Frequency-Dependent Modulation of the Prefrontal Cortex by Low-Intensity Focused Ultrasound: Impact on Mesolimbic Dopamine Signaling

Synchronized neural oscillations are fundamental for cognitive function and orchestrate inhibitory and excitatory neurotransmission and downstream signaling. We hypothesized that low-intensity focused ultrasound (LIFU) with frequency parameters mimicking oscillatory patterns would enable targeted neuromodulation. Building on prior findings of the ability of LIFU to modulate neurotransmission, we investigated the effects of frequency-modulated LIFU applied to the prelimbic cortex (PLC) on dopamine release in the nucleus accumbens (NAcc) core as well as neuronal and astrocytic activity. After three 80-second LIFU stimulations spaced 30 minutes apart, we found that LIFU excited or inhibited NAcc dopamine release for up to 90 minutes, and these effects were dependent on oscillation frequency and sex. In male rats, theta (8 Hz)-coupled beta (16 Hz) LIFU reduced both dopamine release by 58% and the level of the astrocytic marker GFAP by 50%. Similar decreases in dopamine density were observed in females. Delta (2 Hz)-coupled beta (16 Hz) stimulation produced similar inhibitory effects. Conversely, theta (5 Hz)-coupled gamma (50 Hz) LIFU increased dopamine release by 28% in males. However, similar excitation levels were observed only in females with an increased gamma frequency of 70 Hz (coupled with a theta frequency of 7 Hz). Histological analysis revealed no cell death, but both 8:16 Hz and 5:50 Hz LIFU elevated neuronal activation (cFOS) in the PLC in males, while 5:50 Hz also upregulated GFAP by 30%, suggesting astrocytic involvement. Thus, LIFU stimulation of the PLC can be frequency-tuned to selectively excite or inhibit dopaminergic signaling in the NAcc, suggesting a novel approach for manipulating neurotransmission.