Center PI: Malenka, Robert C. Principal Investigator (Project 4): Deisseroth, Karl/Malenka, Robert C. Project Summary Learning and memory must involve changes in neural circuit dynamics yet the mechanisms by which such changes occur remain largely unknown. This project will use a novel in vivo imaging modality, termed fiber photometry, which allows collection of activity patterns from genetically-targeted cells and processes in deep brain structures in freely-moving animals. Using fiber photometry, real-time activity in CA3 pyramidal cell axon projections and CA1 pyramidal cell bodies will be monitored during free behavior and while animals undergo hippocampus-dependent learning and memory tasks. Genetically encoded calcium indicators (GECIs) with different fluorescent properties will be expressed in CA3 and CA1 pyramidal cells so that the relationship between presynaptic activity in axonal projections and postsynaptic activity in their targets can be monitored simultaneously, thus allowing quantification of the relationship between pre- and postsynaptic activity at a defined set of synaptic connections. After validation of this novel method in anesthetized animals, it will be applied to well-established hippocampal-dependent memory tasks including contextual fear conditioning and one-trial avoidance learning with the goal of visualizing in awake behaving animals how CA3 to CA1 circuit dynamics change as learning occurs. In a final series of experiments, which will be entirely based on the results from the other three projects in the Conte Center, molecular interventions designed to modulate LTP or homeostatic synaptic plasticity at CA3-CA1 synapses will be performed to determine their effects on hippocampal circuit dynamics during learning and memory. Thus, this project has the potential to provide long- sought insight into the neural circuit changes that underlie learning and memory as well as elucidate the role of prominent forms of synaptic plasticity in these circuit adaptations. Relevance Learning and memory are due to long-lasting changes in specific circuits in the brain but it has not been possible to observe these changes occur. Using a new sophisticated method that allows visualization of neural circuit dynamics in behaving subjects, this project will define how a specific circuit changes during learning. The information collected will provide important insight into how the brain encodes memory and how this process can malfunction during brain disorders including mental illness.

Public Health Relevance

Center PI: Malenka, Robert C. Principal Investigator (Project 4): Deisseroth, Karl/Malenka, Robert C. Project Narrative Learning and memory involve long-lasting changes in the circuits formed by connections between different nerve cells. This project will use sophisticated techniques to visualize the changes in circuit activity that occur during learning and memory and how certain molecules contribute to these changes. The information collected will provide important insight into how the brain encodes memory and how this process can malfunction during mental illness.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
United States
Zip Code
Zhang, Zhenjie; Marro, Samuele G; Zhang, Yingsha et al. (2018) The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling. Sci Transl Med 10:
Bhouri, Mehdi; Morishita, Wade; Temkin, Paul et al. (2018) Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons. Proc Natl Acad Sci U S A 115:E5382-E5389
Südhof, Thomas C (2018) Towards an Understanding of Synapse Formation. Neuron 100:276-293
Li, Jie; Park, Esther; Zhong, Lei R et al. (2018) Homeostatic synaptic plasticity as a metaplasticity mechanism?-?a molecular and cellular perspective. Curr Opin Neurobiol 54:44-53
Sclip, Alessandra; Acuna, Claudio; Luo, Fujun et al. (2018) RIM-binding proteins recruit BK-channels to presynaptic release sites adjacent to voltage-gated Ca2+-channels. EMBO J 37:
Südhof, Thomas C (2017) Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits. Cell 171:745-769
Liu, Zhihui; Chen, Zijun; Shang, Congping et al. (2017) IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning. Neuron 95:106-122.e5
Jiang, M; Polepalli, J; Chen, L Y et al. (2017) Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism. Mol Psychiatry 22:375-383
Zhou, Qiangjun; Zhou, Peng; Wang, Austin L et al. (2017) The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature 548:420-425
Chew, Kylie S; Fernandez, Diego C; Hattar, Samer et al. (2017) Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus. J Biol Rhythms 32:222-236

Showing the most recent 10 out of 65 publications