Lynch, W. J. | Search bioRxiv

bioRxiv2025

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.

neuroscience↗

bioRxiv2024

Focused Ultrasound modulates dopamine in a mesolimbic reward circuit

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm2 Isppa) of 2-minute LIFU to the prelimbic region (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm2 to the PLC significantly reduced dopamine release by [~] 50% for up to 2 hours. However, double the intensity (26 W/cm2) resulted in less inhibition ([~]30%), and half the intensity (6.5 W/cm2) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling of temperature rise demonstrates a maximum temperature change of 0.5{degrees}C with 13 W/cm2, suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.

neuroscience↗