Abstract Objectives Elevated expression of brain tumor necrosis factor-α (TNF), a proximal inflammatory cytokine, has been shown to promote depressive-like behavior. We previously demonstrated that antidepressant drugs reduce brain TNF levels, supporting the premise that TNF overexpression contributes to depression Methods This study examined whether selectively reducing TNF in the hippocampus, a region critical for mood regulation and antidepressant response, could alleviate depressive-like behavior in rats. To achieve targeted gene silencing, gold nanorod (GNR) nanoplexes conjugated to fluorescently labeled siRNA against TNF were microinjected bilaterally into the CA1 region of male Sprague–Dawley rat hippocampi. Control animals received GNRs carrying scrambled siRNA. Chronic desipramine treatment served as a positive control. Behavioral outcomes were assessed using novelty-induced hypophagia (NIH) and forced swim test (FST) immobility. Confocal and dark-field microscopy verified nanoplex distribution, and immunohistochemistry quantified hippocampal TNF expression. Results Selective TNF silencing in the hippocampus produced antidepressant-like effects comparable to chronic desipramine treatment. TNF nanoplexes significantly reduced latency to approach and consume palatable food in the NIH test and decreased immobility in the FST. These behavioral improvements corresponded with reduced TNF immunoreactivity in hippocampal tissue, confirming effective cytokine knockdown. Conclusions The findings demonstrate that nanoparticle-protected siRNA can successfully reduce brain TNF and produce robust antidepressant-like effects. By identifying hippocampal TNF as a key mediator of neuroinflammation-associated depression, this work highlights a promising molecular target and supports the development of brain-specific, nanotechnology-based therapies that may overcome limitations of conventional antidepressants.
Martuscello et al. (2026) studied this question.