Niladhuri, S. B. | Search bioRxiv

bioRxiv2024

Chemogenetic control of GABAergic activity within the interpeduncular nucleus reveals dissociable behavioral components of the nicotine withdrawal phenotype

Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The habenulo-interpeduncular (Hb-IPN) circuit contains a high concentration of nAChRs and has been identified as a main circuit involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 and not the Epyc subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naive mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naive mice elicits opposite effects on affective and somatic signs of withdrawal. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.

neuroscience↗

bioRxiv2022

Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating vascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we conduced unbiased transcriptional analysis to identify brain endothelial cell signaling pathways dysregulated by SARS-CoV-2 in vivo. This analysis revealed significant suppression of Wnt/{beta}-catenin signaling, a critical regulator of blood brain barrier integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/{beta}-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected blood brain barrier integrity, reduced T cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this therapeutic strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/{beta}-catenin signaling or its downstream effectors could be potential interventional strategies for restoring cognitive health following acute viral infections.

neuroscience↗