Abstracts

Rationale: The loss of neurons within the limbic circuit subserving memory is known to occur in a number of disease conditions. For example, severe hippocampal neurodegeneration is found in mesial temporal lobe sclerosis associated with epilepsy. Recently, high-frequency deep brain stimulation of the anterior nucleus of the thalamus, a convergent node in the limbic circuit, has been shown to have beneficial behavioral effects in patients with treatment-refractory epilepsy (Fisher et al. 2010, Epilepsia 51:899). The basic biological mechanism underlying the therapeutic effect of deep brain stimulation in this circuit is unknown. One possibility is that electrical stimulation of inputs to the hippocampus augments ongoing neurogenesis known to occur in the adult granular cell layer and that repopulation of the dentate gyrus reverses the deleterious effects of hippocampal degeneration. Electrically-induced neurogenesis may be mediated by trophic factors known to regulate neuron survival during neurodevelopment. Methods: Using western blots, we measured the levels of BDNF and other proteins in the hippocampus of rats at 0, 6, 12, 24 and 48 hours after acute high-frequency stimulation of the anterior nucleus (2.5 V, 90 ms, 130 Hz for 1 hour). Results: BDNF protein levels rapidly increased by more than 200% immediately after cessation of stimulation and remained elevated for at least 12 hours. Stereological cell counting revealed that the same electrical stimulation led to a 2.5 fold increase in neurogenesis in the dentate gyrus at five days after stimulation compared to sham controls. We have previously shown that high-frequency stimulation of the anterior nucleus of the thalamus in adult male Wistar rats elicits a wave of neurogenesis within the hippocampus (Tierney et al. Soc. Neurosci. Abstr. 10.3). Conclusions: Together, these findings suggest that stimulation-dependent neurogenesis in the rat hippocampus may be regulated by the over-expression of endogenous trophic proteins.