References

Fraley GS (2002) Role of hindbrain catecholaminergic afferents to the medial hypothalamus in the regulation of penile reflexes in the rat. Neuroscience 2002 Abstracts 681.4. Society for Neuroscience, Orlando, FL.

Summary: The use of ex copula erections, or reflexive erections, has been used for decades in the study of the central pathways and neuroendocrinology of penile erections. However, the exact neuroendocrine pathways involved in developing penile erections are not known. This study utilized molecular neurosurgical techniques combined with behavioral, histological, and molecular analyses to determine a central link between metabolic state and penis erectile function. Utilizing saporin-conugate immunolesion techniques (DSAP), hindbrain catecholaminergic afferents to the hypothalamus that are reported to be glucoresponsive were eliminated. DSAP-lesioned rats had a significantly attenuated glucoprivic feeding response and significantly attenuated penile reflexes compared to controls. Analysis of Nissl-stained spinal cord sections demonstrated a significant reduction in the size of sexually dimorphic motoneurons. Furthermore, qualitative analysis of calcitonin gene-related immunoreactivity (CGRPir) in alternate spinal sections revealed a decrease in CGRPir in sexually dimorphic motor pools. Analysis of hypothalamic mRNA levels showed a significant increase in both oxytocin and neuropeptide Y mRNA, but not b-actin mRNA. No significant differences were seen, however, in the weight of the perineal muscles, seminal vessicles, or in plasma testosterone levels. These data indicate a novel hindbrain-hypothalamic-spinal cord pathway by which potential glucoresponsive neurons effect the ability to achieve penile erection based upon availability of metabolic fuel.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Beach TG, Potter PE, Sue LI, Fisher A, Scott S, Layne KJ, Newell AJ, Roher AE, Walker DG (2002) Cerebral abeta deposition induced by cortical cholinergic deafferentation is reduced by cholinergic therapy. Neuroscience 2002 Abstracts 722.9. Society for Neuroscience, Orlando, FL.

Summary: We have previously shown that cortical cholinergic deafferentation in rabbits results in cerebral Abeta deposition (Neurosci Lett 283:9-12, 2000). We have also shown that cholinergic therapy with acetylcholinesterase inhibitors and muscarinic agonists reduces Abeta concentrations in the CSF and cortex of normal rabbits (Neurosci Lett 310:21-24, 2001; Brain Res 905:220-223, 2001). Here we show that the histologic deposition and biochemical elevations of Abeta induced by cholinergic immunotoxin are reduced by systemic therapy with AF267B, an M1-selective muscarinic agonist, and physostigmine, an acetylcholinesterase inhibitor. Rabbits received i.c.v. injections of an immunotoxin composed of the p75 NTR-directed monoclonal antibody ME20.4 conjugated to saporin, a ribosomal toxin. One group of animals received s.c. AF267B (2 mg/kg/day) while another group received s.c. physostigmine (3 mg/kg/day). Control groups received either i.c.v. immunotoxin or sham lesion (i.c.v. saline) and no treatment. Four weeks after surgery, imunohistochemical staining for Abeta showed frequent positive blood vessels and perivascular diffuse plaques in the control group which received immunotoxin injection and no treatment. This was significantly reduced in animals which received either AF267B or physostigmine. Cerebrospinal fluid Abeta concentrations were also reduced significantly by both drug treatments. These results are directly relevant to humans since cortical cholinergic deafferentation is part of normal human aging.

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Schaevitz LR, Baxter MG, Stearns NA, Huang YY, Lappi DA, Berger-Sweeney J (2002) The efficacy of intraparenchymal anti-p75 immunotoxin on medial septal cholinergic neurons in mice. Neuroscience 2002 Abstracts 778.11. Society for Neuroscience, Orlando, FL.

Summary: We have shown previously that anti-murine-p75-SAP (saporin conjugated to a rat monoclonal antibody against the mouse p75 nerve growth factor receptor) selectively destroys basal forebrain cholinergic neurons in vivo after intracerebroventricular injections (J. Neurosci. 21:8164-73). Cholinergic neuronal loss was more extensive in the medial septum (MS) than the nucleus basalis magnocellularis; it is unclear whether this distinction is due to toxin diffusion from the ventricles or differential sensitivity of the neuronal populations. Intraparenchymal (IPC) injections to specific targets can help resolve the issue. Here, we examine the efficacy of anti-murine-p75-SAP IPC injections on cholinergic neurons. Saline or different doses of toxin (0.1, 0.2, 0.4, 0.9, 4.7, and 9.4 microg/microL) were injected into the MS of adult male C57BL/6J mice. Ten days post lesion, brain sections were stained for choline acetyltransferase and p75 (cholinergic markers) to determine toxin efficacy, and calbindin and parvalbumin (non-cholinergic markers) to determine toxin specificity. Toxin doses below 1.0 microg/microL had no effect on cholinergic or non-cholinergic neurons, while doses above 4.7 microg/microL resulted in the complete destruction of both cholinergic and non-cholinergic neurons. More thorough testing of doses between 1 and 4 microg/microL will be required to determine the optimal toxin dose for IPC injections.

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Fernandez M, Giuliani A, Giardino L, Calza L (2002) In vivo strategies for stem cells regulation in the adult brain: A chance for cholinergic neurons. Neuroscience 2002 Abstracts 483.14. Society for Neuroscience, Orlando, FL.

Summary: Degenerative diseases represent a severe problem in view of very limited repair capability of nervous system. In order to use stem cells in the adult CNS for repair purpose, we are exploring the possibility to influence, in vivo, proliferation, migration and phenotype lineage of stem cells in adult brain using a growth factor, hormone and cytokine cocktail. In this study we used substances appropriate for in vitro cholinergic differentiation in animals lesioned with icv administration of the cholinergic neurons immunotoxin 195IgG-saporine (3microg/4,5microl). Four months after lesion, no ChAT-positive neurons were found in the basal forebrain, acetylcolinesterase-reactive fibres and ChAT activity in the cerebral cortex and hippocampus dramatically decrease, and animals are severely impaired in water maze learning task. An Alzet osmotic Minipump for chronic release (over 14 days) of the mitogen EGF (360ng/days) was then implanted and connected to a icv catheter. This treatment increases proliferation rate in SVZ in lesioned and unlesioned animals as indicated by the widespread distribution of BrDU-positive nuclei in the forebrain. Rats were then treated with retinoic acid (2.25 mg/day, orally). This treatment reduces Ki67 protein in the SVZ in lesioned rats, and this could indicate a progression toward differentiation. TrkA-positive innervation also increase in the basal forebrain of EGF+retinoic acid treated rats and ChAT activity is lightly, but significantly raises by combined EGF + retinoid acid treatment in the hippocampus.

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Fargo KN, Sengelaub DR (2002) Androgen manipulation protects remaining motoneurons from dendritic atrophy after induced motoneuron death. Neuroscience 2002 Abstracts 466.13. Society for Neuroscience, Orlando, FL.

Summary: Androgen treatment facilitates axon regrowth after axotomy of facial and sciatic motoneurons, and reverses castration-induced dendritic atrophy in motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in rats. We assessed whether a similar therapeutic effect of androgen would be seen in dendrites following partial depletion of SNB motoneurons. We injected the toxin saporin, conjugated to choleratoxin (β-saporin), unilaterally into the SNB target muscles, bulbocavernosus (BC) and levator ani (LA), of two groups of adult male rats. One group had been castrated six weeks earlier to induce dendritic atrophy, and received testosterone-filled Silastic capsules coincident with β-saporin injection (SAP+T). The other group had no castration or androgen treatment (SAP-only). Four weeks after β-saporin injection, we injected choleratoxin conjugated HRP into the contralateral (non-saporin injected) BC muscle to label SNB motoneurons. A group of untreated normal males was also included. Cell counts were performed, and dendrites of HRP-labeled SNB motoneurons were reconstructed in three dimensions. β-saporin killed ~65% of motoneurons in the SNB ipsilateral to the saporin-injected muscles; contralateral SNB motoneuron numbers were not affected. SNB dendritic arbors on the non-saporin injected side were ~60% shorter in SAP-only animals compared to those of untreated males; in contrast, dendritic arbors in SAP+T animals were unaffected. These results indicate that a) motoneuron death causes dendritic atrophy in remaining SNB motoneurons, and that b) previous castration and concurrent testosterone replacement protects against this atrophy.

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Gibbs RB (2002) Basal forebrain cholinergic neurons are necessary for estrogen to enhance acquisition of a delayed matching-to-position T-maze task. Horm Behav 42(3):245-257. doi: 10.1006/hbeh.2002.1825

Summary: The author investigated the role of cholinergic neurons of the basal forebrain in cognitive function using a long-term hormone replacement model in rats. Septal infusions of either 1.0 µg or 0.22 µg 192-Saporin (Cat. #IT-01) prevented the therapeutic effects of hormone replacement on cognitive function.

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Kanold PO, Shatz CJ (2002) Developmental regulation of GABA Receptor subunits requires subplate neurons. Neuroscience 2002 Abstracts 530.11. Society for Neuroscience, Orlando, FL.

Summary: Subplate neurons (SP) are required for formation and patterning of thalamocortical connections. In visual cortex, SP ablation before the onset of the critical period, but when LGN axons are already in layer 4, prevents segregation into ocular dominance columns (ODCs) and emergence of functional orientation columns. Recent studies have linked ODC plasticity with maturation of inhibitory circuitry, which requires the appropriate expression and developmental regulation of GABA receptor subunits. We therefore wondered if SP ablation alters GABA-R subunit expression. Focal injections of kainic acid or immunotoxin were made into cat SP between P7-P10, just prior to the onset of ODC formation. 3 weeks later, in situ hybridization revealed that expression of several subunits of the GABA-A receptor was reduced in the ablated region, especially in layer 4. Other genes involved in synaptic function such as Homer and mGluR subunits also decreased in expression. These changes in gene expression suggest that the efficacy of inhibition in layer 4 is reduced. A reduction in postsynaptic GABA receptors is consistent with previously observed increases in BDNF and GAD expression after SP ablation. These observations imply that SP neurons are essential for the maturation of cortical inhibition, which in turn may be needed for the formation of ODCs and for the functional maturation of thalamocortical connections.

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Salo PT, Hogervorst T, Seerattan RA, Rucker D, Bray RC (2002) Selective joint denervation promotes knee osteoarthritis in the aging rat. J Orthop Res 20(6):1256-1264. doi: 10.1016/S0736-0266(02)00045-1

Summary: Noting that mice lose joint afferents with aging, and that this loss precedes osteoarthritis development, the authors investigated the effects of denervating the knee joints of young rats. Injection of 10 µl OX7-SAP (Cat. #IT-02) into the knee joint space produced severe degenerative cartilage changes as well as a significant reduction in the number of joint afferents. These changes indicate that joint denervation predisposes a joint to osteoarthritic changes more severe than those found with aging alone.

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Sheehan JJ, Tsirka SE (2002) Reduction of microglia cell populations before induction of excitotoxicity reduces neurodegeneration. Neuroscience 2002 Abstracts 606.9. Society for Neuroscience, Orlando, FL.

Summary: Excitotoxicity is thought to be a component of many neurodegenerative diseases including Alzheimer’s and stroke. In excitotoxicity, as well as other injury models, microglia have been found to have both neuroprotective and neurodegenerative roles. To lend further insight into this controversy we utilized an immunotoxin selective for monocyte derived cell populations including microglia. The immunotoxin will selectively kill microglia and is not toxic to neurons or other glia populations in culture. In addition, infusion of the immunotoxin into the hippocampus of C57/Bl mice results in a selective reduction in endogenous microglial cell populations in this region. Furthermore, this reduction occurs without any perturbation of other cell types or the extracellular matrix. If depletion of microglia in this manner precedes excitotoxic injury, then hippocampal neurodegeneration is significantly reduced. These results agree with other work in our lab, which suggests that microglial cells exhibit neurotoxic properties in excitotoxicity.

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Mantyh PW (2002) Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63(Suppl 11):6-10.

Summary: The NK-1 receptor system is somewhat unusual in that it is expressed on only 5-7% of neurons in the central nervous system. Dr. Patrick Mantyh reviews how tools such as SP-SAP (Cat. #IT-07) have been used to begin defining the roles of substance P and the NK-1 receptor in affective behavior.

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