Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma.

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. Although 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 pancreatic ductal adenocarcinoma (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 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 the appearance of cancer.

NPY mRNA expression in the prefrontal cortex: Selective reduction in the superficial white matter of subjects with schizoaffective disorder.

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 gamma-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 mRNA, and that lower NPY mRNA expression in the superficial white matter may distinguish subjects with schizoaffective disorder from those with schizophrenia.

Cell proliferation in the striatum during postnatal development: preferential distribution in subregions of the ventral striatum.

Cortico-ventral basal ganglia circuitry is associated with a variety of mental health disorders including obsessive-compulsive disorder and drug addiction, disorders that emerge during childhood through young adulthood, a period in which the cortex and striatum continue to development. 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 at different ages in striatal regions associated with specific frontal cortical areas. The results show cell proliferation throughout the striatum at all postnatal ages. The majority of the new cells were immunoreactive for NG2 chondroitin sulfate, a marker for specific progenitor cells, but not for NeuN, a neuronal marker. Although neurogenesis was not observed, approximately 30% of the new cells appeared to be paired with a neuron. There was a significantly higher degree of cell proliferation during the first postnatal year compared to other striatal regions. Finally, throughout the juvenile years, the ventral striatal areas receiving input from the ventral, medial prefrontal cortex and orbital prefrontal cortex have significantly more new cells compared to other striatal regions. Integrity of the ventral striatum is critical for the development of goal-directed behaviors. The high number of new cells in the ventral striatum during postnatal development 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.