No description available.

HRP applied to cut dorsal and ventral roots of the cat sacral spinal cord labeled afferent axons with swellings in close apposition to labeled preganglionic neurons (PGNs) in the sacral parasympathetic nucleus. Electron microscopy allowed characterization of synaptic contacts between afferents and PGNs. The results suggest that both the dorsal and ventral root afferents can directly activate autonomic preganglionic neurons.

Atrial Naturietic Peptide (ANP) is a neuropeptide that regulates function of the hypothalamic-pituitary-adrenal (HPA) axis, immune and neuroimmune system, and epigenetic factors. Research has indicated that ANP may mediate alcohol intake, withdrawal, and craving like behaviors. ANP receptors are present in the mesocorticolimbic (MCL) reward pathway of the brain, which includes the nucleus accumbens (Acb) and the ventral tegmental area (VTA). The objectives of the present study were to examine the effects of ANP microinjected into Acb subregions (Shell (Sh), Core (Co), ventral to AcbSh) on operant ethanol (EtOH) self-administration and into posterior VTA (pVTA) on EtOH-seeking behavior of female alcohol-preferring (P) rats. In the first experiment, ANP (0, 10 μg, or 100 μg) was microinjected into subregions of the Acb to determine its effects on EtOH self-administration. In the second experiment, ANP was microinjected into pVTA to determine its effects on Pavlovian Spontaneous Recovery (PSR) of responding, a measure of context-induced EtOH-seeking behavior. Administration of ANP directly into the AcbSh significantly reduced EtOH self-administration compared to vehicle, whereas ANP into the AcbCo or areas directly ventral to the AcbSh did not alter responding for EtOH. Microinjection of ANP into the pVTA significantly reduced responding on the EtOH-associated lever during the PSR test. The data indicate that activation of ANP systems in the (a) AcbSh can inhibit EtOH intake, and (b) in the pVTA can inhibit EtOH-seeking behavior. The results suggest that manipulations of the ANP system could be a potential target for pharmacotherapeutic intervention to treat alcohol use disorder. Supported in part by AA07462, AA07611, AA10717, AA10721, AA013522, AA019366, AA020908, AA022287, and AA024612.

During C. elegans embryogenesis, the DD, DA, and DB motor neurons arise from left and right lineages, move towards the midline and intercalate into a single tract to form the ventral nerve cord (VNC). Recently, the non-canonical Wnt-planar cell polarity was shown to regulate cell intercalation during VNC assembly. Disruption of this pathway causes DD neurons to shift anteriorly along the anterior-posterior (AP)-axis. Here, we investigated the role of the canonical Wnt-β-catenin pathway in positioning neurons in the VNC. Mutations in canonical Wnt pathway components, including bar-1/β-catenin and pop-1/TCF, cause the anterior displacement of DD2 towards DD1. In contrast, disruption of the β-catenin destruction complex gene pry-1/Axin results in the posterior displacement of DD1 towards DD2. In order to determine where and when defects occur, we used fluorescent time-lapse imaging to follow DD, DA and RIG neuroblasts during embryogenesis. In wild-type, we found that RIGL and DA2 intercalate between DD1 and DD2 via T1-type cell neighbor exchanges. Dorsal-ventral (DV) constriction of the DD1 and DD2 cell junction results in these cells meeting at a central vertex, which then resolves when the RIGL and DA2 cell junction expands along the AP axis. The resolution of the central vertex results in the spatial displacement of DD1 and DD2 along the AP axis. However, in Wnt-β-catenin mutants, central vertex resolution defects result in decreased spacing between DD1 and DD2 that persist into adulthood.

While physical rehabilitation facilitates some recovery, it is uncommon for patients to recover completely from stroke. Cell based therapies derived from stem cells have produced promising results in enhancing recovery in pre-clinical studies, but the mechanism is not yet completely understood. We previously evaluated human umbilical tissue-derived cells (hUTC) in our non-human primate model of cortical injury, limited to the hand area of primary motor cortex. hUTC treatment, injected intravenously 24 hours after injury, resulted in significantly greater recovery of fine motor function compared to treatment with vehicle. Based on these striking findings, in the current study, we investigated the hypothesis that hUTC treatment leads to functional recovery through reducing cytotoxic responses and enhancing neurorestorative processes following cortical injury. Brain sections were assessed using histological techniques to quantify perilesional oxidative damage, hemosiderin accumulation, microglial activation, Betz cell number, synaptic density, and astrocytic complexity. Brain sections outside of the primary area of injury were also assessed for microglial activation in white matter pathways, cell activation through c-Fos in premotor cortices, and neurogenesis in neurogenic niches. Finally, blood samples from throughout the recovery period and CSF samples from 16 weeks after injury were analyzed for BDNF levels. In the perilesional area, hUTC treatment was associated with lower oxidative damage and hemosiderin accumulation, but not with a difference in microglial activation. hUTC also resulted in a trend toward higher astrocyte complexity and synaptic density in the lesion area, but no difference in ipsilesional Betz cell number. Further, hUTC treatment led to more microglia in white matter pathways, higher c-Fos activation in ventral premotor cortex, and a trend toward higher neurogenesis in the hippocampus. Finally, BDNF levels were higher in blood with hUTC treatment one week after injury, but there was no change beyond one week in blood serum or in CSF, when compared with vehicle. Taken together, these results suggest that hUTC treatment modulates immune responses, limits perilesional damage and cell death, enables neuroplasticity and reorganization, and enhances acute neurotrophic factor secretion. While many cell therapies are currently undergoing clinical trials, this study advances our understanding of the mechanism of cell based therapies.

The nine amino acid peptide vasopressin acts as a neurohormone in the periphery and a neurotransmitter/neuromodulator in the central nervous system. Historically, research on vasopressin neurons and their projections to the pituitary has helped lay the groundwork for our understanding of peptidergic neurotransmission. Currently, our research on central vasopressin projections is driving a revolution in our understanding of social behavior. Vasopressin affects a number of social behaviors from social memory to aggression to affiliative behavior, such as pair-bonding. Further, with the addition of more and more transgenic mouse models of disease states, anxiety and depression related disorders, and social behavior dysfunction, it is important now more than ever to have a clear knowledge of the mouse vasopressin system, which derives from a number of distinct nuclei within the brain. Here, I map out vasopressin immunoreactivity in the mouse brain, and delineate the subset of brain regions with gonadal steroid hormone-dependent vasopressin immunoreactivity. Such projections are thought to derive from the bed nuclei of the stria terminalis and medial amygdala in the telencephalon. Finally, based on data from mice with lesions of the suprachiasmatic nucleus, I outline the subset of regions that likely receive vasopressin from this source. Our research on the anatomy of the vasopressin system of mice and our attempts to delineate the site of origin of the many vasopressin fibers found throughout the brain suggest that a significant amount of the vasopressin innervation deriving from cells in the bed nuclei of the stria terminalis and medial amygdala project to areas in the midbrain involved in serotonin and dopamine transmission, such as the dorsal raphe and ventral tegmental area. These transmitter systems play a crucial role in the control of anxiety and depression levels as well as motivated behavior and emotional regulation. Our results strongly suggest that a direct link exists between these systems, and future plans include an examination of this possibility. It is our hope that this work will further our understanding of the role of vasopressin and other transmitter systems in the regulation of social behaviors.

Ion channels and pumps play critical roles during sea urchin development including mediating the blocks to polyspermy, regulating left-right and dorsal-ventral axis specification, directing ventral PMC migration, and controlling biomineralization of the larval skeleton. We performed a screen of pharmacological ion channel inhibitors, and we chose two inhibitors to investigate further. First, we found that tricaine, a potent inhibitor of voltage-gated sodium channels (VGSCs), induces aberrant skeletal patterning in Lytechinus variegatus larvae. The larval skeleton is secreted by the primary mesenchyme cells (PMCs), which migrate within the blastocoel into a stereotypical pattern. We show that VGSC activity is required for normal PMC migration and skeletal patterning. Timed inhibitor studies identified VGSC activity as specifically required from early gastrula to the onset of late gastrula for normal skeletal patterning. Tricaine inhibits the voltage-gated sodium channel LvScn5a which is strongly expressed in the developing nervous system in pluteus larvae. We found that exogenous expression of an anesthetic-insensitive version of LvScn5a is sufficient to rescue hallmark tricaine-mediated skeletal patterning defects, demonstrating the specificity of the inhibitor. LvScn5a exhibits a ventrolateral ectodermal expression domain in gastrulating embryos that is spatiotemporally congruent with triradiate formation in the ventrolateral PMC clusters at the onset of skeletogenesis. This ectodermal territory normally expresses the patterning cue Wnt5, and we find that the expression of Wnt5 is dramatically spatially expanded by tricaine treatment. We also observe ectopic PMC clusters in tricaine-treated embryos. We found that knockdown of Wnt5 expression is sufficient to rescue tricaine-mediated skeletal patterning defects. These results are consistent with a model in which LvScn5a activity in the ventrolateral ectoderm functions to spatially restrict the expression of the ectodermal patterning cue Wnt5 that in turn induces PMC cluster formation. Together, these findings show that spatially restricted sodium channel activity regulates ectodermal cue expression that, in turn, regulates PMC differentiation and skeletal morphogenesis. Second, we show that V-type H⁺ ATPase (VHA) activity is required for specification of the dorsal-ventral (DV) axis. DV specification is controlled by the TGF-β signal Nodal that specifies the ventral territory and indirectly activates dorsal specification via induction of BMP 2/4 expression. Nodal expression occurs downstream of p38 MAPK, which is transiently, asymmetrically inactive on the presumptive dorsal side of the blastula embryo. VHA activity is required for that transient inactivation of p38 MAPK, and it is required for the subsequent spatial restriction of Nodal expression. We show that VHA inhibition is sufficient to induce global Nodal expression during the blastula stage, resulting in ventralization of the embryo. We show that this phenotype can be rescued by experimentally imposing asymmetric Nodal expression at the 4-cell stage. We discover a VHA-dependent voltage gradient across the DV axis and find that VHA activity is required for hypoxia inducible factor (HIF) activation. We show that neither hyperpolarization nor HIF activation is sufficient to perturb DV specification, which implicates a third unknown pathway connecting VHA activity and p38 MAPK symmetry breaking. These results are consistent with a model in which dorsal VHA activity is required to inhibit Nodal expression and signaling, potentially via dorsal p38 MAPK inhibition. Together, these studies demonstrate that ion channels are required for both DV specification and for normal skeletal patterning.

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No description available.

No description available.