One of the deepest and most central problems in neuroscience is how neurons and circuits manage to balance the need for plasticity with the requirements of neuronal and circuit stability. Pioneering work over the past two decades from the investigators on this program project has established that neurons and circuits solve this stability problem by engaging a set of homeostatic plasticity mechanisms that act to stabilize neuronal excitability around an activity set-point. The study of homeostatic plasticity has now blossomed into a large and diverse field, and a substantial body of literature describing the phenomenology of homeostatic regulation of neuronal excitability and synaptic strength now exists. However, despite much progress, key elements of the conceptual framework for understanding homeostatic regulation of neuronal activity remain completely obscure. In this proposal, we wish to address four outstanding questions in the field: 1) How are neuronal activity set-points built, and what are the molecular identities of the set-point components? 2) How are different set-points in different neurons established? 3) What are the downstream targets of the set-point machinery, and how are these organized to effectively coordinate different forms of homeostatic plasticity? And finally 4), how do network relationships influence set-points? This program project will bring together four of the top researchers in the field of homeostatic plasticity in a synergistic enterprise to determine how activity set-points are built. Our premise is that this process is so fundamental to all nervous systems that it is likely that th functional structures underlying it are evolutionarily conserved. Therefore, we now propose a collaborative and synergistic set of experiments that will leverage the advantages of different vertebrate and invertebrate preparations to uncover the molecular identity of the sensors and effectors that regulate homeostasis of activity set-points. The experiments described here will test novel hypotheses about how a truly fundamental problem in neuroscience is solved, and in the long term are likely to result in a set of new strategies for interventions in numerous neurological disorders that result from impaired homeostatic and compensatory mechanisms.
The ability of neurons and circuits to maintain stable function is absolutely fundamental for maintaining brain health and it is likely that the breakdown of homeostatic mechanisms contributes to a wide range of neurological disorders, including epilepsy, autism, and neurodegenerative diseases. By putting functional/molecular identities onto the constituents of the machinery that generates activity set-points, these experiments may generate a new set of strategies for tackling neurological disorders.
|Joseph, Annelise; Turrigiano, Gina G (2017) All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control. J Neurosci 37:6778-6785|
|Abraira, Victoria E; Kuehn, Emily D; Chirila, Anda M et al. (2017) The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn. Cell 168:295-310.e19|
|Choy, Julian M C; Suzuki, Norimitsu; Shima, Yasuyuki et al. (2017) Optogenetic Mapping of Intracortical Circuits Originating from Semilunar Cells in the Piriform Cortex. Cereb Cortex 27:589-601|
|Cannon, Jonathan; Miller, Paul (2017) Stable Control of Firing Rate Mean and Variance by Dual Homeostatic Mechanisms. J Math Neurosci 7:1|
|O'Toole, Sean M; Ferrer, Monica M; Mekonnen, Jennifer et al. (2017) Dicer maintains the identity and function of proprioceptive sensory neurons. J Neurophysiol 117:1057-1069|
|Williams, Alex H; O'Donnell, Cian; Sejnowski, Terrence J et al. (2016) Dendritic trafficking faces physiologically critical speed-precision tradeoffs. Elife 5:|
|Gjorgjieva, Julijana; Drion, Guillaume; Marder, Eve (2016) Computational implications of biophysical diversity and multiple timescales in neurons and synapses for circuit performance. Curr Opin Neurobiol 37:44-52|
|Crittenden, Jill R; Tillberg, Paul W; Riad, Michael H et al. (2016) Striosome-dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons. Proc Natl Acad Sci U S A 113:11318-11323|
|O'Leary, Timothy; Marder, Eve (2016) Temperature-Robust Neural Function from Activity-Dependent Ion Channel Regulation. Curr Biol 26:2935-2941|
|Steinmetz, Celine C; Tatavarty, Vedakumar; Sugino, Ken et al. (2016) Upregulation of ?3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway. Cell Rep 16:2711-2722|
Showing the most recent 10 out of 15 publications