The effects of prelimbic cortex deep brain stimulation on memory and its implications

Abstract

Deep Brain Stimulation (DBS) is a minimally invasive technique, in which an electrode is implanted in a desired region of the brain. The principle of DBS is to modulate firing of neurons through electrical stimulation supplied via electrodes. Given then ability of DBS to modulate firing of neurons, a key component memory, it is unsurprising that DBS has been investigated as a potential treatment for various neurological and psychiatric diseases, including diseases involving memory such as anxiety disorders and dementia. Despite this, the mechanisms behind how DBS affects memories are still unclear, which has in turn hindered the translational progress. Among the issues that have resulted from the lack of understanding of DBS, an interesting paradox emerges in which the aims of treating dementias and anxiety or addiction seems to be opposite of each other; the aim of treating dementias would be to enhance memory, while treating anxiety or addiction would be to dampen or obliterate maladaptive memories. This somewhat contradictory idea has confused researchers, with some studies showing improvement of memories, while others having shown disruption of memories. Studying the effect of DBS on both models of anxiety and dementia might then hold the key to understanding the effects of DBS on memory and eventually translating DBS to the clinic. In this thesis, I systematically study the effects of DBS on memory in animal models of anxiety and dementia to unravel some of the complexities surrounding the paradoxes seen in the literature, attempting to address these questions holistically by using a multi-disciplinary approach. I first showed that DBS of the prelimbic cortex (PrL) is able to disrupt consolidation of fear memories through dopaminergic modulation. I then showed that chronic PrL DBS is also able to enhance memory function in aged animals, using in-depth microarray analysis to tease out mechanisms. I then tried to make sense of this paradoxical effects using an artificial neural network and modelling in order to overcome current limitations, hypothesizing how PrL DBS can both enhance and disrupt memories. Lastly, I investigated the ethical concerns that emerge from the results and technology that could subsequently eventuate. Overall, I present a comprehensive look into the use of DBS in the modulation of memory.