Prelimbic Cortical Stimulation Improves Spatial Memory Through Distinct Patterns of Hippocampal Gene Expression in Aged Rats

Abstract

Dementia poses major health challenges worldwide, yet current treatments are faced with issues of efficacy and toxicity. Deep brain stimulation (DBS) is a promising non-pharmacological treatment for dementia, but most DBS studies use young healthy animals, which may not be aetiologically relevant. In this study, we used an aged rat model in which cognitive decline occurs through a natural ageing process. We used a Morris water maze (MWM) to determine the effects of prelimbic cortex (PrL) DBS on memory in aged rats. To investigate the underlying mechanisms of the effects of DBS, we carried out microarray, quantitative PCR analysis, and mass spectrometry to detect gene expression and neurotransmitter changes in the hippocampus. We showed PrL DBS improved the performance in MWM, with related distinct patterns of gene expression involving G protein-coupled receptor pathways. We further found neurotransmitter changes in the dorsal hippocampus, which corroborated and extended the microarray findings. Our results suggest that non-neurogenesis pathways play roles in the effects of DBS. Further studies are needed to investigate the effects of DBS on memory beyond neurogenesis and to consider the highlighted pathways suggested by our data.

Dropout in Neural Networks Simulates the Paradoxical Effects of Deep Brain Stimulation on Memory

“…Although CNNs are modeled on the visual cortex, dropout was only applied on fully connected latter layers in the network to represent dropouts applied in the hippocampus rather than in the visual cortex. This mimicked our previous experiments on the effects of prefrontal cortex stimulation on the hippocampus (Tan et al, 2019a(Tan et al, , 2020c.…”

“…To the best of our knowledge, this article is the first to suggest a cohesive mechanism in which disruption of neural activity through DBS can lead to both disruption and enhancement of memory. Although no behavioral experiments were performed in conjunction with our modeling, we based the models on our previous animal behavioral experiments that showed that DBS prior to the behavioral task resulted in memory enhancement (Tan et al, 2020c) and DBS during consolidation of memory resulted in memory disruption (Tan et al, 2019a), which were similarly demonstrated in this present article. However, we acknowledge the simplistic and preliminary nature of our methodology and results.…”

“…Neuromodulation techniques such as deep brain stimulation (DBS) have shown promising results as treatments for memory-related disorders (Tan et al, 2019b(Tan et al, , 2020b), yet the mechanisms behind these effects are still largely unknown. Furthermore, the effects of treatments such as DBS appear to be paradoxical, in that they can both disrupt (Hamani et al, 2010;Tan et al, 2019a) and enhance memories (Hamani et al, 2011;Tan et al, 2020c) even when applied to the same brain target (detailed review in Tan et al, 2020b). We have previously suggested that DBS is able to disrupt memory by ''removing'' nodes in an engram (Tan et al, 2019b).…”

“…Due to limited systematic studies looking at DBS and memory, we based our modeling on the results from our previous studies that showed high-frequency stimulation of the ventromedial prefrontal cortex (vmPFC) could both enhance (Tan et al, 2020c) and disrupt (Tan et al, 2019a) memory. Based on these findings, we focused on the hippocampal engram and implicit associative memories in the proposed simulation.…”

Prelimbic cortical stimulation disrupts fear memory consolidation through ventral hippocampal dopamine D2 receptors

“…Conditioned fear was first investigated in rats using a standard tone‐footshock fear conditioning paradigm, which is a highly robust and established method for testing anxiety (Ganella & Kim, 2014). With the regional specificity of DBS, we then probed the involvement of the hippocampus, a structure interconnected to the ventromedial prefrontal cortex that plays an important role in emotions and memory (Carreno et al, 2016; Jin & Maren, 2015; Liu et al, 2015; Phillips et al, 2019; Tan, Neoh, et al, 2020). Specifically, we found the involvement of the ventral hippocampus, which plays a crucial role in anxiety‐related behaviour and has monosynaptic projections connecting to the ventromedial prefrontal cortex (Adhikari et al, 2010; Padilla‐Coreano et al, 2016).…”