C-type natriuretic peptide (CNP) can be altered during stress and has protective effects in both the heart and brain; the functions of both organs can be positively affected by CNP modulation. Low arousal sounds can modulate heart–brain communication and improve stress responses. Here, we aimed to explore the modulation of CNP and glial fibrillary acidic protein (GFAP) and neuroprotective effects of low arousal theta frequency sound (TFS).

Chronic stress was induced in mice (n > 4) using four different stressors on alternate days for 15 days, followed by TFS therapy on alternate days. Open field and elevated plus maze tests were administered for the behavioral analysis, and enzyme-linked immunosorbent assay was used to analyze corticosterone, dopamine, and serotonin levels. Hematoxylin and eosin and cresyl violet staining were used for the morphological analysis of brain and heart sections, and immunohistochemistry for GFAP and CNP was performed.

TFS significantly increased the time spent in the open arms during the elevated plus maze (p < 0.05) and improved exploration in the open field test (p < 0.05). In both tests, decision-making times were significantly reduced by TFS. Nuclear morphology and GFAP expression demonstrated significantly reduced gliosis in fear pathways after TFS therapy x. CNP levels were restored in fear pathways but not intrinsic cardiac ganglia (responsible for heart–brain communication) in TFS-treated mice. Brain corticosterone and dopamine levels increased after TFS therapy, reflecting restored motivational behaviors.

Low arousal TFS is a potential neuromodulator for treating stress and related complications.