Pedunculopontine tegmental nucleus. Part I: cytoarchitecture, transmitters, development and connections

The present review compiles data on the cytoarchitecture, transmitters, development, afferent and efferent connections of the pedunculopontine tegmental nucleus (PPN). PPN is a reticular formation nucleus, located in the pontomesencephalic tegmentum, closely associated with the ascending limb of the superior cerebellar peduncle. Its most typical cells are cholinergic and comprise the Ch5 neuronal group of Mesulam. It contains also glutamatergic neurons that may contain glutamate as a sole transmitter or as a co-transmitter of acetylcholine. The cholinergic neurons use also the gaseous transmitter nitric oxide, being the most prominent nitrergic neurons in the central nervous system (CNS). In aged animals, there is practically no cell loss but there are certain drastic changes in the somatodendritic morphology. PPN has an extremely rich afferent input. All basal ganglia send axons to PPN, the strongest connection being from the substantia nigra (SN), followed by pathways arising from the subthalamic nucleus (STN) and from both pallidal segments (PAL). PPN receives afferents also from the cerebral cortex, from areas of the limbic system and hypothalamus, from the cerebellum, from the brainstem - particularly serotoninergic axons from the raphe nuclei and noradrenergic axons from the locus ceruleus - as well as from the spinal cord. The efferent connections of PPN are extremely diverse, and some of them are carried out by axons that emit divergent collaterals to two different structures. The heaviest efferent pathway of PPN is destined to the thalamus, innervating virtually all thalamic nuclei, and especially the "nonspecific" intralaminar nuclei, that innervate broad ares of the cerebral cortex. All basal ganglia are innervated and in most cases the connection is bilateral. The most significant pathway innervates the dopaminergic neurons of SN, followed by a connection to STN and PAL. Other PPN efferent connections reach the cerebellum, the superior colliculus, nuclei of cranial nerves, the reticular formation, and the spinal cord. The reviewed connections of PPN suggest that it is involved significantly in the arousal systems, and is implicated in the disturbances of sleep and wakefulness. PPN is also involved in the motor functions of CNS, as well as in the movement disorders.Biomedical Reviews 2003; 14: 95-120

The Intrinsic Connectome of the Rat Amygdala

The connectomes of nervous systems or parts there of are becoming important subjects of study as the amount of connectivity data increases. Because most tract-tracing studies are performed on the rat, we conducted a comprehensive analysis of the amygdala connectome of this species resulting in a meta-study. The data were imported into the neuroVIISAS system, where regions of the connectome are organized in a controlled ontology and network analysis can be performed. A weighted digraph represents the bilateral intrinsic (connections of regions of the amygdala) and extrinsic (connections of regions of the amygdala to non-amygdaloid regions) connectome of the amygdala. Its structure as well as its local and global network parameters depend on the arrangement of neuronal entities in the ontology. The intrinsic amygdala connectome is a small-world and scale-free network. The anterior cortical nucleus (72 in- and out-going edges), the posterior nucleus (45), and the anterior basomedial nucleus (44) are the nuclear regions that posses most in- and outdegrees. The posterior nucleus turns out to be the most important nucleus of the intrinsic amygdala network since its Shapley rate is minimal. Within the intrinsic amygdala, regions were determined that are essential for network integrity. These regions are important for behavioral (processing of emotions and motivation) and functional (memory) performances of the amygdala as reported in other studies

Amygdala and subcortical vision: recognition of threat and fear

The amygdala (Am) is a relatively voluminous gray substance, located in the depth of the ventromedial temporal lobe. The Am has diverse afferent and efferent connections throughout the neuraxis, and is involved in the modulation of neuroendocrine functions, visceral effector mechanisms, and in complex patterns of behavior: learning and memory, aggression and defense, pain modulation, reproduction, food intake, etc. A recently revealed important function of the Am is that it acts as the brain 'lighthouse' which constantly monitors the environment for stimuli which signal a threat to the organism. The data from patients with extensive lesions of the striate cortex indicate that unseen fearful and fear-conditioned faces elicit increased Am responses. Thus, also extrageniculostriate pathways are involved. A multisynaptic pathway from the retina to the Am via the superior colliculus and several thalamic nuclei was recently suggested. We here present data based on retrograde neuronal labeling that the parabigeminal nucleus emits a substantial bilateral projection to the Am. This small cholinergic nucleus (Ch8 group) in the midbrain tegmentum is a subcortical relay visual center that is reciprocally connected with the superior colliculus. We suggest the existence of a second extrageniculostriate multisynaptic connection to Am: retina - superior colliculus - parabigeminal nucleus - Am. This pathway might be very effective since all tracts listed above are bilateral. The function of the Am by the rapid response to the sources of threat before conscious detection is significantly altered by various neuropsychiatric diseases.Biomedical Reviews 2008; 19: 1-16

Erythropoietin and the effect of oxygen during proliferation and differentiation of human neural progenitor cells

<p>Abstract</p> <p>Background</p> <p>Hypoxia plays a critical role in various cellular mechanisms, including proliferation and differentiation of neural stem and progenitor cells. In the present study, we explored the impact of lowered oxygen on the differentiation potential of human neural progenitor cells, and the role of erythropoietin in the differentiation process.</p> <p>Results</p> <p>In this study we demonstrate that differentiation of human fetal neural progenitor cells under hypoxic conditions results in an increased neurogenesis. In addition, expansion and proliferation under lowered oxygen conditions also increased neuronal differentiation, although proliferation rates were not altered compared to normoxic conditions. Erythropoietin partially mimicked these hypoxic effects, as shown by an increase of the metabolic activity during differentiation and protection of differentiated cells from apoptosis.</p> <p>Conclusion</p> <p>These results provide evidence that hypoxia promotes the differentiation of human fetal neural progenitor cells, and identifies the involvement of erythropoietin during differentiation as well as different cellular mechanisms underlying the induction of differentiation mediated by lowered oxygen levels.</p

Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis

Liver cirrhosis represents the common end-stage of chronic liver diseases regardless of its etiology. Patients with compensated disease are mostly asymptomatic, however, progression to a decompensated disease stage is common. The available stratification strategies are often unsuitable to identify patients with a higher risk for disease progression and a limited prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the blood by immune-cells. While osteopontin, the most prominent member of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or prognostic value of bone sialoprotein (BSP) are scarce and partly inconclusive. In this study, we analyzed the diagnostic and prognostic potential of circulating BSP in comparison to other standard laboratory markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt (TIPS). Serum levels of BSP were similar in patients with different disease stages and were not indicative for prognosis. Interestingly, BSP serum levels did correlate inversely with portal pressure, as well as its surrogates such as platelet count, the portal vein cross-sectional area and correlated positively with the portal venous velocity. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal hypertension in patients with liver cirrhosis

Development of a biodegradable microstent for minimally invasive treatment of Fallopian tube occlusions

Obstructions of the Fallopian tube represent one of the most common reasons for an unfulfilled desire to have children. Microstent technology opens up new therapeutic possibilities to restore the natural lumen of the Fallopian tube within a single treatment. Within the current work we developed a self-expandable biodegradable microstent for gynecological applications. Based on a novel microstent design, prototypes were manufactured from poly-L-lactide tubing by means of fs-laser cutting. Microstent prototypes were characterized morphologically by means of scanning electron microscopy and biaxial laser scanning. As manufactured, a microstents outside diameter of about 2.3 mm and a strut thickness/width of about 114 µm/103 µm was measured. Mechanical characterization of microstents included bending as well as crimping and release behavior. After crimping to a minimum diameter of 0.8 mm and consecutive release, a microstent recovery to a diameter of 1.8 mm was found. Therefore, proof-of-concept for the self-expandable microstent could be successfully provided. © 2020 by Walter de Gruyter Berlin/Boston 2020

Olfactory Performance as an Indicator for Protective Treatment Effects in an Animal Model of Neurodegeneration

Background: Neurodegenerative diseases are often accompanied by olfactory deficits. Here we use a rare neurovisceral lipid storage disorder, Niemann–Pick disease C1 (NPC1), to illustrate disease-specific dynamics of olfactory dysfunction and its reaction upon therapy. Previous findings in a transgenic mouse model (NPC1-/-) showed severe morphological and electrophysiological alterations of the olfactory epithelium (OE) and the olfactory bulb (OB) that ameliorated under therapy with combined 2-hydroxypropyl-ß-cyclodextrin (HPßCD)/allopregnanolone/miglustat or HPßCD alone.Methods: A buried pellet test was conducted to assess olfactory performance. qPCR for olfactory key markers and several olfactory receptors was applied to determine if their expression was changed under treatment conditions. In order to investigate the cell dynamics of the OB, we determined proliferative and apoptotic activities using a bromodeoxyuridine (BrdU) protocol and caspase-3 (cas-3) activity. Further, we performed immunohistochemistry and western blotting for microglia (Iba1), astroglia (GFAP) and tyrosine hydroxylase (TH).Results: The buried pellet test revealed a significant olfactory deterioration in NPC1-/- mice, which reverted to normal levels after treatment. At the OE level, mRNA for olfactory markers showed no changes; the mRNA level of classical olfactory receptor (ORs) was unaltered, that of unique ORs was reduced. In the OB of untreated NPC1-/- mice, BrdU and cas-3 data showed increased proliferation and apoptotic activity, respectively. At the protein level, Iba1 and GFAP in the OB indicated increased microgliosis and astrogliosis, which was prevented by treatment.Conclusion: Due to the unique plasticity especially of peripheral olfactory components the results show a successful treatment in NPC1 condition with respect to normalization of olfaction. Unchanged mRNA levels for olfactory marker protein and distinct olfactory receptors indicate no effects in the OE in NPC1-/- mice. Olfactory deficits are thus likely due to central deficits at the level of the OB. Further studies are needed to examine if olfactory performance can also be changed at a later onset and interrupted treatment of the disease. Taken together, our results demonstrate that olfactory testing in patients with NPC1 may be successfully used as a biomarker during the monitoring of the treatment

Acetylcholine Neurotransmitter Receptor Densities in the Striatum of Hemiparkinsonian Rats Following Botulinum Neurotoxin-A Injection

Cholinergic neurotransmission has a pivotal function in the caudate-putamen, and is highly associated with the pathophysiology of Parkinson's disease. Here, we investigated long-term changes in the densities of the muscarinic receptor subtypes M1, M2, M3 (mAchRs) and the nicotinic receptor subtype α4β2 (nAchRs) in the striatum of the 6-OHDA-induced hemiparkinsonian (hemi-PD) rat model using quantitative in vitro receptor autoradiography. Hemi-PD rats exhibited an ipsilateral decrease in striatal mAchR densities between 6 and 16%. Moreover, a massive and constant decrease in striatal nAchR density by 57% was found. A second goal of the study was to disclose receptor-related mechanisms for the positive motor effect of intrastriatally injected Botulinum neurotoxin-A (BoNT-A) in hemi-PD rats in the apomorphine rotation test. Therefore, the effect of intrastriatally injected BoNT-A in control and hemi-PD rats on mAchR and nAchR densities was analyzed and compared to control animals or vehicle-injected hemi-PD rats. BoNT-A administration slightly reduced interhemispheric differences of mAchR and nAchR densities in hemi-PD rats. Importantly, the BoNT-A effect on striatal nAchRs significantly correlated with behavioral testing after apomorphine application. This study gives novel insights of 6-OHDA-induced effects on striatal mAchR and nAchR densities, and partly explains the therapeutic effect of BoNT-A in hemi-PD rats on a cellular level

Are Metastases from Metastases Clinical Relevant? Computer Modelling of Cancer Spread in a Case of Hepatocellular Carcinoma

Background: Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions. Methods: The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data. Results: The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient’s death. Conclusion: The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e.