The function of a biological neuronal network is determined by the intrinsic properties of its constituent neurons, their spatial connectivity, and the adaptive strengthening/weakening of those connections as informed by the network!s spatiotemporal pattern of electrical and chemical signaling. Deciphering the neuronal code - the rules by which spatiotemporal connectivity translates to function - remains to be a major scientific challenge, largely due to the lack of experimental tools that enable both the preparation of well- defined neuronal circuits with controlled connections and the simultaneous mapping of physical connectivity among, and signal propagation between, many neurons. The project proposed herein aims to develop new nano- and microelectronic tools that address these particular issues. Specifically, we will develop: (1) planar patch-clamp arrays (element number >100, element pitch <200 ?m) that enable the real-time monitoring of multiple neurons in dissociated culture or slice preparations and (2) vertical nanowire arrays that can perturb and modify neuronal differentiation and synapse formation through the controlled introduction of biochemical signals in a cell-specific fashion. These new tools will then be used, in combination with optical excitation and imaging schemes, to probe, at both the local and global levels, the real-time dynamics of constituent neurons within a given neuronal network upon application of precisely defined perturbations. Combined together, these tools will also provide a new platform for assaying, in a parallel fashion, the biochemical and genetic pathways that govern neuronal differentiation and growth. The proposed research, which combines recent advances in neurobiology with cutting-edge developments in nanomaterials synthesis and microfabrication, will allow for the meticulous study of extant network connectivity and stimuli- and reward-induced synaptic adaptation. The information gained through these studies will be crucial for systematically translating any network!s connectivity to its function, and thus help to unravel the design principles of the brain.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (P2))
Program Officer
Jones, Warren
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Arts and Sciences
United States
Zip Code
Wang, Lili; Shalek, Alex K; Lawrence, Mike et al. (2014) Somatic mutation as a mechanism of Wnt/?-catenin pathway activation in CLL. Blood 124:1089-98
Shalek, Alex K; Satija, Rahul; Shuga, Joe et al. (2014) Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature 510:363-9
Kucsko, G; Maurer, P C; Yao, N Y et al. (2013) Nanometre-scale thermometry in a living cell. Nature 500:54-8
Na, Yu-Ran; Kim, So Yeon; Gaublomme, Jellert T et al. (2013) Probing enzymatic activity inside living cells using a nanowire-cell ""sandwich"" assay. Nano Lett 13:153-8
Shalek, Alex K; Satija, Rahul; Adiconis, Xian et al. (2013) Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498:236-40
Robinson, Jacob T; Jorgolli, Marsela; Park, Hongkun (2013) Nanowire electrodes for high-density stimulation and measurement of neural circuits. Front Neural Circuits 7:38
Yosef, Nir; Shalek, Alex K; Gaublomme, Jellert T et al. (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496:461-8
Robinson, Jacob T; Jorgolli, Marsela; Shalek, Alex K et al. (2012) Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits. Nat Nanotechnol 7:180-4
Shalek, Alex K; Gaublomme, Jellert T; Wang, Lili et al. (2012) Nanowire-mediated delivery enables functional interrogation of primary immune cells: application to the analysis of chronic lymphocytic leukemia. Nano Lett 12:6498-504