The internal state of the brain can profoundly affect animal behavior, including sensory perception, emotion, decision-making, and cognition. Animal’s brain state is highly dynamic: it switches between sleep and wakefulness over the circadian cycles, and changes dramatically even during periods of wakefulness. Effective transitions among brain states is critical for the survival and the fitness of animal survivals. Insufficient sleep causes cognitive impairments and increases the risk of various diseases, such as diabetes, cardiovascular disease, etc. Fluctuation of brain arousal during wakefulness serves as a real-time modulator for governing appropriate behaviors, important for the execution of complex tasks and mental health. However, the mechanism underlying brain state dynamics and the functions of different brains states remains largely unexplored. Our group will explore the neuronal mechanism regulating brain state in health and disease, investigate how brain state modulates animal behavior and uncover the relationship between brain state and brain metabolism.

　　1. Basal ganglia control of brain state and motor behaviors

　　Animal's brain arousal level normally covaries with the motor activity across sleep-wake cycles. My previous work found that the Substantia Nigra pars reticulata (SNr), a main output nucleus of the basal ganglia, is a common hub for brain state and motor control (Liu et al., Science, 2020). However, the basal ganglia circuits to ensure correlated change of brain state and motor output is still unclear. For example, how do the direct, indirect, and hyperdirect pathways of the basal ganglia play differential but coordinated roles? how does the basal ganglia modulate the thalamocortical network for brain state control? How do abnormal basal ganglia circuits lead to sleep dysfunction and movement problems in movement disorders such as Parkinsons disease. We will combine circuit tracing, optogenetic manipulation, optogenetic assisted extracellular recording, in-vivo two-photon /single-photon imaging/wide-field fluorescence imaging to systematically explore these issues.

　　2. Neuromodulatory systems for brain state regulation

　　The reticular activating system is essential for maintaining appropriate brain arousal level across behaviors. It includes cholinergic system, various monoamine systems and multiple neuropeptide system. All these neuromodulatory neurons project diffusively to the cortex and thalamus, thereby activating the thalamocortical system. However, these neuromodulatory systems also exhibited certain differences: they show differential firing profile across behaviors; their projection targets are distinct; and their dysfunction are normally related to different mental disorders. Analyzing how various neuromodulating systems work together to effectively regulate brain state dynamics is a key step to understand how brain state regulates behavior. Combining optogenetics and in-vivo imaging, we will examine brain-wide activities of multiple neuromodulatory systems across different brain states and behaviors and explore the neural circuit for their coordinating actions.

　　3. The role of different brain states for learning and memory

　　Animal normally benefits from sleep or even a short rest after learning, with enhanced formation or consolidation of memory. However, our understanding of the role of different brain states on learning and memory is still very limited. Especially, previous studies using sleep deprivation to investigate the function of sleep are mostly correlative. It is difficult to perturb sleep specifically without affecting many other physiological functions. Moreover, the functions of different sub-states of sleep are largely missing. We will develop closed-loop optogenetic methods to explore the causal function of different brain states for different aspects of sleep. We will further explore the relationship between sleep, memory and neuroplasticity.

　　4. The relationship between brain state and brain metabolism

　　As the most energy-consuming organ of an animal body, the brain also produces the most metabolic waste. Brain metabolite rate is closely linked to brain activities. Abnormal accumulation of metabolites in the brain is the main cause of many neurodegenerative diseases. Recent studies have shown that sleep can promote the removal of metabolic waste in the brain. However, it is largely unclear how different brain states regulate neuronal metabolism and what kind of metabolic waste is involved. In recent years, biochemists have developed a variety of genetically-encoded fluorescent sensors for exploring the dynamic changes of cell metabolism. We will develop or apply existing fluorescent sensor on living brains to monitor the dynamic changes of different metabolic reactions in a cell-type specific manner to explore the correlation between brain state and brain metabolism. Furthermore, we will explore the relationship between sleep, metabolic waste and disease development in degenerative disease animal models.