Improvements in memory after medial septum stimulation are associated with changes in hippocampal cholinergic activity and neurogenesis

Abstract

Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.

Figure 1

Effect of MS-DBS on spatial memory. Latency indicates the time required for the rat to find the escape platform during training trails. During training trails, all groups gradually acquired the location of the platform (a). After a delay of two days, spatial memory was improved by MS-DBS (b). Time spent in the platform zone (P < 0.05) and number of crossings (P < 0.005) was significantly different between lesion and normal groups. However, the stimulation group did not differ from the normal group. There was no disruption of motor function in any group. Data are shown as mean ± SEM (a). Indices are expressed as the percentage of normal group values (b). MS: medial septum; DBS: deep brain stimulation: Dist: distance.

Figure 2

Cresyl violet stained coronal section and slide of atlas [35] at MS level. Arrow heads show the tract of the electrode in the MS.

Figure 3

Representative pictures showing the effects of the cholinergic lesion on the basal forebrain. The normal group had numerous ChAT immunopositive neurons in the MS (a). The lesion (b), implantation (c), and stimulation (d) groups displayed a loss of cholinergic neurons in the MS. Scale bar represents 500 μm. ChAT: choline acetyltransferase; MS: medial septum.

Figure 4

Effects of MS-DBS on adult hippocampal neurogenesis revealed by doublecortin immunohistochemistry. Representative pictures show the effects of basal forebrain cholinergic deficits and MS-DBS on hippocampal neurogenesis (a–d). Many doublecortin immunopositive cells were observed in the normal group (a). However, the number of these cells was decreased in the lesion (b) and implantation (c) groups, in which basal forebrain cholinergic neurons were damaged, but not in the stimulation group (d). After counting the immunopositive cells (e), we found that the number of cells in the normal group was significantly different from that in the lesion group (P < 0.05). However, there was no difference between the lesion group and the implantation group, which was only implanted with an electrode in the MS. The number of doublecortin immunopositive cells was significantly increased in the stimulation group (P < 0.05), which had damaged basal forebrain cholinergic neurons and received electrical stimulation of the MS.

Figure 5

Effect of MS-DBS on AChE activity. In the prefrontal cortex, AChE activity of the stimulation group was significantly increased more than that in implantation group (P < 0.05). Hippocampal AChE activity in the lesion (P < 0.05) and implantation (P < 0.005) groups was significantly less than that in the normal group. However, AChE activity in the stimulation group was equivalent to that in the normal group. The AChE activity was expressed as the optical density of the colorimetric reading at 405 nm. Values are mean ± SEM. OD: optical density.