RESUMO
The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. We sought to understand whether neuronal activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neuronal activity. In particular, neuronal activity regulates BBB efflux transporter expression and function, which is critical for excluding many small lipophilic molecules from the brain parenchyma. Furthermore, we found that neuronal activity regulates the expression of circadian clock genes within brain endothelial cells, which in turn mediate the activity-dependent control of BBB efflux transport. These results have important clinical implications for CNS drug delivery and clearance of CNS waste products, including Aß, and for understanding how neuronal activity can modulate diurnal processes.
Assuntos
Barreira Hematoencefálica/fisiologia , Relógios Circadianos/genética , Ritmo Circadiano/genética , Células Endoteliais/fisiologia , Neurônios/fisiologia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Barreira Hematoencefálica/efeitos dos fármacos , Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Drogas Desenhadas/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Feminino , Homeostase/efeitos dos fármacos , Homeostase/genética , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacosRESUMO
The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control the movement of ions, molecules, and cells between the blood and the parenchyma. This "blood-brain barrier" is initiated during angiogenesis via signals from the surrounding neural environment, and its integrity remains vital for homeostasis and neural protection throughout life. Blood-brain barrier dysfunction contributes to pathology in a range of neurological conditions including multiple sclerosis, stroke, and epilepsy, and has also been implicated in neurodegenerative diseases such as Alzheimer's disease. This review will discuss current knowledge and key unanswered questions regarding the blood-brain barrier in health and disease.
