This proposal describes a mentored research project with the goal of providing further training to the principal investigator (PI) to achieve a successful transition into an independent career in Neuroscience. The investigator, Dr. Pascal Kaeser, has a strong track record in molecular and cellular neuroscience using a variety of approaches. The experiments described here will allow the investigator to obtain training in an array of electrophysiological experiments. The research described makes use the unique resources at the Stanford Institute for Neuro-Innovation and Translational Neuroscience (SINTN) in the laboratories of Dr. Thomas C. S?dhof and Dr. Robert C. Malenka. The two mentors, Dr. S?dhof and Dr. Malenka, are experts in the analysis of synaptic transmission and plasticity;moreover, Dr. Malenka is an experienced addiction researcher. Together, their two laboratories create an excellent environment for the investigator to learn physiological approaches for studying the role of RIM proteins in synaptic plasticity and addiction-related behaviors. Drug addiction is an important disease with major social and economical consequences for the individual and the society. Although much progress was made in the definition of the underlying circuits, a better understanding of the neurobiology of drug addiction and the underlying synaptic changes is critical to progress in prevention and treatment. RIM proteins are central components of presynaptic active zones that orchestrate neurotransmitter release into a coherent process and mediate most if not all forms of presynaptic plasticity. To date very little is known about the participation of the presynaptic neurotransmitter release machinery in reward-based learning and addiction. The nucleus accumbens (NAc) is a key brain area in the mesolimbic dopamine system that is involved in reward and reward-based learning. The overall goal of this grant is to characterize the RIM-dependence of synaptic transmission in the NAc, and to assess RIM's contribution to addiction-related behaviors. It is hypothesized that RIMs are necessary in the NAc for normal synaptic plasticity and cocaine-induced behaviors.
The specific aims, which make use of multiple constitutive and conditional KO mice generated by the investigator, include: 1) Determining which RIM1 and/or 2 isoforms are expressed in the NAc, 2): examining the involvement of RIM1 and/or 2 in presynaptic short-term and long-term plasticity in the NAc, 3) determining the participation of RIM1 and/or 2 in cocaine-induced behavioral sensitization (BeS) and conditioned place preference (CPP), and 4) exploring whether RIM-dependent presynaptic plasticity in the NAc is required for BeS and CPP. The vibrant research environment in the laboratories of Dr. S?dhof and Dr. Malenka, the unique genetic models that were developed by the investigator during his postdoctoral training, and the exceptional resources at Stanford University form an ideal setting for the investigator to perform these exciting experiments, to learn electrophysiology and, ultimately, for a successful transition into an independent career in Neuroscience.

Public Health Relevance

Understanding the molecular neurobiology of addiction is crucial for improving prevention and treatment of this disease. The experiments outlined in this grant proposal will allow correlating specific forms of synaptic plasticity in a key brain area of addiction with cocaine-induced behaviors. At large, they help understanding how drugs of abuse utilize the brains memory mechanisms to create long-lasting memories of reward.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA029044-04
Application #
8244567
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Sorensen, Roger
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$144,645
Indirect Cost
$10,714
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Han, Yunyun; Babai, Norbert; Kaeser, Pascal et al. (2015) RIM1 and RIM2 redundantly determine Ca2+ channel density and readily releasable pool size at a large hindbrain synapse. J Neurophysiol 113:255-63
Lacoste, Baptiste; Comin, Cesar H; Ben-Zvi, Ayal et al. (2014) Sensory-related neural activity regulates the structure of vascular networks in the cerebral cortex. Neuron 83:1117-30
Kaeser, Pascal S; Regehr, Wade G (2014) Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release. Annu Rev Physiol 76:333-63
Liu, Changliang; Bickford, Lydia S; Held, Richard G et al. (2014) The active zone protein family ELKS supports Ca2+ influx at nerve terminals of inhibitory hippocampal neurons. J Neurosci 34:12289-303
Fioravante, Diasynou; Chu, YunXiang; de Jong, Arthur Ph et al. (2014) Protein kinase C is a calcium sensor for presynaptic short-term plasticity. Elife 3:e03011
Kaeser, Pascal S; Deng, Lunbin; Fan, Mingming et al. (2012) RIM genes differentially contribute to organizing presynaptic release sites. Proc Natl Acad Sci U S A 109:11830-5
Haws, M E; Kaeser, P S; Jarvis, D L et al. (2012) Region-specific deletions of RIM1 reproduce a subset of global RIM1α(-/-) phenotypes. Genes Brain Behav 11:201-13
Narboux-Nême, Nicolas; Evrard, Alexis; Ferezou, Isabelle et al. (2012) Neurotransmitter release at the thalamocortical synapse instructs barrel formation but not axon patterning in the somatosensory cortex. J Neurosci 32:6183-96
Deng, Lunbin; Kaeser, Pascal S; Xu, Wei et al. (2011) RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of Munc13. Neuron 69:317-31
Kaeser, Pascal S (2011) Pushing synaptic vesicles over the RIM. Cell Logist 1:106-110

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