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Two respiration-related rhythm generators, the pre-Bötzinger complex inspiratory and the parafacial pre-inspiratory rhythm generators, have been identified in the medulla of rodents that produce intrinsic periodic bursts. Although both generators can be independently active under specific conditions, they interact as a coupled oscillator system to regulate the respiratory rhythm. Here, we summarize different mechanisms of modulation of the respiratory rhythm in the brainstem-spinal cord preparation of newborn rats and discuss factors determining rhythm generator dominance. We show two different modes of respiratory rhythm generation in the brainstem-spinal cord preparation that depends on the background stimulation level. [ABSTRACT FROM AUTHOR]

The object of this study was to investigate the source localization of event-related potentials (ERPs) related to cross-modal semantic interference effect. Twenty-eight healthy volunteers participated in the study, in which ERPs were measured while subjects judged the semantic relationship between a test picture and a preceding context picture where a superimposed context word was either semantically related (related condition) or unrelated (unrelated condition) to the test picture. The source localization of the equivalent current dipoles (ECDs) of the ERP components, which significantly varied between the related and the unrelated condition when the pictures were semantically unrelated, was determined by the scalp-skull-brain dipole tracing (SSB-DT) method using a two-dipole model. Three distinct components were observed in the difference ERPs obtained by subtracting the ERPs of the unrelated condition from those of the related condition: An early positive component arising in the latency range of 380–420 ms, a negative component in the latency range of 520–560 ms, and a late positive component in the latency range of 680–720 ms. According to the SSB-DT method, significant ECDs were found only for the negative component. The ECDs of the negative component were localized in the right anterior cingulate gyrus and the left superior temporal gyrus, which was nearly in accordance with the source generator of the response conflict negativity reported in previous studies. [ABSTRACT FROM AUTHOR]

Studies in human and other primates reveal that the amygdala, orbitofrontal and ventromedial frontal cortices, and cerebral cortex in and near the superior temporal sulcus (STS) region are important components of facial cognition. We investigated neural mechanisms that were involved in recognizing facial expressions in patients with Parkinson’s disease (PD) by visual event-related potentials and the dipole-tracing method. Our result showed that dysfunction of the amygdala in patient with PD changes the neural substrates that are normally used to recognize facial expression. Instead of amygdala, STS region in patients with PD were predominantly involved in response to fearful facial expression, as compared with normal subjects. [ABSTRACT FROM AUTHOR]

The expression of Noh, one of the most traditional performing arts in Japan, does not present external expressions or attitudes but interior expressions. We examined how we sympathized their interior expressions without body expression and word, and how the interior expressions are made in the actor’s brain. We simultaneously recorded EEG activities and respiratory movements during performing sad emotions in the Noh actors. Their chest walls were hyper inflated and breathing rhythm increased during the performance and negative potential changes were recorded from 300msec before to 300msec after the onset of inspiration. Dipoles, estimated during the pre-inspiratory potential changes using the dipole tracing method, were located in the temporal lobe especially in hippocampus, amygdala and insula. The results suggest that sad emotions in Noh are expressed in increasing of breathing rate and the sources of EEG potential changes related to the respiration are located in limbic and paralimbic areas. [ABSTRACT FROM AUTHOR]

To search for genes that cause human congenital respiratory failure, we undertook several studies using wild type mice and gene-deficient mice that exhibit respiratory failure. 1) To assess respiratory abnormality, ventilatory parameters were determined by whole-body plethysmography of prenatal and neonatal mice. 2) To clarify the mechanism of respiratory failure, respiratory neuron activity was examined by electrophysiological and optical imaging analysis using a brainstem-spinal cord preparation. 3) To search for the genes related to central respiratory failure in brainstem, alteration of gene expression in the medulla oblongata during transition from embryonic respiration to external respiration was examined by DNA microarray. To date, we have studied several lines of gene-deficient mice exhibit respiratory failure, and we propose a model of central respiratory failure as a syndrome resembling congenital central hypoventilation. [ABSTRACT FROM AUTHOR]

We visualized respiratory neuron network activity in the medulla of the rat and mouse in vitro by optical recordings using voltage-sensitive dye. The brainstem and spinal cord of 0- to 1-day-old Wistar rats and 0-day-old mice isolated under deep ether anaesthesia were incubated in a modified Krebs solution containing a fluorescent voltage-sensitive dye. Fluorescence signals corresponding to respiratory activity were detected by a CCD image sensor. Pre-inspiratory neuron activity appeared in the limited region of the rostral ventrolateral medulla [i.e. para-facial respiratory group (pFRG) region], preceding the onset of inspiratory activity by about 500 ms. During the inspiratory phase, plateau activity appeared in the more caudal ventrolateral medulla at the level of most rostral roots of the XIIth nerve (i.e. the pre-Bötzinger complex level). We found that pre-inspiratory neurons which were a predominant subtype of the pFRG neurons were located in the area immediately beneath the ventral pia mater at the level of the facial nucleus. We also analyzed respiratory neuron activity in the wild type and two kinds of knock-out mice that exhibit respiratory failure leading to neonatal death due to dysfunction of central respiratory neuron activity. The optical recordings clearly detected the difference in the spatio-temporal pattern between the wild type and both knockout mice. [ABSTRACT FROM AUTHOR]

Respiration is spontaneous activity regulated in the brainstem for metabolic purposes. However, respiratory activity can be changed voluntarily, which could be related to supplementary and pre-motor areas in the cortex (Ramsay et al. 1993). In addition, breathing is altered unconsciously by many types of cognitive inputs such as auditory and visual stimuli (Mador and Tobin 1991). Not only these external stimuli, but also emotions or the internal state changes breathing patterns. Therefore, the final respiratory outputs could be results produced from an interaction between metabolism and higher functions, namely, the brainstem and the limbic and cortical structures. Respiratory psychophysiology studies in humans have reported that various emotions alter respiratory patterns (Boiten et al. 1994). On the other hand, recent neuroimaging studies have investigated the neuroanatomical correlates of emotions, especially fear and anxiety (Morris et al. 1998; Reiman et al. 1989). Emotions are not phenomena within the brain itself but involve physiological changes of the whole body. Respiration is one of the physiological outputs altered by emotions. Besides metabolic, emotional and volitional breathing, respiration has another function, the role of olfaction. Smelling is largely dependent on inhaling; we are able to sense an odor by sniffing. In this chapter we focus on the relation between the limbic areas and respiration by showing our results obtained in humans. In addition, we also report results from our previous study regarding new insights into respiration through olfaction. [ABSTRACT FROM AUTHOR]

Many studies about the effect of stressors on immune activities were reported, but the mechanisms of those effects were obscure yet. Restraint water immersion stress reduced splenic NK cell activity (NK activity) measured by cytotoxicity to YAC-1 cells in rats through both humoral and neural mechanisms. Electrical lesion of hypothalamic paraventricular nucleus (PVN) markedly enhanced NK activity, but the lesion of ventromedial hypothalamic nucleus (VMH) depressed NK activity. These results suggest that the stress may inhibit NK activity through the activation of hypothalamic paraventricular nucleus. [ABSTRACT FROM AUTHOR]

We have investigated excitatory synaptic transmission from the lateral part of the supratrigeminal region (lSuV) to the trigeminal motor nucleus (MoV) in neonatal and juvenile rat brain stem slice preparations by high-speed optical recording techniques and gramicidin perforated-patch recordings. Electrical stimulation of lSuV evoked optical responses in MoV. An antidromic response in lSuV was evoked by MoV stimulation while synaptic transmission was suppressed by substitution of external Ca2+ with Mn2+. Application of CNQX and APV to MoV reduced the optical responses in MoV evoked by ISuV stimulation in both neonatal and juvenile rats. Application of strychnine to MoV also suppressed the optical responses in MoV of neonatal rats. On the other hand, strychnine enhanced the optical responses in MoV of juveniles. Gramicidin perforated-patch recordings from trigeminal motoneurons (TMNs) revealed that glycinergic postsynaptic potentials evoked by lSuV stimulation were depolarizing in neonatal rats but become hyperpolarizing in juveniles. We conclude that inputs from lSuV excite TMNs through activation of glutamate or glycine receptors in neonatal rats, whereas glycine receptor activation in TMNs becomes inhibitory in juveniles. Such postnatal change of synaptic transmission from lSuV to MoV might be involved in the transition from suckling to mastication. [ABSTRACT FROM AUTHOR]

“Barreloids” and “barrels” are patch-like structure representing single whiskers observed in the ventroposterior thalamic nucleus (VP) and somatosensory cortex in rodents, respectively. They are characteristic structure observed during the early neonatal period, which is an important period for the development of the networks in VP and somatosensory cortex. Various neurotransmitter systems have been reported to be involved in the development of these structure including, serotonergic, glutamatargic, GABAergic and cholinergic ones. The present study indicated that immunoreactivity for a calcium binding protein, S-100B, was transiently found as “barreloids” in VP at postnatal day (PND) 7 and as “barrels” in the somatosensory layer IV at PND 15, respectively. “Barrel” - like 5-hydroxytriptamine transporter (5-HTT) immunoreactivity was also found in the somatosensory cortex at PND 15. Morphological findings indicated that S-100B was present in cellular nuclei and released into extracellular space in both the thalamus and cortex. S-100B is suggested to be involved in the formation or remodeling of networks in VP and the somatosensory cortex via modulating calcium levels intra- and extracellularly beside changes in related neurotransmitters. [ABSTRACT FROM AUTHOR]

Although blockade by antidepressants of monoamine uptake into nerve endings is one of the cornerstones of the monoamine hypothesis of depression, there is a clear discrepancy between the rapid effects of antidepressants in increasing synaptic concentrations of monoamine and the lack of immediate clinical efficiency of antidepressant treatment. Pharmacogenomics, functional genomics and proteomics are powerful tools that can be used to identify genes/ESTs or molecular systems affected by antidepressants. Using a differential cloning strategy, we and other groups have isolated genes that are differentially expressed in the brain after chronic antidepressant treatment. Some of these candidate genes may encode functional molecular systems or pathways induced by chronic antidepressant treatment. Defining the roles of these molecular systems in drug-induced neural plasticity is likely to transform the course of research on the biological basis of depression. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. [ABSTRACT FROM AUTHOR]

The biological basis for the therapeutic mechanisms of depression are still unknown. We have previously performed EST analysis and identified some common biological changes induced after chronic antidepressant treatment as antidepressant related genes/ESTs: ADRG#1-707. Then, we developed our original cDNA microarray on which ADRG#1-707 were spotted, for rapid secondary screening of candidate genes as the novel therapeutic targets. With this microarray, we found that the expression of some of the ADRGs were related to neurotransmiter release and located on synaptic vesicle. Indeed, VAMP2/synaptobrevin, cysteine string protein, synapsin I, Rab-IA and Rab-3B were induced after chronic sertraline treatment in rat frontal cortex. Western blot analysis also demonstrated the induction of these ADRGs at protein levels after chronic treatment with imipramine and sertraline. In addition, synaptophysin and secretogranin II, often used as a marker protein for small synaptic vesicle or large dense core granule were significantly increased after chronically treatment with antidepressants. On the other hand, the expression of SNAP-25 and syntaxin-1, which are used as markers for synapse and make a SNARE-complex with VAMP2, were not affected by these treatments. These results suggested that the number of synaptic vesicles, but not the number of synapses, was increased after chronic antidepressant treatment. The synaptic vesicles and proteins may be a new target molecular system for antidepressant. [ABSTRACT FROM AUTHOR]

Using forward (i.e. positional cloning in canine narcolepsy) and reverse (i.e. mouse gene knockout) genetics, genes involved in the pathogenesis of narcolepsy (hypocretin/orexin ligand and its receptor) in animals have been identified. Mutations in hypocretin related-genes are rare in humans, but hypocretin-ligand deficiency is found in many cases. This discovery is likely to lead to the development of new diagnostic tests and treatments. Hypocretins/orexins are novel hypothalamic neuropetides also involved in various hypothalamic functions such as energy homeostasis, autonomic and neuroendocrine functions. Hypocretin-deficient narcolepsy thus appears now to be a more complex condition than a simple sleep disorder, and it may serve a disease model to study the most fundamental hypothalamic function. [ABSTRACT FROM AUTHOR]

In developmental neuroscience, 5-bromo-2′-deoxyuridine (BrdU) is extensively used as a useful tool for labeling proliferating cells. Doses ranging from 10 to 100 mg/kg are commonly injected into animals. However, several lines of evidence demonstrated that BrdU has genotoxicity. The present study demonstrates that 1) a single injection of BrdU at 100 mg/kg into pregnant mice on gestation day 11.5 induced cell death in the neuroepithelium of certain brain areas such as the frontal neocortex, but not other areas such as the mesencephalic tegmentum and pons, 2) injections of BrdU into adult mice at 100 or 300 mg/kg did not induce cell death in the subventricular zone (SVZ) of the lateral ventricle, known to be a site of adult neurogenesis. These findings strongly suggest that 1) sensitivity to the genotoxicity differes among fetal neural stem cells, 2) BrdU-labeling should be avoided when early neurogenesis is being observed. [ABSTRACT FROM AUTHOR]

Recently it has been reported that pituitary adenylate cyclase-activating polypeptide (PACAP) possesses diverse physiological functions in central nervous system. In this study, the effect of physiological concentrations of PACAP on the differentiation of neural stem cells is described. When neural stem cells were exposed to 0.2 nM PACAP, total number of the cells decreased during the 8 days-culture. However, number of MAP2-immunopositive cells decreased while GFAP-immunopositive cells increased depending on the concentration of PACAP (0.2–2 nM). Neural stem cells were differentiated into astrocytes even at a concentration below 2 nM. These results indicate that PACAP at a low concentration prefers induction of differentiation into astrocytes rather than proliferation in neural stem cells. [ABSTRACT FROM AUTHOR]

Lipid peroxidation is induced by reactive oxygen species and is involved in acute neuronal damage. Thus, controlling this process may be a realistic therapeutic strategy for treating or preventing neuronal damage. However, the study of free radicals in body fluids is currently severely hampered by technical difficulties in their detection. We have developed an ex vivo electron spin resonance (ESR) method, that employs 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap, to measure the alkoxyl radical (OR) in human blood. We found that this method can detect OR produced by treating human blood ex vivo. Analysis of jugular venous and radial arterial blood from patients with acute neuronal damage revealed higher OR levels in the venous blood compared to arterial samples. In brain death patients, however, the jugular vein OR spectrum was similar to the radial artery OR level. The ratio between radial artery and jugular vein levels, expressed as the RI (radical intensity) ratio = aORI/jORI, was calculated. A rterial-jugular bulb RI ratio below 1, together with accepted clinical criteria (unresponsive coma with brainstem areflexia), may provide a non-invasive assessment of cerebral circulatory arrest that can help to predict brain death. This novel ex vivo ESR method may be very useful for measuring oxidative stress in patients with acute neuronal damage. [ABSTRACT FROM AUTHOR]

The incidence of stroke is gradually increasing in the industrialized world and a major cause of long-lasting disability. To determine the mechanism of neuronal cell death after stroke and develop the new strategy of therapy, several studies had been performed during the past decade and some proinflammatory cytokines were identified as the therapeutic candidate. However, the critical actions of proinflammatory cytokines are still largely unknown in detail because the cytokines play a role on small amount, show the short half-life, and have multiple functions for depending on the amount and time of expression. We present here the pathophysiological events of cerebral ischemia and the action and possibility of proinflammatory cytokines from the recent results. [ABSTRACT FROM AUTHOR]

The blood- brain barrier (BBB) has emerged as a regulatory interface that controls the exchange of informational molecules between the blood and the central nervous system (CNS) fluids (the brain interstitial and the cerebrospinal fluid). As such, it is a pivotal point in a humoral-based, endocrine-like communication between the CNS and peripheral tissues. For example, the BBB controls the entry of major feeding hormones into the CNS from the blood, including leptin. Impaired transport of leptin across the BBB is an early cause of leptin resistance. Leptin transport is regulated by alpha1-adrenergics, which simulate transport, and triglycerides, which inhibit it. The ability of triglycerides to inhibit leptin transport may have evolved as a response to the hypertriglyceridemia of starvation. If so, their ability to inhibit leptin transport in obesity may be a metabolic case of mistaken identity. [ABSTRACT FROM AUTHOR]

Central histaminergic neurons located in the posterior hypothalamus affect many autonomic behaviors. We examined the roles of these neurons in respiration in conscious histamine H1 receptor-knockout (H1RKO) and wild-type (WT) mice. Acute stepwise hypercapnia increased respiratory frequency (f), tidal volume (VT), and minute ventilation (VE) in both genotypes. However, H1RKO mice showed a lower f response and a higher VT response than those of WT mice. The VT-TI relation curve for H1RKO mice was shifted to the right and upward relative to that for WT mice, suggesting that in H1RKO mice the termination of inspiration is delayed by an increase in the inspiratory off switch (IOS) threshold. Increased body temperature increased the f response to hypercapnia in WT but not in H1RKO mice. This polypnea during hypercapnia was due mainly to a reduction in TE. These results suggest that central histaminergic neurons contribute to the termination of inspiration in the IOS mechanism and to polypnea during hyperthermia via activation of H1 receptors. [ABSTRACT FROM AUTHOR]

Neuronal damages in lumbar spinal cord are known to induce the motor deficit after systemic ischemia including cardiac arrest and heart attack. Recently we reported that the neuronal damages in the hippocampus and lumbar spinal cord were induced after the combination of cardiac arrest and massive hemorrhagic shock. In the model, the neurons in intermediate gray matter were showed necrotic neuronal cell death at 1 d after ischemia. However, the damages of white matter did not understood well. Therefore, we focused on the white matter damages and have checked on the processes of the demyelination in limber spinal cord after severe systemic ischemia using electron microscopy. At 1 d, the myelin sheaths was collapsed and dissociated from axon although the axons seemed relatively intact. At 7 d, many shrank axons were observed and some of axons were disappeared. This result suggested the progressively demyelination was observed in ventral white matter in lumber spinal cord prior to axonal degeneration after severe systemic ischemia. [ABSTRACT FROM AUTHOR]