Chemically guided electrical stimulation as a cell type-specific treatment for depression in rodents

Waye, Shannon C. (2025) Chemically guided electrical stimulation as a cell type-specific treatment for depression in rodents. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Major depressive disorder is a mental health condition that severely impacts the lives of those affected. Although many treatments have been developed to alleviate symptoms, their efficiency is limited by low response rates and unwanted side effects. Advancements in the field of neurostimulation provide a promising new avenue for treatment; however, research is still ongoing to determine the optimal parameters and underlying mechanisms of the procedure. In this thesis, I examine the efficacy of a novel combination therapy for depression that applies transcranial direct current stimulation (tDCS) to neurons that have been chemically primed for excitability using the small-conductance, calcium-activated potassium channel antagonist, NS8593, in order to selectively activate a specific subset of neurons in the prefrontal cortex. First, we identified a subthreshold dose for both treatments individually that failed to elicit any behavioural or neurochemical changes in adult rats. These electrical and chemical doses (0.05mA and 1.0mg/kg, respectively) were then combined into one treatment known as EC stimulation and examined across a battery of behavioural tests in the olfactory bulbectomy (OBX) model of rodent depression. We found that EC stimulation reversed OBX-induced hyperlocomotion in the open field test, while also blocking anxiety-related behaviours in the open field and novelty suppressed feeding tests that manifested following tDCS application. These effects were associated with increased serotonin (5-HT) turnover in the left prefrontal cortex and hippocampus, as indicated by a reduction in overall 5-HT and corresponding increase in its metabolite, 5-HIAA. Combination treatment also blocked the increase in hippocampal dopamine that was observed following administration of tDCS or NS8593 alone. However, these effects were observed solely in male rats, as females failed to exhibit a depressive-like phenotype following OBX. The societal burden imposed by increasing depression rates makes the development of novel interventions for the disorder a priority for public health. Taken together, these results support further preclinical development of EC stimulation as a safe and effective novel treatment for depression.

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