Project Desciption

Single action potentials (APs) backpropagate into the higher-order dendrites of striatal spiny projection neurons during cortically driven "up" states. Prior in vitro studies suggest that the timing of these backpropagating APs relative to the arriving cortico-striatal excitatory inputs determines changes in dendritic calcium concentration, which is critical for synaptic plasticity and potentiation1,2,3,4,5. There is also growing evidence that this change in calcium and plasticity is heavily dependent on dopaminergic feedback from the VTA, critical for reinforcement learning in the brain, rendering the plasticity mechanism neo-Hebbian or three-factor modulated1,3. Yet, the dynamics of this form of neuromodulated plasticity in vivo remains poorly understood. A major reason is the lack of suitable tools and methods to record both dopaminergic modulation and the resultant electrophysiological dynamics simultaneously with high spatio-temporal resolution. Suh recordings necessitate the integration of both electrophysiology and electrochemistry across depth and breadth of the striatum that has not yet been realized. In this project, we aim to realize a state-of-the-art flexible CMOS probe with both neural amplifiers and integrated potentiostats for simultaneous electrophysiology and electrochemical recordings from the striatum of α-synuclein (αSyn) preformed fibril (PFF) seeded mice (synucleinopathy model). In addition, using a combination of two-photon targeted somatic whole-cell6 and nanopipette dendritic recordings7, two-photon calcium imaging, optogenetics and high-speed behavioral monitoring we will elucidate how dopamine modulates cortico-striatal plasticity in a behaviorally dependent manner. To gain mechanistic insights we will use a spatial-light-holography (SLM) based two-photon uncaging platform to probe how stimulation of specific synaptic input patterns across the dendrite regulate plasticity and overall somatic gain in both wild-type mice and the αSyn model. Eventually, our study will highlight how αSyn aggregation and prion-like propagation lead to time-dependent differences in branch-specific potentiation in neurons, cooperativity between synapses, and eventual somatic spike output.

Start Date

August 2022

Postdoctoral Qualifications

The ideal candidate will have a PhD in Electrical engineering, Biomedical engineering or Biomedical Sciences including Neuroscience or other related fields, and have a strong instrumentation, fabrication, and experimental background. Other relevant interests include experience with CMOS circuit design, wet lab experiments electrophysiology, and two-photon imaging. The successful candidate will work in a multi-disciplinary setting and have a deep interest in using electrical and optical methods to dissect neural circuit mechanisms, and be an excellent communicator.

Co-Advisors

Prof. Krishna Jayant (BME) "kjayant@purdue.edu"; https://nanoneurotech.com/
Prof. Jean-Christophe Rochet (MCMP) "jrochet@purdue.edu"

Bibliography

1. Pawlak, V, Kerr, JND., et al., J. Neuroscience, 2008, 5,28 (10) 2435-46
2. Fu, M., et al., Nature, 2012, 483(7387), p.92.
3. Murayama, M.; et al., Nature 2009, 457, 7233, 1137-1141.
4. Schiller, J.; et al., Nature 2000, 404, 6775, 285
5. Stuart, G. J.; Spruston, N. Nature neuroscience 2015, 18, 12, 1713-1721
6. Jayant, K.; et al, Cell Reports, 2019, 26, 1, 266-278
7. Jayant, K.; et al., Nature Nanotechnology 2017, 12, 335–342,