Experience-induced cell-type-specific secreted molecules

Sensory experience induces in each type of neuron in the cortex the expression of a cell-type-specific set of secreted molecules (Mardinly*, Spiegel* et al, Nature 2016). This suggests an organizational principle whereby each neuron in the cortex regulates its synaptic inputs in a cell-autonomous manner via the experience-induced transcription of a specific set of locally-acting secreted factors that rewire the cortex according to a circuit-wide homeostatic logic. We are now combining biochemical, molecular and electrophysiological approaches to test this idea by identifying and characterizing the experience-induced secreted factors that regulate excitatory, inhibitory and neuromodulatory synaptic inputs to disinhibitory neurons.

Function and connectivity of disinhibitory neurons

Disinhibitory neurons neurons in the upper layers of the cortex regulate the function of local circuits by inhibiting other inhibitory neurons in response to sensory and neuromodulatory inputs from distal brain regions. Selective molecular marker have been identified for some types of disinhibitory neurons (e.g. VIP neurons in layer 2/3 ), but no genetic tools are available to specifically label disinhibitory neurons in cortical layer 1. We are identifying molecular markers that selectively label layer 1 GABAergic neurons and we are testing the hypothesis that these neurons disinhibit local excitatory neurons to regulate behaviorally relevant forms of cortical plasticty. We take an interdisciplinary approach and study the molecular, morphological and functional properties of L1 disinhibitory neurons, their wiring patterns and the molecular identity of their synaptic partners.

Cell-type-specific regulation of experience-induced gene expression

Experience and the resulting neuronal activity induce in cortical inhibitory neurons cell-type-specific gene programs that adapt the synaptic connectivity of each type of neuron according to a circuit-wide homeostatic logic (Spiegel*, Mardinly* et al, Cell 2014). We are studying the genomic and transcriptional mechanisms that underly the cell-type-specificity and internal regulation of experience-induced transcriptional networks. We are particularly interested in the mechanisms that drive the cell-type-specific expression of experience-induced secreted molecules that regulate specific sets of synapses (e.g. Igf1 in disinhibitory VIP neurons). We are combining genomic and molecular approaches to characterize the genomic regions and transcriptional regulators that drive experience-induced gene expression in subtypes of cortical inhrbitory neurons. Our goal is to use this molecular knowledge to manipulate the experience-induced expression of genes that regulate the plasticity of specific sets of synapses and to thereby test how the plasticity of these synapses regulates adaptive behavior.