Science Advances
Microglia Morphology and Proinflammatory Signaling in the Nucleus Accumbens during Nicotine Withdrawal
Smoking is the largest preventable cause of death and disease in the United States. However, <5% of quit attempts are successful, underscoring the urgent need for novel therapeutics. Microglia are one untapped therapeutic target. While previous studies have shown that microglia mediate both inflammatory responses in the brain and brain plasticity, little is known regarding their role in nicotine dependence and withdrawal phenotypes. Here, we examined microglial changes in the striatum—a mesolimbic region implicated in the rewarding effects of drugs and the affective disruptions occurring during withdrawal. We show that both nicotine and withdrawal induce microglial morphological changes; however, proinflammatory effects and anxiogenic behaviors were observed only during nicotine withdrawal. Pharmacological microglial depletion during withdrawal prevented these effects. These results define differential effects of nicotine and withdrawal on inflammatory signaling in the brain, laying the groundwork for development of future smoking cessation therapeutics.
Ongoing projects
Pathophysiology of Blood Brain Barrier in Nicotine Dependence
Cigarette smoking associated vascular diseases are the leading cause of mortality worldwide with more than 140,000 deaths each year only in United States. Smoking is an independent risk factor for development of cerebrovascular diseases and nearly doubles the risk for having an ischemic stroke. Nicotine is the primary psychoactive compound found in tobacco, which mediates dependency on cigarettes. In addition to its rewarding effects in the brain, nicotine also increases vascular blood flow and is associated with hypertension and stroke. Vascular dysfunction is generally associated with compromised blood brain barrier (BBB) integrity, leading to brain injury and subsequent neurological deficits. The BBB is the physical, physiological, and biochemical barrier controlling the cerebral homeostasis and regulates the flux of biomolecules and xenobiotics in and out of the brain parenchyma. Endothelial cells are the main component of neurovascular unit, providing integrity to BBB via tight junction proteins and acting as “gate-keepers” of the brain. However, the specific mechanism by which nicotine elicits BBB dysfunction is also unknown. Therefore, this project is to systematically investigate the vascular remodeling, BBB function, and subsequent neuroimmune responses in the mesocorticolimbic pathway following chronic nicotine treatment and acute withdrawal. We hypothesize that nicotine and/or inflammatory signals arising from nicotine exposure damages BBB endothelial cells, leading to compromised BBB integrity, elevated BBB leakage, and subsequent neuroinflammatory response in the brain.
Cigarette smoking associated vascular diseases are the leading cause of mortality worldwide with more than 140,000 deaths each year only in United States. Smoking is an independent risk factor for development of cerebrovascular diseases and nearly doubles the risk for having an ischemic stroke. Nicotine is the primary psychoactive compound found in tobacco, which mediates dependency on cigarettes. In addition to its rewarding effects in the brain, nicotine also increases vascular blood flow and is associated with hypertension and stroke. Vascular dysfunction is generally associated with compromised blood brain barrier (BBB) integrity, leading to brain injury and subsequent neurological deficits. The BBB is the physical, physiological, and biochemical barrier controlling the cerebral homeostasis and regulates the flux of biomolecules and xenobiotics in and out of the brain parenchyma. Endothelial cells are the main component of neurovascular unit, providing integrity to BBB via tight junction proteins and acting as “gate-keepers” of the brain. However, the specific mechanism by which nicotine elicits BBB dysfunction is also unknown. Therefore, this project is to systematically investigate the vascular remodeling, BBB function, and subsequent neuroimmune responses in the mesocorticolimbic pathway following chronic nicotine treatment and acute withdrawal. We hypothesize that nicotine and/or inflammatory signals arising from nicotine exposure damages BBB endothelial cells, leading to compromised BBB integrity, elevated BBB leakage, and subsequent neuroinflammatory response in the brain.
