The ability to adapt to and learn from experiences is critically important for an animal’s survival and underlies many of our cognitive capabilities. As most neural circuits contain many different types of neurons, key questions in neurobiology concern the types of neurons within a neural circuit where these adaptations occur, the molecular mechanisms that mediate them and the manner through which the molecular changes in the different types of neurons lead to adaptive behaviors. To answer these questions, we study the neocortex which is composed of multiple types of precisely connected excitatory, inhibitory and neuromodulatory neurons and which mediates many of our cognitive functions. We currently focus in our research on inhibitory neurons as these neurons are key regulators of cortical circuit plasticity but are molecularly only poorly understood. Specifically, we are trying to understand how experience via the activation of cell-type-specific transcriptional programs rewires inhibitory circuits in the cortex and how the plasticity of inhibitory circuits regulates adaptive behaviors.
GABAergic neurons and disinhibition
Cortical inhibitory neurons use the neurotransmitter GABA and are highly diverse in their developmental origin, molecular and electrophysiological properties, connectivity and circuit functions. We are particularly interested in types of inhibitory neurons that specialize in integrating neuromodulatory and excitatory inputs from distal cortical regions to regulate the activity of local circuits via the inhibition other inhibitory neurons (so called dis-inhibitory neurons). We hypothesize that by studying experience-induced transcriptional networks in disinhibitory neurons we will be able to identify the molecular mechanisms through which our environment (via sensory inputs) and our internal state (e.g. our emotional and/or attentional state via neuromodulatory inputs) interact with our existing genetic background to regulate adaptive behaviors.
Experience-induced transcriptional networks
Sensory experience and the resulting neuronal activity regulate synapse development and function through several distinct mechanisms, including the transcriptional induction of regulators of synaptic function. Upon membrane depolarization, calcium enters neurons and initiates a signaling cascade that impinges on the nucleus and activates a transcriptional program. This genetic program is composed of early-induced transcription factors that are induced in all types of neurons, and of cell-type-specific late-induced effector genes that are regulated by the immediate-early TFs and that include many regulators of synaptic function (e.g. Bdnf in excitatory neurons, Igf1 in GABAergic VIP neurons). Strikingly, the ubiquitously induced TFs have different functions in different types of neurons: NPAS4 for example acts as a circuit-wide homeostatic regulator that functions via cell-type-specific regions of the genome to activate cell-type-specific transcriptional programs (Spiegel*, Mardinly* et al, Cell 2014). Each neuronal subtype also expresses a distinct set of experience-induced growth factors that seem to regulate locally specific synaptic inputs onto the neuron in which each factor is expressed. This idea is supported by our findings on IGF-1, a growth factor that we found to be expressed and induced specifically in disinhibitory neurons where IGF-1 selectively promotes inhibitory inputs to these neurons and thereby regulates visual cortex function (Mardinly*, Spiegel* et al, Nature 2016).