The rostral migratory stream (RMS) is viewed as a glia-enriched conduit of forward-migrating neuroblasts in which chemorepulsive signals control the pace of forward migration. Here we demonstrate the existence of a scaffold of neurons that receive synaptic inputs within the rat, mouse, and human fetal RMS equivalents. These neurons express secretagogin, a Ca²⁺-sensor protein, to execute an annexin V-dependent externalization of matrix metalloprotease-2 (MMP-2) for reconfiguring the extracellular matrix locally. Mouse genetics combined with pharmacological probing in vivo and in vitro demonstrate that MMP-2 externalization occurs on demand and that its loss slows neuroblast migration. Loss of function is particularly remarkable upon injury to the olfactory bulb. Cumulatively, we identify a signaling cascade that provokes structural remodeling of the RMS through recruitment of MMP-2 by a previously unrecognized neuronal constituent. Given the life-long presence of secretagogin-containing neurons in human, this mechanism might be exploited for therapeutic benefit in rescue strategies. Significance Persisting proliferative capacity and regeneration in the adult brain are confined to a minority of regions. In the murine brain, the olfactory system is supplied by thousands of newly born neuroblasts daily to support sensory plasticity. Here, we reveal a neuronal scaffold that resides within and alongside this migratory route [termed the “rostral migratory stream” (RMS)] to guide forward migration of newly born neuroblasts. These neurons can externalize the enzyme matrix metalloprotease-2 to loosen the extracellular matrix, thus producing permissive corridors for migrating neuroblasts. This mechanism is likely phylogenetically conserved because it exists in the RMS equivalent in human fetal brains. This inducible mechanism might be pharmacologically targeted for therapeutic benefit.

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naïve animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems.

An abnormal course of the umbilical vein is a rare anomaly. Its association with the congenital absence of the ductus venosus is common. We found 3 cases of an abnormal course of the umbilical vein and an absent ductus venosus. In 2 of these cases, the umbilical vein turned down and continued in the internal iliac vein, and no ductus venosus was found. One of these pregnancies was terminated. From the continued pregnancy a growth-retarded baby was born. At follow-up examinations, mild microcephaly, mildly elevated levels of ammonia, delayed speech and mild muscular hypotonia were found. In the third case, the umbilical vein turned up from the level of umbilical ring and the anterior of the liver above the diaphragma and connected directly into the right atrium. Associated complex congenital heart malformations – transposition of the great arteries, and ventricular septal defect – were diagnosed prenatally. In the umbilical vein from the placenta to the umbilical ring, the flow was low velocity continuous; from the umbilical ring to the right atrium, the flow was biphasic high velocity (90 cm/s). Such an elevated blood flow could be a sign of increased cardiac preload. The long-term neurological follow-up of babies with prenatally diagnosed venous malformations is necessary.

Key points: Sensory neurons that detect painful and non‐painful stimulation of body tissues have axons that project to the dorsal horn of the spinal cord, where their terminations are partially segregated into superficial (I–II) and deep (III–IV) dorsal horn laminae, respectively. The dorsal horn contains many excitatory and inhibitory interneurons whose axons synapse on other dorsal horn neurons to enhance or suppress sensory transmission. This study used a localized stimulation technique (laser scanning photostimulation) for high‐resolution mapping of synaptic connections between dorsal horn interneurons, in an in vitro‘slice’ preparation of the mouse lumbar spinal cord. Some neurons in superficial layers of the dorsal horn have long dendrites that extend ventrally into deeper layers of the dorsal horn, and these neurons can receive excitatory or inhibitory synaptic input from neurons in the deeper layers. These interlaminar connections may be involved in interactions between transmission of signals underlying painful versus non‐painful sensations. Abstract  The primary goal of this study was to map the transverse distribution of local excitatory and inhibitory synaptic inputs to mouse lamina I spinal dorsal horn neurons, using laser scanning photostimulation. A sample of lamina II neurons was also studied for comparison. Lamina I neurons received excitatory synaptic input from both laminae I–II and the outer part of III–IV, especially the II/III border region, while the inhibitory input zones were mostly confined within I–II. The excitatory synaptic input zones showed a pronounced medial asymmetry, which was correlated with a matching asymmetry in the dendritic fields of the neurons. Inhibitory input from laminae III–IV was found in a subpopulation of neurons occupying a highly restricted zone, essentially one cell layer thick, immediately below the lamina I/II border, with morphological and physiological properties that were distinct from other laminar populations in the superficial dorsal horn, and that suggest a critical role in interlaminar communication. This subpopulation also received excitatory input from laminae III–IV. Within this subpopulation, inhibitory III–IV input was correlated with the presence of long ventral dendrites. Correlations between the distribution of synaptic input zones and dendritic fields support the concept that interlaminar communication is mediated in part via contacts made onto ventrally extending dendrites of superficial laminae neurons. The results point to the presence of cell type specificity in dorsal horn circuitry, and show how the study of connectivity can itself help identify previously unrecognized neuronal populations.

It has been hypothesized that alpha2-adrenoceptors (alpha2-ARs) may be involved in the pathomechanism of colitis, however, the results are conflicting since both aggravation and amelioration of colonic inflammation have been described in response to alpha2-AR agonists. Therefore, we aimed to analyse the role of alpha2-ARs in acute murine colitis. The experiments were carried out in wild-type (WT), alpha2A-, alpha2B- and alpha2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2 %), alpha2-AR ligands were injected intraperitoneally (i.p.). The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by ELISA and proteome profiler array, respectively. The non-selective alpha2-AR agonist clonidine induced a modest aggravation of DSS-induced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels or histological score. Clonidine induced similar changes in alpha2B- and alpha2C-AR KO mice, whereas it failed to affect the disease activity index (DAI) scores and caused only minor weight loss in alpha2A-AR KO animals. On the other hand, selective inhibition of alpha2A-ARs by BRL 44408 significantly delayed the development of colitis, reduced the colonic levels of MPO and the cytokines/chemokines CCL3, CXCL2, CXCL13 and G-CSF, and elevated that of TIMP-1. Here we report that activation of alpha2-ARs aggravates murine colitis, an effect mediated by the alpha2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.