Pivotal Region Research Articles

Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks.

Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large-scale functional brain networks across different forms of isolated focal dystonia, including patients with task-specific (TSD) and nontask-specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia-cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large-scale functional networks, where abnormal regional interactions contribute to network-wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder-specific network aberrations.

Altered neurotrophic factors' expression profiles in the nucleus of the solitary tract of spontaneously hypertensive rats.

Our previous findings suggest that the nucleus of the solitary tract (NTS), a pivotal region for regulating the set point of arterial pressure, exhibits abnormal inflammation in pre-hypertensive and spontaneously hypertensive rats (SHRs), with elevated anti-apoptotic and low apoptotic factor levels compared with that of normotensive Wistar-Kyoto (WKY) rats. Whether this chronic condition affects neuronal growth and plasticity in the NTS remains unknown. To unveil the characteristics of the neurodevelopmental environment in the NTS of SHRs, we investigated the expression of neurotrophic factors transcripts in SHRs. RT(2) Profiler PCR Array targeting rat neurotrophins and their receptors was used to screen for differentially expressed transcripts in the NTS of SHRs compared to that of WKY rats. Protein expression and physiological functions of some of the differentially expressed transcripts were also studied. Gene and protein expressions of glial cell line-derived neurotrophic factor family receptor alpha-3 (Gfrα-3) factor were both upregulated in the NTS of adult SHRs. Gene expressions of corticotropin-releasing hormone-binding protein (Crhbp), interleukin-10 receptor alpha (Il-10ra) and hypocretin (Hcrt) were downregulated in the NTS of adult SHRs. The Gfrα-3 transcript was increased and the Hcrt transcript was decreased in the NTS of young pre-hypertensive SHRs, suggesting that these profiles are not secondary to hypertension. Moreover, microinjection in the NTS of hypocretin-1 decreased blood pressure in adult SHRs. These results suggest that altered neurotrophic factors transcript profiles may affect the normal development and function of neuronal circuitry that regulates cardiovascular autonomic activity, thereby resulting in manifestations of neurogenic hypertension in SHRs.

Geoeconomics in the Long War

AbstractIn Neil Smith's American Empire (2003, University of California Press), he makes the case that the current moment of US global ambition is characterized by a network of imperial power that is “exercised in the first place through the world market and only secondarily, when and if necessary, in geopolitical terms”. For Smith, it was crucial that in the din of US geopolitics in the post‐9/11 period we did not lose sight of “the deeper geo‐economic aspiration for global control”, in a “war on terror” that is really a war to “fill in the interstices of globalization” (p xiv). In American Empire, Smith identified three moments of US global ambition over the last century. In this paper, I extend back the starting point for Smith's third moment to a period in the 1990s when United States Central Command (CENTCOM) became fully operational in the military‐economic securitization of the most pivotal region on earth, what it terms the “Central Region”. By drawing on the concept of “geoeconomics”, which Smith increasingly used in his later writing, I show how CENTCOM's mission from the outset can be most aptly described as one of “geoeconomic deterrence”. I highlight in particular how enabling commercial markets has been a key element of grand strategy in what CENTCOM calls its “long war” in the Middle East and Central Asia. In addition, I outline recent calls for the US military to become further and more broadly involved in what some commentators have called “messy capitalism”. I ask the question what kind of capitalism and in whose interests, before concluding by reflecting upon Neil Smith's assessment of the fated contradictions of contemporary US imperial ambition.

Early-life overnutrition influences spatial memory and hippocampal microgliosis

The early life nutritional environment can program hypothalamic microglial proliferation, with a predisposition to a central proinflammatory profile long-term. We hypothesise that long-term microgliosis caused by overnutrition during critical developmental periods extend beyond the hypothalamus into the hippocampus, a pivotal region in memory formation, and that this will disrupt cognition. To test this idea, we manipulated the litter sizes Wistar rat pups were suckled in, ensuring that the pups were raised in litters of 4 (neonatally overfed) or 12 (control). This model of manipulation produces long-term obesity as well as microglial priming in the hypothalamus in the neonatally overfed. Once the rats reached adulthood, we observed the effects of early life overfeeding on cognitive function using the radial arm maze to investigate rat spatial learning and memory. We also examined hippocampal microglial number and density using immunohistochemistry for ionized calcium binding protein (Iba1). Adult rats that were overfed as neonates did not consolidate spatial working and reference memory as efficiently as their control counterparts, despite reaching criterion at the same time. This was accompanied by microgliosis in the dentate gyrus of the hippocampus in the neonatally overfed. These findings suggest early-life diet may influence spatial memory formation at the level of the hippocampus.

Unsupervised Texture Segmentation of Natural Scene Images Using Region-based Markov Random Field

In analyzing natural scene images, texture plays an important role because such images are full of various textures. Although texture is crucial information in analyzing natural scene images, the texture segmentation problem is still hard to solve since the texture often exhibit non-uniform statistical characteristics. Although there are several supervised approaches that partition an image according to pre-defined semantic categories, the ever-changing appearances in the natural images make such schemes intractable. To overcome this limitation, we propose a novel unsupervised texture segmentation method for natural images by using the Region-based Markov Random Field (RMRF) model which enforces the spatial coherence between neighbor regions. We introduce the concept of pivot regions which plays a decisive role to incorporate local data interaction. By forcing pivot regions to adhere to initial labels, we make the Markov Random Field evolve fast and precisely. The proposed algorithm based on the pivot regions and the MRF for encapsulating spatial dependencies between neighborhoods yields high performance for the unsupervised segmentation of natural scene images. Quantitative and qualitative evaluations prove that the proposed method achieves comparable results with other algorithms.

Insight into structural rearrangements and interdomain interactions related to electron transfer between flavin mononucleotide and heme in nitric oxide synthase: A molecular dynamics study

Calmodulin (CaM) binding to nitric oxide synthase (NOS) enables a conformational change, in which the FMN domain shuttles between the FAD and heme domains to deliver electrons to the active site heme center. A clear understanding of this large conformational change is critical, since this step is the rate-limiting in NOS catalysis. Herein molecular dynamics simulations were conducted on a model of an oxygenase/FMN (oxyFMN) construct of human inducible NOS (iNOS). This is to investigate the structural rearrangements and the domain interactions related to the FMN–heme interdomain electron transfer (IET). We carried out simulations on the iNOS oxyFMN·CaM complex models in [Fe(III)][FMNH−] and [Fe(II)][FMNH] oxidation states, the pre- and post-IET states. The comparison of the dynamics and conformations of the iNOS construct at the two oxidation states has allowed us to identify key factors related to facilitating the FMN–heme IET process. The computational results demonstrated, for the first time, that the conformational change is redox-dependent. Predictions of the key interacting sites in optimal interdomain FMN/heme docking are well supported by experimental data in the literature. An intra-subunit pivot region is predicted to modulate the FMN domain motion and correlate with existence of a bottleneck in the conformational sampling that leads to the electron transfer-competent state. Interactions of the residues identified in this work are proposed to ensure that the FMN domain moves with appropriate degrees of freedom and docks to proper positions at the heme domain, resulting in efficient IET and nitric oxide production.

Neuroimaging signature of neuropsychiatric disorders.

This review focuses on new findings related to structural and functional changes in large-scale brain networks (i.e., pathoconnectomics) that occur in neuropsychiatric disorders, particularly Parkinson's disease, Alzheimer's disease and Gilles de la Tourette syndrome. Many neuropsychiatric disorders involve dysfunction in neuronal regions that are defined as hubs; these regions are pivotal regions of information transfer in large-scale brain networks. In neuropsychiatric disorders with neurodevelopmental mechanisms, the common connectivity profiles remain unclear as both hyper- and hypoconnectivity profiles have been reported. Neurodegenerative neuropsychiatric disorders are commonly characterized by a diminished local and global efficiency of large-scale brain networks. The connectome, which is largely underpinned by the network science and graph theoretical approaches, is relevant to the field of neuropsychiatry and could be successfully used for the differential diagnosis for neuropsychiatric disorders and for predicting the progression of such disorders. The analysis of large-scale brain network dynamics generates new insights into the mechanisms of action of invasive and noninvasive brain stimulation and guides further investigations of new therapeutic targets.

Pathological uncoupling between amplitude and connectivity of brain fluctuations in epilepsy.

Amplitude and functional connectivity are two fundamental parameters for describing the spontaneous brain fluctuations. These two parameters present close coupling in physiological state, and present different alteration patterns in epilepsy revealed by functional MRI (fMRI). We hypothesized that the alteration of coupling between these two imaging parameters may be underpinned by specific pathological factors of epilepsy, and can be employed to improve the capability for epileptic focus detection. Forty-seven patients (26 left- and 21 right-sided) with mesial temporal lobe epilepsy (mTLE) and 32 healthy controls underwent resting-state fMRI scans. All patients were detected to have interictal epileptic discharges on simultaneous electroencephalograph (EEG) recordings. Amplitude-connectivity coupling was calculated by correlating amplitude and functional connectivity density of low-frequency brain fluctuations. We observed reduced amplitude-connectivity coupling associated with epileptic discharges in the mesial temporal regions in both groups of patients, and increased coupling associated with epilepsy durations in the posterior regions of the default-mode network in the right-sided patients. Moreover, we proposed a new index of amplitude subtracting connectivity, which elevated imaging contrast for differentiating the patients from the controls. The findings indicated that epileptic discharges and chronic damaging effect of epilepsy might both contribute to alterations of amplitude-connectivity coupling in different pivotal regions in mTLE. Investigation on imaging coupling provides synergistic approach for describing brain functional changing features in epilepsy.

Last deglacial and Holocene lake level variations of Qinghai Lake, north-eastern Qinghai-Tibetan Plateau

Qinghai Lake is of significance for paleoclimate research because it lies in a pivotal region that is influenced by both the mid-latitude Westerlies and the low-latitude Asian summer monsoon (ASM). Most published lake level histories of Qinghai Lake are interpreted from drill-core proxies. Here we combine geomorphic shoreline investigations with optically stimulated luminescence dating to constrain lake level variations since the last deglacial. The results indicate that two periods of highstands occurred during the last deglacial (approximate to 16-14.9 and approximate to 12.6-12.2 ka), and that lake levels were 6-7.4m higher than at present. Lake levels dropped abruptly during the Younger Dryas, and were generally low with frequent fluctuations during the early Holocene. Qinghai Lake reached its highest Holocene level, 9.1m higher than modern, at approximate to 5 ka, and has regressed during the past 2 ka. We propose that high lake levels during the last deglacial were due mainly to melting glacial and permafrost waters, supplemented by enhanced Westerlies precipitation and decreased evaporation during Heinrich Event 1 (approximate to 16-14.9 ka) and increased ASM rainfall during the BOlling-Allerod warm period (approximate to 14-12 ka). Lake level fluctuations during the Holocene were generally in accordance with moisture variations in the marginal monsoon zones of inland China.

Workspace and pivot point for robot-assisted endoscope guidance in functional endonasal sinus surgery (FESS).

For the further development of robot-assisted endoscope guidance in functional endoscopic sinus surgery (FESS), ground data about the workspaces and endoscope movements in conventional FESS are needed. Applying a self-developed marker-based tracking system, we collected the pose data (position and orientation) of the endoscope and all other instruments used in five real sinus surgeries. The automated segmentation of the endoscope poses shows the shape of a hourglass, with a pivot region or pivot point at the 'waistline' of the hourglass, close to the nasal entrance in the nasal dome. We were able to identify a pivot point at the waistline of the segmented endoscope poses. The size of the pivot point corresponds with the diameter of the 4 mm endoscope. Because of the reduction to four degrees of freedom for endoscope motions (three rotations and one translation), easier and safer robot-assisted endoscope guidance becomes feasible.

The NO/sGC/PKG signaling pathway in the NAc shell is necessary for the acquisition of morphine-induced place preference.

There is evidence that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway in the basal lateral amygdala and hippocampus plays a key role in memory processing, but it is not known if this NO signaling pathway in the nucleus accumbens (Gomes et al., 2006), a known pivotal region in reward memory, is essential for drug-associated reward memory. We therefore investigated the effect of the NO/sGC/PKG signaling pathway in the nucleus accumbens (NAc) on morphine-induced conditioned place preference (CPP). Results showed that a preconditioning microinjection of the NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) into the NAc shell, but not into the core, significantly blocked the acquisition of morphine CPP. The blockage effect of L-NAME on the acquisition of CPP was imitated by the neuronal NOS inhibitor 7-nitroindazole, 3-bromo-, sodium salt (7-NI), the sGC inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and the PKG inhibitor Rp-8Br-PET-cGMPS. The 7-NI- or ODQ-induced effect was reversed by premicroinjection of the sGC activator YC-1 or the PKG activator 8-Br-cGMP in the NAc shell. However, microinfusion of 7-NI, ODQ, or Rp-8Br-PET-cGMPS into the NAc shell or the core had no effect on the expression of morphine CPP. These findings indicate that the NO/sGC/PKG signaling pathway in the NAc shell is critical for the acquisition of morphine-induced place preference, whereas the same signaling pathway in the NAc shell or core is not involved in the retrieval of morphine-induced place preference.

Functional Mapping of the Neuronal Substrates for Drug Tolerance in Drosophila

Physical dependence on alcohol and anesthetics stems from neuroadaptive changes that act to counter the effects of sedation in the brain. In Drosophila, exposure to either alcohol or solvent anesthetics have been shown to induce changes in expression of the BK-type Ca(2+)-activated K(+) channel gene slo. An increase in slo expression produces an adaptive modulation of neural activity that generates resistance to sedation and promotes drug tolerance and dependence. Increased BK channel activity counteracts the sedative effects of these drugs by reducing the neuronal refractory period and enhancing the capacity of neurons for repetitive firing. However, the brain regions or neuronal populations capable of producing inducible resistance or tolerance remain unknown. Here we map the neuronal substrates relevant for the slo-dependent modulation of drug sensitivity. Using spatially-controlled induction of slo expression we identify the mushroom bodies, the ellipsoid body and a subset of the circadian clock neurons as pivotal regions for the control of recovery from sedation.

Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome

Gilles de la Tourette syndrome is a clinically heterogeneous disorder with poor known pathophysiology. Recent neuropathological and structural neuroimaging data pointed to the dysfunction of cortico-basal ganglia networks. Nonetheless, it is not clear how these structural changes alter the functional activity of the brain and lead to heterogeneous clinical expressions of the syndrome. The objective of this study was to evaluate global integrative state and organization of functional connections of sensori-motor, associative and limbic cortico-basal ganglia networks, which are likely involved in tics and behavioural expressions of Gilles de la Tourette syndrome. We also tested the hypothesis that specific regions and networks contribute to different symptoms. Data were acquired on 59 adult patients and 27 gender- and age-matched controls using a 3T magnetic resonance imaging scanner. Cortico-basal ganglia networks were constructed from 91 regions of interest. Functional connectivity was quantified using global integration and graph theory measures. We found a stronger functional integration (more interactions among anatomical regions) and a global functional disorganization of cortico-basal ganglia networks in patients with Gilles de la Tourette syndrome compared with controls. All networks were characterized by a shorter path length, a higher number of and stronger functional connections among the regions and by a loss of pivotal regions of information transfer (hubs). The functional abnormalities correlated to tic severity in all cortico-basal ganglia networks, namely in premotor, sensori-motor, parietal and cingulate cortices and medial thalamus. Tic complexity was correlated to functional abnormalities in sensori-motor and associative networks, namely in insula and putamen. Severity of obsessive-compulsive disorder was correlated with functional abnormalities in associative and limbic networks, namely in orbito-frontal and prefrontal dorsolateral cortices. The results suggest that the pattern of functional changes in cortico-basal ganglia networks in patients could reflect a defect in brain maturation. They also support the hypothesis that distinct regions of cortico-basal ganglia networks contribute to the clinical heterogeneity of this syndrome.

Acute reductions in blood flow restricted to the dorsomedial medulla induce a pressor response in rats

The brainstem nucleus of the solitary tract (nucleus tractus solitarii, NTS) is a pivotal region for regulating the set-point of arterial pressure, the mechanisms of which are not fully understood. Based on evidence that the NTS exhibits O2-sensing mechanisms, we examined whether a localized disturbance of blood supply, resulting in hypoxia in the NTS, would lead to an acute increase in arterial pressure. Male Wistar rats were used. Cardiovascular parameters were measured before and after specific branches of superficial dorsal medullary veins were occluded; we assumed these were drainage vessels from the NTS and would produce stagnant hypoxia. Hypoxyprobe-1, a marker for detecting cellular hypoxia in the post-mortem tissue, was used to reveal whether vessel occlusion induced hypoxia within the NTS. Following vessel occlusion, blood flow in the dorsal surface of the medulla oblongata including the NTS region showed an approximately 60% decrease and was associated with hypoxia in neurons located predominantly in the caudal part of the NTS as revealed using hypoxyprobe-1. Arterial pressure increased and this response was pronounced significantly in both magnitude and duration when baroreceptor reflex afferents were sectioned. These results suggest that localized hypoxia in the NTS increases arterial pressure. We suggest this represents a protective mechanism whereby the elevated systemic pressure is a compensatory mechanism to enhance cerebral perfusion. Whether this physiological mechanism has any relevance to neurogenic hypertension is discussed.

Transient, Three-Dimensional Flow Field Simulation through a Mechanical, Trileaflet Heart Valve Prosthesis

Thromboembolic complications are one of the major challenges faced by designers and researchers in development of artificial organs with blood-contacting devices such as heart valve prostheses, especially mechanical valves. Besides increasing the thrombogenic potential, these valves change the hydrodynamic performance of the heart. In this study, the flow through a trileaflet, mechanical heart valve prosthesis was modeled with transient computational fluid dynamics to analyze flow patterns causing thrombus formations on valves. The valve was simulated under conditions of a test rig (THIA II), which was specially designed to analyze different valves with respect to thrombosis. The main goal of this study was to mimic the exact conditions of the test rig to be able to compare numerical and experimental results. The boundary conditions were obtained from experimental data as leaflet kinematics and pressure profiles. One complete cycle of the valve was simulated. Numerical flow and pressure results were analyzed and compared with experimental results. Shear stress and shear rates were determined with respect to thrombogenic potential, especially in the pivot regions, which seem to be the main influence for activation and deposition of thrombocytes. Approximately 0.7% of the blood volume moving through the fluid domain of the valve was exposed to shear rates high enough to cause platelet activation. However, shear rates of up to 20,000 s⁻¹ occurred in pivot regions. The pressure differences between the simulation and experimental data were approximately 2.5% during systole and increased up to 25% during diastole. The presented method, however, can be used to gain more information about the flow through different heart valve prostheses and, thus, improve the development process.

Contributions of vascular inflammation in the brainstem for neurogenic hypertension

Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that primary hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1, were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat: SHR) compared to normotensive Wistar Kyoto (WKY) rats. We have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Despite the inflammatory state in the NTS of SHR, transcripts of some inflammatory molecules such as chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3 were down-regulated in the NTS of SHR compared to WKY rats. This may be compensatory to avoid further strong inflammatory activity. More importantly, we found that down-regulation of Ccl5 in the NTS of SHR may be pro-hypertensive since microinjection of Ccl5 into the NTS of SHR decreased arterial pressure but was less effective in WKY rats. Leukocyte accumulation of the NTS microvasculature may also induce an increase in vascular resistance and hypoperfusion within the NTS; the latter may trigger release of pro-inflammatory molecules which via paracrine signaling may affect central neural cardiovascular activity conducive to neurogenic hypertension. All told, we suggest that vascular inflammation within the brainstem contributes to neurogenic hypertension by multiple pathways.

Increased anti-apoptotic conditions in the nucleus tractus solitarii of spontaneously hypertensive rat

Since the nucleus tractus solitarii (NTS) is a pivotal region for regulating the set-point of arterial pressure, we propose here its role in the development of neurogenic hypertension. Given the findings of recent studies suggesting that the NTS of spontaneously hypertensive rats (SHR) exhibits a specific inflammatory state characterized by leukocyte accumulation within the NTS microvasculature, we hypothesized that gene expression levels of apoptotic factors are altered in the NTS of SHR compared to normotensive Wistar–Kyoto rats (WKY). To test this hypothesis, we used RT2 Profiler PCR arrays targeting apoptosis-related factors. We found that gene expression of the death receptor Fas (tumor necrosis factor receptor superfamily, member 6) and the cysteine–aspartic acid protease caspase 12 were down-regulated in the NTS of both adult hypertensive and young pre-hypertensive SHR compared to age-matched WKY. On the other hand, an anti-apoptotic factor, neuronal apoptosis inhibitory protein, was highly increased in the NTS of SHR. These results suggest that the NTS of SHR exhibits an anti-apoptotic condition. Furthermore, this profile appears not to be secondary to hypertension. Whether this differential gene expression in the NTS contributes to the hypertensive state of the SHR via alteration of neuronal circuitry regulating cardiovascular autonomic activity awaits elucidation.

Mental number line training in children with developmental dyscalculia

Developmental dyscalculia (DD) is a specific learning disability that affects the acquisition of mathematical skills in children with normal intelligence and age-appropriate school education (prevalence 3-6%). One essential step in the development of mathematical understanding is the formation and automated access to a spatial representation of numbers. Many children with DD show a deficient development of such a mental number line. The present study aimed to develop a computer-based training program to improve the construction and access to the mental number line. Sixteen children with DD aged 8-10 years and 16 matched control children completed the 5-week computer training. All children played the game 15 min a day for 5 days a week. The efficiency of the training was evaluated by means of neuropsychological tests and functional magnetic resonance imaging (fMRI) during a number line task. In general, children with and without DD showed a benefit from the training indicated by (a) improved spatial representation of numbers and (b) the number of correctly solved arithmetical problems. Regarding group differences in brain activation, children with DD showed less activation in bilateral parietal regions, which reflects neuronal dysfunction in pivotal regions for number processing. Both groups showed reduced recruitment of relevant brain regions for number processing after the training which can be attributed to automatization of cognitive processes necessary for mathematical reasoning. Moreover, results point to a partial remediation of deficient brain activation in dyscalculics after consolidation of acquired and refined number representation. To conclude, the present study represents the first attempt to evaluate a custom-designed training program in a group of dyscalculic children and results indicate that the training leads to an improved spatial representation of the mental number line and a modulation of neural activation, which both facilitate processing of numerical tasks.

Heterogeneous distribution of the serotonin 5‐HT1A receptor mRNA in chemically identified neurons of the mouse rostral brainstem: Implications for the role of serotonin in the regulation of wakefulness and REM sleep

The 5-HT(1A) receptor (5-HT(1A)R) plays a key role in the inhibitory influence of serotonin (5-HT) on rapid eye movement (REM) sleep in rodents. However, the neuronal networks mediating such influence are mostly unknown, notably in the mouse. This led us to map 5-HT(1A)R mRNA, by in situ hybridization histochemistry (ISHH), and to characterize the neuronal phenotype of 5-HT(1A)R mRNA-positive neurons by dual ISHH and ISHH combined with immunohistochemistry, throughout the mouse rostral brainstem, a pivotal region for the generation of REM sleep and cortical activation. 5-HT(1A)R mRNA was found in most 5-HT neurons in the dorsal raphe (DR), the median raphe (MnR), the B9, and the interpeduncular (IP) nuclei. 5-HT(1A)R mRNA-positive neurons were also identified in individualized clusters of gamma-aminobutyric acid (GABA)ergic neurons in the DR and in neurons of an undetermined phenotype in the MnR. In addition, 1) GABAergic neurons of the ventral portion of Gudden's dorsal tegmental nucleus (DTg), the IP, and the caudal portion of the deep mesencephalic nucleus (DpMe), and 2) glutamatergic neurons scattered in the caudal pontine reticular nucleus (PnC) and densely packed in the internal lateral parabrachial subnucleus (PBil) also expressed 5-HT(1A)R mRNA. In contrast, no specific 5-HT(1A)R-related ISHH signal was generally detected in brainstem cholinergic and catecholaminergic neurons. These results emphasize the role of 5-HT(1A)R as an autoreceptor and the phenotypical heterogeneity of 5-HT(1A)R-expressing neurons within the DR and the MnR in the mouse brain. They also provide a neuroanatomical basis for understanding the influence of 5-HT(1A)R on REM sleep and wakefulness.

Evidence of specific inflammatory condition in nucleus tractus solitarii of spontaneously hypertensive rats

Since the nucleus tractus solitarii (NTS) is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of neurogenic hypertension. Recent studies have suggested that proinflammatory molecules, such as junctional adhesion molecule 1 (JAM-1) are highly expressed in the NTS of an animal model of human essential hypertension, the spontaneously hypertensive rat (SHR), compared with normotensive rats (Wistar-Kyoto, WKY). Moreover, we have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Based on this evidence, we hypothesized that gene expression of cytokines/chemokines is altered in the NTS of SHR. We have screened for abnormally expressed inflammatory mediators in the NTS of SHR using the RT2 Profiler PCR arrays, which were designed specifically to target major cytokines/chemokines. The specific PCR array revealed that seven genes were less expressed in the NTS of SHR compared with WKY rats (more than twofold differences), while only two genes were more expressed in the SHR. Moreover, we identified that some of these validated molecules exhibit important functional roles for cardiovascular homeostasis at the level of the NTS. We suggest that abnormal gene expression of proinflammatory molecules, such as JAM-1, causes leukocyte accumulation within the vasculature in the NTS of SHR. Consequently, gene expression of specific cytokines/chemokines may be downregulated to avoid further strong inflammatory activity in the NTS of SHR at the expense of an alteration in neuronal activity that leads to cardiovascular autonomic pathology. Importantly, to allow translation of our work, these novel insights need to be assessed in hypertensive human brainstem tissue; their confirmation could lead to novel therapeutic approaches for one of the world's most prevalent diseases.