Our main goal is to elucidate how the context regulates the behavior as well as the underlying neurobiological mechanism.

Our daily life events take place in certain contexts, which are integrated perceptions of both internal and external states such as sensory cues in the environment. Memories about sensory experiences are tightly linked to the context in which they were formed. The contextualization of sensory experiences is fundamental for learning and memory, and is essential for individual survival. Therefore, we use associative learning behavioral paradigm in rodents to characterize how the context regulates the behavior elicited by sensory cues, and aim to dissect the underlying neurobiological mechanisms, particularly at the neural circuit level. We address these questions by multidiscipline approaches including state-of-the-art mouse genetics, trans-synaptic viral tracing, optogenetics, microendoscope (miniscope) imaging, electrophysiology and behavior analysis.

1. Context encoding in the hippocampus
The hippocampus is well known for its cognitive functions in spatial navigation and memory, but also for its pivotal role in context-dependent associative learning. However, little is known about how context perception is generated in the hippocampus and how the context is encoded in the hippocampal circuits. Using large-scale Ca2+ imaging with miniscope in free moving animals, we aim to identify the neural assemble responsible for the context encoding. Furthermore, we will determine how the context encoding differs between distinct contexts and how it changes after associative learning.
The context perception is a “higher” cognitive function, which integrates various types of sensory information with auditory, visual and olfactory modalities.  We are investigating how the context encoding overlaps/interacts with various types of neural coding (e.g. place cell) in the hippocampus at single-cell and population levels.

2. Input and output of subtypes of hippocampal cells
Hippocampus has a rich array of diverse cell types, which can be classified by cellular markers or anatomical projections. We are currently focusing on the projection cells in ventral hippocampus because our recent studies suggest that there are different subpopulations projecting to distinct targets and playing differential roles in behaviors (Cell, 2016). Using trans-synaptic rabies tracing, we aim to identify the presynaptic inputs to different projection neurons and probe their functional roles in context-dependent fear conditioning in combination of optogenetics and miniscope imaging. This approach would enable us to tease out functional roles of specific neural circuits/pathways in context-dependent behaviors, which are often anatomically intermingled in a salt-and-pepper like manner.

3. Contextual regulation in anxiety disorders
Fear extinction is an active form of learning such that fear responses to a conditional stimulus (CS) decrease because of the omission of an aversive unconditional stimulus (US). This provides the neurobiological basis for extinction-based exposure therapies in clinical treatments for anxiety disorders such as post-traumatic stress disorder (PTSD). However, PTSD often relapses after exposure therapies largely due to that fear extinction is highly specific to the extinction context. We are adapting the established behavior paradigms for these anxiety disorders in the lab and testing the hypothesis that hippocampal projections to amygdala and medial prefrontal cortex govern such context-specific extinction. Furthermore, we will manipulate these circuits by optogenetics during the extinction training, in order to reduce the context specificity and generalize the extinction learning, which may provide insights in current therapeutic treatments of anxiety disorders.

4. Contextual regulation in primate cognition and perception
The context is instrumental to resolve ambiguities and conflicts in the cognition and perception in both human and non-human primates. For example, it is common that the same words in human languages could represent opposite meaning in different contexts. In collaboration with other laboratories in the institute, we are establishing behavioral paradigms in primate to quantitatively describe the role of contextual regulation in behaviors. We will then perform brain-wide fMRI imaging to identify the key brain regions and compare the results with those from rodent studies. Ultimately, we aim to elucidate the circuit mechanism for contextual regulation of primate behaviors and eventually delineate a unified mathematical model to simulate contextual regulations in various types of behaviors.

Ph.D. and Postdoc positions available! Please send you CV, research interest and reference letters to chun.xu@ion.ac.cn

Current projects for international master and Ph.D. students would involve multiple methodologies in the following sections. You are welcome to discuss in detail by email if you are interested in any part of these directions.

• Developing trans-synaptic tracing tools

The anatomical structure of neural circuits is the basis for physiological function and behaviors.  We are developing trans-synaptic tracing tools for circuit tracing combing recent development of rabies vectors and HSV vectors. This project will involve molecular biology, cell culture, in vitro transfection, immunostaining and confocal imaging. 

• Dissecting the neural circuits underlying context-dependent behaviors

This project will involve stereotaxic injection, optogenetic and DREADDS experiments in behaving animals. Candidates with interests/experiences in electrophysiology and behavioral experiments are encouraged to apply. 

• Developing automatic and flexible behavior setup

This project is aimed to develop automatic and flexible behavior setup to quickly control the various elements in the behavior context. This will involve PCB design and automatic control. In parallel, we are also developing quantitative data analysis for behavioral and electrophysiological experiments compatible for our behavioral setup.

2003 - 2009 Ph.D. Institute of Neuroscience, Chinese Academy of Sciences

   

2009 - 2016 Postdoc. Friedrich Miescher Institute, Basel, Switzerland

   

l  Fadok J, Krabbe S, Markovic M, Courtin J, Xu, C., Massi L, Botta P, Bylund K, Muller C, Kovacevic A, Tovote P and Lüthi A (2017) A competitive inhibitory circuit for selection of active and passive fear responses. Nature 542:96–100

l  Glangetas C, Massi,L, Fois G, Jalabert M, Girard D, Diana M, Yonehara K, Roska B, Xu, C., Lüthi A, Caille S, and Georges F (2017) NMDA-receptor-dependent plasticity in the Bed Nucleus of the Striaterminalis triggers long-term anxiolysis. Nature Communication 8: 14456

l  Xu, C., Krabbe, S., Gründemann, J., Botta, P., Fadok, J., Osakada, F., Saur, D., Grewe, B., Schnitzer, M.,Callaway, E. and Lüthi, A.* (2016) Distinct hippocampal pathways mediate dissociable roles of context in memory retrieval. Cell 167(4):961-972

(Preview by Cembrowski, M. and Spruston, N. 167:888-889)

l  Botta, P., Demmou, L., Kasugai, Y., Markovic, M., Xu, C, Fadok, J., Lu, T., Poe, M., Xu, L., Cook, J., Rudolph, U., Sah, P., Ferraguti, F., Lüthi, A.* (2015) Regulating anxiety with extrasynaptic inhibition. Nature Neuroscience 18(10):1493-500

l  Wlodarczyk, A., Xu, C., Song, I., Doronin, M., Wu, YW., Walker, M. and Semyanov, A.* (2013) Tonic GABA_A conductance decreases membrane time constant and increases EPSP-spike precision in hippocampal pyramidal neurons. Front. Neural Circuits 7:205.

l  Yu, Y.#, Xu, C.#, Pan. X., Ren, H., Wang, W., Meng, X., Huang, F. and Chen, N.* (2010)Identification and functionalanalysis of novel mutations of the CLCNKB gene in Chinese patients with classic Bartter syndrome. Clinical Genetics,77(2): 155-162. (#, equal contribution)

l  Xu, C., Zhao, MX., Poo, M.*and Zhang, X.* (2008)GABA_B receptor activation mediates frequency-dependent plasticity of developing hippocampal GABAergic synapses. Nature Neuroscience, 11:1410 – 1418.

The Director Award of Institute of Neuroscience, CAS (2005, 2007)

The Director Award of Chinese Academy of Sciences (2009)

EMBO long-term fellowship (2011-2013)