The many classes of neurons in the mammalian brain use many different neurotransmitters to communicate. Nevertheless, it has generally been assumed that each neuron uses one principal neurotransmitter. This notion has dominated the analysis of the contributions of synaptic transmission to circuit function and behavior. However, we and others have found that many neurons in the mammalian brain actually release several neurotransmitters at the same time, often targeting each neurotransmitter to a specific and different postsynaptic cell class. We propose that the co-released neurotransmitters act in concert to have consistent and mutually reinforcing effects on their enclosing circuit. Here we propose to study the integration and coordination of peptidergic, GABAergic, and cholinergic signaling and reveal how these diverse signaling molecules act together to dictate the activity and plasticity state of cerebral cortex. The pathways that we have uncovered are potentially powerful means of regulating cortical function and may, in the future, be exploited to restore cognitive function in neurodegenerative disorders.
Neurons in the brain communicate using a large diversity of chemical signals and it is the concerted action of these signals that determine the activity and plasticity of neural circuits as well as animal behavior. We propose to follow up on previous findings from the lab that reveal that many individual neurons actually release multiple chemicals, each onto different classes of cells. We will determine how the integrated and simultaneous action of these molecules controls brain circuitry.
|Zhang, Peng; Lu, Hong; Peixoto, Rui T et al. (2018) Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships. Cell 174:1450-1464.e23|
|Hrvatin, Sinisa; Hochbaum, Daniel R; Nagy, M Aurel et al. (2018) Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. Nat Neurosci 21:120-129|
|Chen, Yao; Granger, Adam J; Tran, Trinh et al. (2017) Endogenous G?q-Coupled Neuromodulator Receptors Activate Protein Kinase A. Neuron 96:1070-1083.e5|
|Wallace, Michael L; Saunders, Arpiar; Huang, Kee Wui et al. (2017) Genetically Distinct Parallel Pathways in the Entopeduncular Nucleus for Limbic and Sensorimotor Output of the Basal Ganglia. Neuron 94:138-152.e5|
|Gross, Garrett G; Junge, Jason A; Mora, Rudy J et al. (2013) Recombinant probes for visualizing endogenous synaptic proteins in living neurons. Neuron 78:971-85|
|Olson, Jeremy P; Kwon, Hyung-Bae; Takasaki, Kevin T et al. (2013) Optically selective two-photon uncaging of glutamate at 900 nm. J Am Chem Soc 135:5954-7|
|Ding, Jun B; Oh, Won-Jong; Sabatini, Bernardo L et al. (2011) Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. Nat Neurosci 15:215-23|
|Higley, Michael J; Gittis, Aryn H; Oldenburg, Ian A et al. (2011) Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PLoS One 6:e19155|
|Giessel, Andrew J; Sabatini, Bernardo L (2011) Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels. PLoS One 6:e20939|