In the mammalian central nervous system (CNS), axonal arbors are most often large and highly branched. What is the computational function of the axonal arbor and its array of presynaptic terminals and how does its structure and function change as a result of experience? We have developed a preparation that allows us to image cytosolic Ca transients, a consequence of spike firing, in an axonal arbor in the intact brain of the unanesthetized adult rat. We propose to use this preparation to address three central questions in neuronal circuit function.
Aim 1 : When action potentials invade the cerebellar mossy fiber axonal arbor, how are they spatially distributed to evoke Ca transients in the array of presynaptic terminals? Preliminary data from spontaneous firing suggests that mossy fiber axonal signal distribution is neither entirely reliable nor accounted for by simple branch-point failure rules. Rather, one terminal can have spike-driven Ca signals while another, a few microns away, on the same axonal segment does not. To determine whether the spatial pattern of presynaptic Ca failure is stereotyped or stochastic, we shall implant electrodes in the middle cerebellar peduncle to artificially activate ascending mossy fibers with various patterns of stimuli and compare with those driven by tactile stimuli, spontaneous movement or proprioceptive signals.
Aim 2 : Is the spatio-temporal pattern of Ca signal distribution in the mossy fiber axon sculpted by GABAergic inhibition from Golgi cells? Golgi cell axons form boutons which release GABA onto mossy fiber terminals, thereby activating GABA-B receptors. We shall record both spontaneous Ca transients and those evoked by a range of stimuli (tactile, proprioceptive, peduncle electrode) together with GABA-B receptor agonists, antagonists and allosteric modulators applied to a port in the cranial window.
Aim 3 : In trace eyelid conditioning, a simple form of associative learning, is the spatial representation of the CS across an array of ponto- cerebellar mossy fiber terminals modified by experience? Specifically, is it altered by habituation, associative learning, pseudoconditioning or extinction? We shall record CS-evoked and electrode-evoked mossy-fiber Ca transients in 3-D mapped axonal arbors, during and following behavioral training.

Public Health Relevance

The goal of this project is to determine how axons, the information-sending fibers of neurons, process and distribute information in the brain. We have developed a preparation to image Ca transients, a consequence of spike firing, in an axonal arbor in the intact adult rat brain, allowing us to address central questions in neuronal circuit function. This is basic neuroscience that illuminates memory and cerebellar diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Diering, Graham H; Nirujogi, Raja S; Roth, Richard H et al. (2017) Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355:511-515
Xiao, Mei-Fang; Xu, Desheng; Craig, Michael T et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6:
Agarwal, Amit; Wu, Pei-Hsun; Hughes, Ethan G et al. (2017) Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes. Neuron 93:587-605.e7
Akassoglou, Katerina; Merlini, Mario; Rafalski, Victoria A et al. (2017) In Vivo Imaging of CNS Injury and Disease. J Neurosci 37:10808-10816
Wang, Qiang; Chiu, Shu-Ling; Koropouli, Eleftheria et al. (2017) Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons. Neuron 96:1084-1098.e7
Roth, Richard H; Zhang, Yong; Huganir, Richard L (2017) Dynamic imaging of AMPA receptor trafficking in vitro and in vivo. Curr Opin Neurobiol 45:51-58
Perea, Gertrudis; G├│mez, Ricardo; Mederos, Sara et al. (2016) Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. Elife 5:
Ma, Zhiguo; Stork, Tobias; Bergles, Dwight E et al. (2016) Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour. Nature 539:428-432
Kim, Yu Shin; Anderson, Michael; Park, Kyoungsook et al. (2016) Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain. Neuron 91:1085-1096
Zhang-Hooks, YingXin; Agarwal, Amit; Mishina, Masayoshi et al. (2016) NMDA Receptors Enhance Spontaneous Activity and Promote Neuronal Survival in the Developing Cochlea. Neuron 89:337-50

Showing the most recent 10 out of 23 publications