Deep Brain Stimulation of the Medial Septal Area Can Modulate Gene Expression in the Hippocampus of Rats under Urethane Anesthesia

Abstract

We studied the effects of stimulation of the medial septal area on the gene expression in the dorsal and ventral hippocampus. Rats under urethane anesthesia were implanted with a recording electrode in the right hippocampus and stimulating electrode in the dorsal medial septum (dMS) or medial septal nucleus (MSN). After one-hour-long deep brain stimulation, we collected ipsi- and contralateral dorsal and ventral hippocampi. Quantitative PCR showed that deep brain stimulation did not cause any changes in the intact contralateral dorsal and ventral hippocampi. A comparison of ipsi- and contralateral hippocampi in the control unstimulated animals showed that electrode implantation in the ipsilateral dorsal hippocampus led to a dramatic increase in the expression of immediate early genes (c-fos, arc, egr1, npas4), neurotrophins (ngf, bdnf) and inflammatory cytokines (il1b and tnf, but not il6) not only in the area close to implantation site but also in the ventral hippocampus. Moreover, the stimulation of MSN but not dMS further increased the expression of c-fos, egr1, npas4, bdnf, and tnf in the ipsilateral ventral but not dorsal hippocampus. Our data suggest that the activation of medial septal nucleus can change the gene expression in ventral hippocampal cells after their priming by other stimuli.

The Induction of Long-Term Potentiation by Medial Septum Activation under Urethane Anesthesia Can Alter Gene Expression in the Hippocampus

“…A comparison of the early gene expression in the ipsilateral and contralateral dorsal and ventral hippocampi showed a clear increase in the expression of immediate early genes in both ipsilateral hippocampal parts compared with the contralateral hippocampi. These results support our previous observations [ 12 ] that the implantation of electrodes leads to an increase in the majority of early response genes both at the site of implantation (dorsal ipsilateral hippocampus) and in the distant hippocampal part (ventral ipsilateral hippocampus) but not in the contralateral hippocampi. As we discussed previously [ 12 ], the most likely explanation for this nonlocal effect in the ipsilateral hippocampus is a wave of spreading depression (currently, some researchers also call it spreading depolarization) which is initiated at the site of the hippocampal damage by the implanted electrode and spreads over the entire ipsilateral hippocampus.…”

“…These results support our previous observations [ 12 ] that the implantation of electrodes leads to an increase in the majority of early response genes both at the site of implantation (dorsal ipsilateral hippocampus) and in the distant hippocampal part (ventral ipsilateral hippocampus) but not in the contralateral hippocampi. As we discussed previously [ 12 ], the most likely explanation for this nonlocal effect in the ipsilateral hippocampus is a wave of spreading depression (currently, some researchers also call it spreading depolarization) which is initiated at the site of the hippocampal damage by the implanted electrode and spreads over the entire ipsilateral hippocampus. The occurrence of a spreading depression in one of the hippocampi helps us to detect additional changes that are otherwise hidden.…”

“…Presumably, these changes may serve as additional epigenetic factors that can alter the readiness of hippocampal cells to the induction of transcriptional changes after certain stimuli. Our current and previous [ 12 ] data suggest that changes in the expression of early genes caused by putative spreading depressions after electrode implantation in the hippocampus were similar to the changes observed in non-anesthetized animals [ 37 ]. This comparison suggests that urethane is likely to have a negligible effect on the detected changes in the expression of early genes, but we cannot completely exclude this influence.…”

“…It is important to stress that in the aforementioned studies, LTP was induced by stimulation of the dorsal part of the MSA (dMSA), whose stimulation induces a clear postsynaptic response in the hippocampus. The more ventral parts of the MSA (the medial septal nucleus and diagonal bands of Broca’s area) contain more cholinergic cells than the dMSA, and their stimulation does not result in an electrophysiological response in the hippocampus [ 11 ] but can alter gene expression in the hippocampus [ 12 ]. Moreover, low-frequency dMSA stimulation had practically no effect on hippocampal cells in terms of transcriptional activity [ 12 ].…”

“…The more ventral parts of the MSA (the medial septal nucleus and diagonal bands of Broca’s area) contain more cholinergic cells than the dMSA, and their stimulation does not result in an electrophysiological response in the hippocampus [ 11 ] but can alter gene expression in the hippocampus [ 12 ]. Moreover, low-frequency dMSA stimulation had practically no effect on hippocampal cells in terms of transcriptional activity [ 12 ]. The latter is quite paradoxical since dMSA activation may induce LTP, which requires changes in the expression of genes for long-term maintenance of acquired changes in the synaptic strength [ 13 , 14 ].…”