Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Whereas genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of PDAC would produce pathologic changes in pancreatic neurons and innervation. Using a lineage labeled genetically engineered mouse model of PDAC we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia (PanIN) were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede appearance of cancer.
Background-Alterations in the inhibitory circuitry of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia include reduced expression of the messenger RNA (mRNA) for somatostatin (SST), a neuropeptide present in a subpopulation of γ-aminobutyric acid (GABA) neurons. Neuropeptide Y (NPY) is expressed in a subset of SST-containing interneurons and lower levels of NPY mRNA have also been reported in schizophrenia spectrum disorders. However, whether the alterations in these two transcripts identify the same, particularly vulnerable, subset of GABA neurons has not been examined.Methods-We used in situ hybridization to quantify NPY mRNA levels in DLPFC gray and white matter from 23 pairs of subjects with schizophrenia or schizoaffective disorder and matched normal control subjects; results were compared to those from a previous study of SST mRNA expression in the same subjects.Results-In contrast to SST mRNA, NPY mRNA levels were not significantly lower in the gray matter of subjects with schizophrenia or schizoaffective disorder. However, NPY, but not SST, mRNA expression was significantly lower in the superficial white matter of subjects with schizoaffective disorder.Conclusion-These findings suggest that the alterations in SST-containing interneurons in schizophrenia and schizoaffective disorder are selective for the subset that do not express NPY
The ventral striatum receives topographic input from the orbital frontal cortex (OFC), anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC), areas associated with incentive-based learning. In addition, cortico-striatal projections from the dorsal prefrontal cortex (dorsal PFC) and the motor/premotor areas are also organized topographically. Cortico-ventral basal ganglia circuitry is associated with a variety of mental health disorders including obsessivecompulsive disorder, and drug addiction, disorders that emerge during childhood through young adulthood. Growing evidence indicates that cortical and striatal development continues through this period. Moreover, cell proliferation, which is associated with development and plasticity, also continues in the cortex and striatum through adulthood. Given the implication of cortico-basal ganglia circuitry in diseases emerging during postnatal development, we studied cell proliferation in striatal regions associated with specific frontal cortical areas at different ages. The results show cell proliferation throughout the striatum at all postnatal ages. The majority of the new cells were immunoreactive for the chondroitn sulfate NG2, a marker for glia, but not NeuN, a neuronal marker. Although neurogenesis was not observed, approximately 30% of the new cells were associated with neurons. There was a significantly higher degree of cell proliferation during the first year postnatal compared to other striatal regions. Finally, the ventral striatal areas receiving input from the vmPFC and OFC have significantly more new cells throughout the juvenile years compared to other striatal regions. Taken together, these results indicate that new cells in the ventral striatum may be particularly important for the refinement of the cortico-striatal network, and in the formation of neural ensembles fundamental to learning during behavioral development.
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