Goodson, M. | bioRxiv Science

bioRxiv2025

Sensory neurostimulation promotes stress resilience with frequency-specificity

Chronic stress is a major risk factor for neuropsychiatric disorders, acting via increased neuroinflammation and disrupted synaptic plasticity. While non-invasive visual or audiovisual neurostimulation (AV flicker) at 40Hz has been shown to modulate brain immune signaling and improve cognitive performance in mouse models of Alzheimers disease, its effects in the context of stress remain unknown. Here we show that AV flicker protects against stress-induced behavioral, microglial, astrocytic, and synaptic changes in a sex- and frequency-specific manner. Male and female mice underwent 28 days of chronic unpredictable stress with concomitant daily AV flicker exposure at 10Hz, 20Hz, or 40Hz. Stress-induced behaviors were most effectively mitigated by 10Hz AV flicker in males and 40Hz AV flicker in females. In the medial prefrontal cortex, AV flicker normalized the balance of mature and immature dendritic spines and counteracted stress-induced molecular changes in neurons, microglia, and astrocytes, including in key neuropsychiatric risk genes. These findings show that frequency optimized AV flicker induces resilience to chronic stress.

neuroscience↗

bioRxiv2023

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinsons disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

immunology↗