The Cardin lab is interested in understanding the mechanisms that promote functional flexibility in cortical circuits, and how the activity of those circuits contributes to perception and behavior. To tackle these issues, we use a vertical integration approach, applying multiple techniques at varying levels to examine a specific circuit in awake behaving animals. We use intra- and extracellular electrophysiology, optogenetics, 2-photon calcium imaging, pupil imaging, and behavioral tasks to investigate local circuits in the primary visual cortex. Our goal is to identify links between these different levels of analysis, from cellular and synaptic interactions to local circuits to large networks to visual perception and behavior.

State-dependent regulation of cortical function

We are particularly interested in understanding how distinct cohorts of neurons are recruited to be active in the cortical circuit at different times. In the cortex, both spontaneous activity and sensory processing are regulated by changes in behavioral state on a millisecond timescale. Using pupil diameter and locomotor activity as metrics for arousal, we have characterized the adaptive regulation of cortical visual processing by excitatory and inhibitory neurons.

We use state monitoring in combination with visual cortex-dependent behavioral tasks, electrophysiology, and 2-photon imaging to dissect the circuit interactions underlying this process. We are using tools for targeted imaging of specific GABAergic populations and neuromodulatory inputs to the cortex to further examine state-dependent recruitment of excitatory and inhibitory populations.

GABAergic modulation of visual processing

GABAergic inhibition modulates the amplitude and precision of sensory responses, controls response gain, and regulates the integration of synaptic inputs by target neurons. However, the diversity of GABAergic interneurons is a major challenge to understanding local cortical excitatory-inhibitory interactions. Each GABAergic population exhibits distinct properties and exerts influence over target cells at different moments, and many interneurons target other inhibitory cells as well as excitatory pyramidal neurons. Using an intersectional genetic approach to target multiple GABAergic populations for optogenetic manipulation and 2-photon imaging in vivo, we are investigating the role of interneuron-to-interneuron connections in the cortical circuit. We are further using imaging and optogenetic manipulation to explore the role of GABAergic inhibition in visual perception.

Development of cortical circuits

Very little is known about the specific roles of the diverse GABAergic populations in cortical circuit maturation. Inhibition plays a key role in critical period plasticity, but the role of dendrite-targeting interneurons and interneuron-to-interneuron interactions in early postnatal circuit development remains largely unknown. Using targeted manipulations, cell dealth, and deletion of key developmental genes in combination with electrophysiology and 2-photon imaging, we are uncovering previously unknown roles for interneurons in the postnatal development of visual cortical circuits.

Models of neurodevelopmental disorders

Cognition and perception are impaired in many neurodevelopmental disorders, such as schizophrenia and autism. Considerable evidence suggests that disruption of the normal excitatory-inhibitory interactions in the cortex may contribute to this disruption. We use genetic models of developmental disorders to examine how abnormal or interrupted development affects cortical circuit maturation. Using conditional deletion of target genes like MeCP2 and ErbB4, we examine the contribution of distinct GABAergic populations to disease-related phenotypes. We also use novel viral CRISPR/Cas9 tools to induce whole-brain and local genetic mutations at varying developmental ages. In combination with electrophysiology and imaging, these approaches provide sensitive screens for convergent neural phenotypes underlying cortical dysfunction.