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Anirvan Ghosh

Research

Development and Functional Analysis of Neural Circuits

Perhaps the most remarkable feature of the developing brain is its ability to self-organize into functional circuits. We interested in understanding the mechanisms that mediate the development and function of neural circuits, and how they are disrupted in neurodevelopmental disorders such as autism. In the past few years we have identified a number of novel molecular interactions that regulate the development and function of hippocampal and cortical connectivity, and developed approaches to study the impact of connectivity on behavior.

Molecular Mechanisms of Synapse Formation and Specificity

The function of the brain depends critically on precise connections between populations of neurons, yet we know very little about the mechanisms that allow neurons to select appropriate synaptic partners. This problem, which is a fundamental unsolved problem in neural development, is one area of focus in the lab. We are using the hippocampus and striatum to study the mechanisms of synapse formation and synaptic specificity. We are particularly interested in exploring the role of LRR proteins, Neuroligins, and Neurexins in specifying the synaptic architecture of the developing brain.

Functional Analysis of Cortical Circuits

Another area of interest in the lab is to understand how patterns of connectivity lead to behavior. Higher brain functions, such as perception and attention, result from the coordinated activity of neurons in the cerebral cortex. We are using two powerful genetic approaches: transgenic tools that have been developed to enable selective control of specific neurons in mice, and viral tools that have been developed to enable selective control in non-transgenic animals, to understand the roles of different classes of neurons in mediating visually-driven behaviors. This is a collaborative effort of five laboratories (Scanziani, Ghosh, Callaway, Reynolds, Deisseroth) and involves the development and refinement of tools for activating and inactivating the three major classes of inhibitory interneurons in mouse and monkey. These tools will then be used to selectively inactivate each of these classes of neurons, to test and refine theories about their function in higher order brain function.

In a related set of studies we are dissecting the circuitry that mediates socially-directed behavior in rodents. We are using a combination of chemogenetic, optogenetic and functional imaging approaches to understand the connectivity of medial prefrontal cortex and how that contributes to social affinity and aversion. We are also developing pharmacological approaches to restore social circuit dysfunction in autism spectrum disorder.

Publications

  • Ghosh A, Michalon A, Lindemann L, Fontoura P, Santarelli L (2013) Drug Discovery for Autism Spectrum Disorders: Challenges and Opportunities. Nature Reviews Drug Discovery 12:777-790.
  • Wilke, SA, Raam T, Antonios JK, Bushong EA, Koo EH, Ellisman EH, Ghosh A (2014) Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease. PLOS One 9(1):e84349
  • Niewoehner J, Bohrmann B, Collin L, Urich E, Sade H, Maier P, Rueger P, Stracke J, Lau W, Tissot AC, Loetscher H, Ghosh A*, Freskgård P* (2014) Increased brain penetration and potency of a therapeutic antibody using a novel monovalent molecular shuttle. Neuron 81(1):49-60 (*corresponding authors)
  • Cruz-Martín A, El-Danaf RN, Osakada F, Sriram B, Dhande OS, Nguyen PL, Callaway EM, Ghosh A*, Huberman AD*. (2014) A dedicated circuit linking direction selective retinal ganglion cells to primary visual cortex. Nature 507:358-361 (*corresponding authors)
  • O’Sullivan ML, Martini F, von Daake S, Comoletti D, Ghosh A (2014) LPHN3, a Presynaptic Adhesion-GPCR Implicated in ADHD, Regulates the Strength of Neocortical Layer 2/3 Synaptic Input to Layer 5. Neural Dev 9(1):7. doi: 10.1186/1749-8104-9-7
  • Stachniak TJ , Ghosh A, Sternson SM (2014) Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→hindbrain pathway for feeding behavior. Neuron 82:797-808
  • Savas JN, de Wit J, Comoletti D, Zemia R, Ghosh A, Yates III JR (2014) Ecto-Fc MS identifies ligand-receptor interactions through extracellular domain Fc fusion protein baits and shotgun proteomic analysis. Nature Protocols 9:2061-2074
  • Naryshkin NA, Weetall M, [multiple authors], Ghosh A, Metzger F (2014) SMN2 splicing modifiers improve motor function and longevitiy in mice with spinal muscular atrophy. Science 345:688-693
  • De Wit J, Ghosh A (2014) Control of Neural Circuit Formation by Leucine-Rich Repeat Proteins. Trends in Neuroscience 37:539-550