Purpose of study: Vagus nerve stimulation (VNS) is used to treat pharmacotherapy-resistant epilepsy. Observations of mood elevation during VNS therapy for epilepsy suggested that such treatment might also show efficacy for refractory major depression. The molecular mechanism(s) underlying its therapeutic action remains unclear, however. By using a rat model of VNS we previously showed that acute VNS increases the gene expression of growth factors in the rat brain as well as the release of norepinephrine. We have now examined the effects of chronic VNS on hippocampal cell proliferation as well as on the expression of DCX and BDNF in rat brain and whether such effects might be associated with behavioral changes similar to those induced by chronic antidepressant drugs. Methods: Male Sprague-Dawley rats were used and a VNS therapy stimulator (Cyberonics, Houston, TX) was implanted. Cell proliferation in the hippocampus of rats subjected to acute (3h) or chronic (1 month) VNS was examined by injection of bromodeoxyuridine (BrdU) and immunohistochemistry. Expression of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) was evaluated by immunofluorescence staining. Behavioral effects were studied in the forced swim and elevated plus- maze tests. Results: Acute VNS induced an increase in the number of BrdU+ cells in the dentate gyrus that was apparent 24 h (2200±159; P < 0.05) and 3 weeks (2448±129; P < 0.01) after treatment compared with that apparent in sham-operated controls (1760±74). It also induced long- lasting increases in the amount of DCX immunoreactivity (+39%; P < 0.05) and in the number of DCX+ neurons (+57%; P<0.01). Neither the number of BrdU+ cells nor the amount of DCX immunoreactivity was increased 3 weeks after the cessation of chronic VNS. Moreover, VNS induced long-lasting increases in the amount of BDNF immunoreactivity and the number of BDNF+ cells (+104% and +40% respectively; P < 0.001). VNS also affected the dendritic complexity of DCX+ neurons in the hippocampus. Nevertheless, in contrast to chronic imipramine, chronic VNS had no effect on the behavior ofratsintheforcedswimorelevatedplus-mazetests. Conclusions: In the hippocampus VNS induced cell proliferation and persistent changes in morphology ofDCX+ neurons. These effects were accompanied by a robust increase in the expression of BDNF, which may play an important role in consolidating the changes in neuronal connections as suggested by the increased complexity of the dendritic arborization. Thus, some of the effects of chronic VNS appear to be similar to those induced by chronic treatment with antidepressant drugs but do not correlate with corresponding behavioral changes. Although further clinical and experimental studies are necessary to better understand the mechanisms of VNS, our results show that the promotion of neurogenesis and the expression of growth factors are rapidly induced by VNS differently from antidepressant. Whether such early newly generated neurons contribute to existing or de novo networks that might mediate antiepileptic or antidepressant effects remains to be determined.
Vagus nerve stimulation induces cell proliferation and changes in neuronal morphology in the rat hippocampus
BIGGIO, FRANCESCA;FOLLESA, PAOLO;
2010-01-01
Abstract
Purpose of study: Vagus nerve stimulation (VNS) is used to treat pharmacotherapy-resistant epilepsy. Observations of mood elevation during VNS therapy for epilepsy suggested that such treatment might also show efficacy for refractory major depression. The molecular mechanism(s) underlying its therapeutic action remains unclear, however. By using a rat model of VNS we previously showed that acute VNS increases the gene expression of growth factors in the rat brain as well as the release of norepinephrine. We have now examined the effects of chronic VNS on hippocampal cell proliferation as well as on the expression of DCX and BDNF in rat brain and whether such effects might be associated with behavioral changes similar to those induced by chronic antidepressant drugs. Methods: Male Sprague-Dawley rats were used and a VNS therapy stimulator (Cyberonics, Houston, TX) was implanted. Cell proliferation in the hippocampus of rats subjected to acute (3h) or chronic (1 month) VNS was examined by injection of bromodeoxyuridine (BrdU) and immunohistochemistry. Expression of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) was evaluated by immunofluorescence staining. Behavioral effects were studied in the forced swim and elevated plus- maze tests. Results: Acute VNS induced an increase in the number of BrdU+ cells in the dentate gyrus that was apparent 24 h (2200±159; P < 0.05) and 3 weeks (2448±129; P < 0.01) after treatment compared with that apparent in sham-operated controls (1760±74). It also induced long- lasting increases in the amount of DCX immunoreactivity (+39%; P < 0.05) and in the number of DCX+ neurons (+57%; P<0.01). Neither the number of BrdU+ cells nor the amount of DCX immunoreactivity was increased 3 weeks after the cessation of chronic VNS. Moreover, VNS induced long-lasting increases in the amount of BDNF immunoreactivity and the number of BDNF+ cells (+104% and +40% respectively; P < 0.001). VNS also affected the dendritic complexity of DCX+ neurons in the hippocampus. Nevertheless, in contrast to chronic imipramine, chronic VNS had no effect on the behavior ofratsintheforcedswimorelevatedplus-mazetests. Conclusions: In the hippocampus VNS induced cell proliferation and persistent changes in morphology ofDCX+ neurons. These effects were accompanied by a robust increase in the expression of BDNF, which may play an important role in consolidating the changes in neuronal connections as suggested by the increased complexity of the dendritic arborization. Thus, some of the effects of chronic VNS appear to be similar to those induced by chronic treatment with antidepressant drugs but do not correlate with corresponding behavioral changes. Although further clinical and experimental studies are necessary to better understand the mechanisms of VNS, our results show that the promotion of neurogenesis and the expression of growth factors are rapidly induced by VNS differently from antidepressant. Whether such early newly generated neurons contribute to existing or de novo networks that might mediate antiepileptic or antidepressant effects remains to be determined.
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