Glial cell line-derived neurotrophic factor (GDNF) supports growth and survival of dopaminergic (DA) neurons. A replication-defective adenoviral (Ad) vector encoding human GDNF injected near the rat substantia nigra was found to protect DA neurons from the progressive degeneration induced by the neurotoxin 6-hydroxydopamine (6-OHDA) injected into the striatum. Ad GDNF gene therapy reduced loss of DA neurons approximately threefold 6 weeks after 6-OHDA lesion, as compared with no treatment or injection of Ad lacZ or Ad mGDNF (encoding a biologically inactive deletion mutant GDNF). These results suggest that Ad vector-mediated GDNF gene therapy may slow the DA neuronal cell loss in humans with Parkinson's disease.

We investigated the movement of interstitially infused macromolecules within the central nervous system (CNS) in rats with high and low blood pressure (BP)/heart rate and in rats euthanized immediately before infusion (no heart action). Adeno-associated virus 2 (AAV2), fluorescent liposomes, or bovine serum albumin was infused into rat striatum (six hemispheres per group) by convection-enhanced delivery (CED). After infusion, distribution volumes were evaluated. The rats with high BP/heart rate displayed a significantly larger distribution of the infused molecules within the injected site and more extensive transport of those molecules to the globus pallidus. This difference was particularly apparent for AAV2, for which a 16.5-fold greater distribution of viral capsids was observed in the rats with high BP/heart rate than in the rats with no heartbeat. Similar results were observed for liposomes, despite their larger diameter. The distribution of all infused molecules in all rats that had low or no blood flow was confined to the space around brain blood vessels. These findings show that fluid circulation within the CNS through the perivascular space is the primary mechanism by which viral particles and other therapeutic agents administered by CED are spread within the brain and that cardiac contractions power this process.

Anterograde transport, retrograde transport, and immunohistochemical techniques were used to characterize the organization of neural inputs to the paraventricular (PVH) and supraoptic (SO) nuclei from the C1, C2, and C3 adrenergic cell groups in the rostral medulla. The results are as follows: 1) Phenylethanolamine-N-methyltransferase-immunoreactive (PNMT-IR) fibers and terminals were distributed to all parts of the parvicellular division of the PVH; the dorsal and dorsal medial subdivisions received the most prominent inputs, the lateral and ventral medial parts the least. Sparse terminal fields were found consistently in the magnocellular division of the PVH and in the SO. 2) A combined retrograde transport-immunohistochemical method was used to estimate the number and proportion of cells in the regions of the C1, C2, and C3 cell groups that contribute to the PNMT-IR innervation of the PVH. On average, 232 +/- 37 retrogradely labeled cells in the C1 cell group, 73 +/- 32 in the C2 cell group, and 96 +/- 26 in the C3 group stained positively for PNMT-IR. These values comprised 70%, 84%, and 89%, respectively, of all retrogradely labeled neurons in these regions. 3) Fibers and terminals arising from the regions of each of the three adrenergic cell groups were labeled by local injections of the anterogradely transported plant lectin PHA-L. Each component projection was found to distribute in a very similar fashion and to mimic the overall distribution of PNMT-IR; differential projection patterns within the PVH or SO were not seen consistently following deposits in any of the individual adrenergic cell groups or at different rostrocaudal levels of any individual cell group. 4) A dual anterograde tracing (PHA-L)-immunohistochemical (PNMT) labeling method revealed an appreciable number of varicosities arising from the regions of C1, C2, and C3 cell groups to contain PNMT-IR. These results suggest that adrenergic inputs to the PVH and SO, while arising from distinct medullary cell groups and presumably relaying different types of sensory information, are in a position to influence similar groups of parvicellular neurosecretory and/or autonomic-related projection neurons.

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The cellular localization of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) gene expression in the rat hippocampus was studied by in situ hybridization using 35S-labeled RNA-probes, complementary to either 513 bases of the rat brain mineralocorticoid receptor (MR)-mRNA or 500 bases of the rat liver glucocorticoid receptor (GR)-mRNA. Neurons in CA1, CA2, and the dentate gyrus expressed both receptor genes at high levels. The MR-mRNA was demonstrated in all pyramidal cell fields (CA1-4) of the hippocampal formation and the granular neurons of the dentate gyrus. In contrast, GR-mRNA was mainly restricted to CA1 and CA2 pyramidal cell fields and the dentate gyrus. This pattern of hybridization was found to agree with the cellular distribution of the two types of corticosteroid receptors detected previously in the hippocampus by autoradiography of the radio-labeled receptors and by immunocytochemistry of the receptor protein. These observations suggest that the corticosteroid receptors described previously as type 1 and type 2 are encoded by MR- and GR-mRNA, respectively. Although both the MR and GR genes are co-expressed in some hippocampal neurons, the unique patterns of distribution of the two receptor mRNAs in the hippocampal formation suggest that the genes for these receptors are differentially regulated. Moreover, the microanatomy of MR and GR expression provides insight into molecular mechanisms underlying the characteristic action of various steroids on behaviors involved in stress and circadian regulation.