Astrocytes modulate the effects of cocaine in low frequency neuro-vascular oscillations in mice

Low-frequency oscillations (LFOs) in neurovascular system reflect brain activity and are disrupted by cocaine, likely contributing to its neuropathological effects. However, cellular mechanisms underlying this disruption remain poorly understood. We utilize a multimodal imaging platform (MIP) integrating GCaMP6f-based calcium fluorescence imaging and optical coherence Doppler tomography to investigate how acute and chronic cocaine alter LFOs within the neuro-astroglio-vascular (NAV) network in prefrontal cortex (PFC) of isoflurane-anesthetized mice. Astrocytes are selectively modulated via GFAP-DREADDs(Gi) to assess their roles in regulating LFOs. Results show acute cocaine enhances LFOs and their synchronization within NAV network; GFAP-DREADDs(Gi) activation, modulating astrocytic Ca²⁺, abolishes this effect of cocaine. Chronic cocaine increases basal LFOs, but chronic GFAP-DREADDs(Gi) activation abolishes these effects in astrocytes and CBF, though not in neurons. Interestingly, LFOs' responses to acute cocaine in chronically cocaine exposed mice concomitantly treated with GFAP-DREADDs(Gi) activation are similar to those in drug naïve mice, indicating that chronic GFAP-DREADDs(Gi) activation prevents adaptations to chronic cocaine on NAV network. These findings reveal astrocytes are essential modulators for acute and chronic cocaine-induced enhancement of cortical LFOs in PFC, suggesting astrocytes as a potential therapeutic target to mitigate cocaine-related neurovascular dysfunction.