is suggested that synthesis of CRH in hypertensive PVN is enhanced. Increased activity of CRH‐producing neurons in the PVN of hypertensive patients is proposed not only to entail hyperactivity of the hypothalamo‐pituitary‐adrenal axis, but also of the sympathetic nervous system and, thus, to be involved in the pathogenesis of hypertension. J. Comp. Neurol. 443:321–331, 2002.

Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock

Abnormalities in autonomic activity resulting in disturbances of the diurnal rhythm of many physiologic processes were recently revealed in hypertensive patients. These findings suggest deteriorations in the functioning of the suprachiasmatic nucleus (SCN), which is known to be the biological clock of mammals. To test this hypothesis, we carried out an immunocytochemical study of the SCN of primary hypertension patients who had died due to myocardial infarction or brain hemorrhage, and compared them with those of individuals with a normal blood pressure who had never had any autonomic disturbances and died from myocardial infarction after chest trauma or from hypothermia. We found that the staining for the three main neuronal populations of the SCN; i.e., vasopressin, vasoactive intestinal polypeptide, and neurotensin, reduced by more than 50% in the hypertensives compared with controls. The present data indicate a serious dysregulation of the biological clock in hypertensive patients. Such a disturbance may cause a harmful hemodynamic imbalance with a negative effect on circulation, especially in the morning, when the inactivity‐activity balance changes. The difficulty in adjusting from inactivity to activity might be involved in the morning clustering of cardiovascular events. J. Comp. Neurol. 431:320–330, 2001.

Emergence of the silicon human and network targeting drugs

The development of disease may be characterized as a pathological shift of homeostasis; the main goal of contemporary drug treatment is, therefore, to return the pathological homeostasis back to the normal physiological range. From the view point of systems biology, homeostasis emerges from the interactions within the network of biomolecules (e.g. DNA, mRNA, proteins), and, hence, understanding how drugs impact upon the entire network should improve their efficacy at returning the network (body) to physiological homeostasis. Large, mechanism-based computer models, such as the anticipated human whole body models (silicon or virtual human), may help in the development of such network-targeting drugs. Using the philosophical concept of weak and strong emergence, we shall here take a more general look at the paradigm of network-targeting drugs, and propose our approaches to scale the strength of strong emergence. We apply these approaches to several biological examples and demonstrate their utility to reveal principles of bio-modeling. We discuss this in the perspective of building the silicon human.

Vasopressin (VP) and neuropeptide FF (NPFF) systems in the normal and hypertensive human brainstem.

Vasopressin (VP)‐, neuropeptide FF (NPFF)‐, and tyrosine hydroxylase (TH)‐expressing neurons were studied by means of single and double immunocytochemistry in the human brainstem of controls who died suddenly due to trauma and of patients who suffered from essential hypertension and died due to acute myocardial infarction, while in one case there was brain hemorrhage. In the control and hypertensive groups VP fibers and NPFF neurons and fibers were the most abundantly present in the dorsal vagal complex, especially in the dorsal motor nucleus of the vagus. Numerous VP and NPFF fibers formed synaptic‐like contacts with neuronal profiles in the dorsointermediate, centrointermediate, ventrointermediate, caudointermediate, and caudal parts of the dorsal motor nucleus of vagus as well as adjacent medial and intermediate subnuclei of the solitary nucleus. VP, but not NPFF, positive fibers were found to vastly contact TH‐positive neuronal profiles in A2/C2, A2, and ambiguus nucleus (Amb). The density of VP fibers in the dorsal motor nucleus of the vagus and Amb did not differ between hypertensive patients and controls, whereas the density of NPFF fibers in hypertensives was 3.19 times lower in the dorsal motor nucleus of vagus and markedly decreased in the Amb. In both groups, VP and NPFF were scarcely present in the pain pathways, suggesting that these peptides are not crucially involved in nociceptive control in human. The reduction of NPFF release within the dorsal motor nucleus and Amb could serve as a possible cause of the impairment of cardiac vagal control in hypertensive patients. J. Comp. Neurol. 519:93‐124, 2011.

Distribution of the neuropeptide FF1 receptor (hFF1) in the human hypothalamus and surrounding basal forebrain structures: immunohistochemical study.

Neuropeptides with C‐terminal RFamide and their receptors NPFF1 (FF1) and NPFF2 (FF2) have been implicated in a wide variety of functions, including nociception and autonomic and neuroendocrine regulation. Recent studies indicate that the FF1, but not FF2, mRNA is highly expressed in the human hypothalamus. In the present study, localization of FF1 in the human hypothalamus and surrounding regions was studied immunohistochemically by using an antibody against human FF1 (hFF1). Brain sections from healthy 30–50‐year‐old individuals were used for hFF1 immunohistochemistry. The highest density of hFF1‐stained cells was found in the posterior division of the bed nucleus of the stria terminalis and in the zona incerta. A moderate density of cells was observed in the perifornical nucleus, infundibular nucleus, tuberomammillary nucleus, and lateral tuberal nucleus. A lesser density was revealed in the dorsomedial hypothalamic nucleus, basal nucleus of Meynert, and anterior amygdaloid area. Only scattered hFF1 cells were found in the suprachiasmatic nucleus and hypothalamic paraventricular nucleus. hFF1 cells and fibers were absent in the supraoptic and mammillary nuclei. Single and double strands of hFF1‐immunopositive punctate varicosities marked cellular processes of different caliber. The density of hFF1‐immunostained fiber networks did not always coincide with that of hFF1‐immunostained cells. hFF1 immunoreactivity was also found in the wall of blood vessels within most brain areas studied. Localization of hFF1 in discrete regions of the hypothalamus and extended amygdala may provide important insights into the role of amidated neuropeptides in central autonomic and neuroendocrine control in the human brain. J. Comp. Neurol. 474:487–503, 2004.

Macromolecular networks and intelligence in microorganisms

Living organisms persist by virtue of complex interactions among many components organized into dynamic, environment-responsive networks that span multiple scales and dimensions. Biological networks constitute a type of information and communication technology (ICT): they receive information from the outside and inside of cells, integrate and interpret this information, and then activate a response. Biological networks enable molecules within cells, and even cells themselves, to communicate with each other and their environment. We have become accustomed to associating brain activity – particularly activity of the human brain – with a phenomenon we call “intelligence.” Yet, four billion years of evolution could have selected networks with topologies and dynamics that confer traits analogous to this intelligence, even though they were outside the intercellular networks of the brain. Here, we explore how macromolecular networks in microbes confer intelligent characteristics, such as memory, anticipation, adaptation and reflection and we review current understanding of how network organization reflects the type of intelligence required for the environments in which they were selected. We propose that, if we were to leave terms such as “human” and “brain” out of the defining features of “intelligence,” all forms of life – from microbes to humans – exhibit some or all characteristics consistent with “intelligence.” We then review advances in genome-wide data production and analysis, especially in microbes, that provide a lens into microbial intelligence and propose how the insights derived from quantitatively characterizing biomolecular networks may enable synthetic biologists to create intelligent molecular networks for biotechnology, possibly generating new forms of intelligence, first in silico and then in vivo.

Role of neuropeptide FF in central cardiovascular and neuroendocrine regulation

Neuropeptide FF (NPFF) is an octapeptide belonging to the RFamide family of peptides that have been implicated in a wide variety of physiological functions in the brain including central cardiovascular and neuroendocrine regulation. The effects of these peptides are mediated via NPFF1 and NPFF2 receptors that are abundantly expressed in the rat and human brain. Herein, we review evidence for the role of NPFF in central regulation of blood pressure particularly within the brainstem and the hypothalamic paraventricular nucleus (PVN). At a cellular level, NPFF demonstrates distinct responses in magnocellular and parvocellular neurons of the PVN, which regulate the secretion of neurohypophyseal hormones and sympathetic outflow, respectively. Finally, the presence of NPFF system in the human brain and its alterations within the hypertensive brain are discussed.

Neuropeptide FF2 receptor distribution in the human brain: An immunohistochemical study

Human neuropeptide FF2 (hFF2) receptor has been postulated to mediate central autonomic regulation by virtue of its ability to bind with high affinity to many amidated neuropeptides. In the present immunohistochemical study, we identified hFF2 positive neurons in the forebrain and medulla oblongata of individuals, who died suddenly of mechanical trauma or hypothermia. Morphologically, these neurons demonstrated features identified with both projection neurons and interneurons. In the forebrain, the highest density of hFF2 expressing neurons was observed in the anterior amygdaloid area and dorsomedial hypothalamic nucleus, especially in its caudal part. A lesser density of hFF2 neurons was identified in the ventromedial hypothalamic nucleus, lateral and posterior hypothalamic areas whereas few cells were visualized in the paraventricular hypothalamic nucleus, perifornical nucleus, horizontal limb of the diagonal band, ventral division of the bed nucleus of the stria terminalis, nucleus basalis of Meynert and ventral tegmental area. In the medulla, significant numbers of hFF2 neurons were observed in the dorsal motor nucleus of vagus and to a lesser extent in the area of catecholaminergic cell groups, A1/C1. These data provide first immunohistochemical evidence of hFF2 localization in the human brain, which is consistent with that reported for tissue distribution of FF2 mRNA and FF2 binding sites within the brain of a variety of mammalian species. The distribution of hFF2 may help in identifying the role of amidated neuropeptides in the human brain within the context of central autonomic and neuroendocrine regulation.

Neuropeptide FF Distribution in the Human and Rat Forebrain: a Comparative Immunohistochemical Study

Neuropeptide FF (NPFF) is an octapeptide implicated in a variety of physiological functions, including nociception, cardiovascular responses, and neuroendocrine regulation. The NPFF gene and its mRNA are highly conserved across species. A comparative study of NPFF distribution in the human and rat forebrain was carried out by using single NPFF and double NPFF + vasopressin (VP) immunohistochemistry. NPFF is extensively localized within neurochemical circuits of human and rat forebrain. Semiquantitative analysis revealed that the densities of NPFF cells and fibers in many forebrain nuclei in the human correlate well with those observed for the same structures in the rat. High numbers of NPFF positive neurons in the dorsomedial hypothalamic nucleus and a dense plexus of NPFF fibers surrounding the fornix within the bed nucleus of the stria terminalis were identified in the human and rat forebrain. Within the hypothalamus of both species, dense NPFF innervation was observed in the perinuclear zone of the supraoptic nucleus (SO) just dorsolateral to the VP‐positive neurons. Extensive NPFF innervation of ventricular ependyma and brain microvasculature were common for both species. At the same time, obvious differences in NPFF localization between the two species were also apparent. For example, in contrast to the rat SO, no NPFF‐ or NPFF‐ + VP‐immunostained cells were observed in the human SO. Knowledge of NPFF neuroanatomical localization in the human brain and the relationship of these observations to those in the rat brain may provide insight into the role of this peptide in central cardiovascular and neuroendocrine regulation. J. Comp. Neurol. 496:572–593, 2006.