The development of mammalian cortex is instructed by patterns of spontaneous and sensory-evoked activity that propagate across the brain. The role of different neuronal sub-types, and particularly interneurons, as mediators of this early activity is relatively unexplored, but disrupted interneuron function has been implicated in numerous neurodevelopmental disorders including amblyopia and autism. These neurodevelopmental disorders typically cause deficits in visual processing, which may be studied to infer the underlying circuit-level dysfunction, and could reveal general principles for the pathophysiology of the disease process across cortex. Disruptions specifically in vasoactive intestinal peptide-expressing interneurons (VIP-INs), the third largest class of genetically-defined interneurons in the brain, have recently been shown to cause deficits in modulation of cortical function by brain state, also known as cortical control, which is a hallmark clinical finding in multiple neurodevelopmental disorders. This suggests that the activity of these cells is instructive for the development of the neural circuitry underlying cortical control, but the normal function of these cells during development has never been described. In adulthood, VIP-INs have been shown to mediate the interplay between local- and long- range cortical connectivity and sub-cortical neuromodulatory input, making them well-positioned for control of cortical function. This study will examine the role of VIP-INs in the formation of the cortical control circuit in visual cortex during juvenile development.
Aim 1 will reveal the development of functional connectivity between long- range cortical areas and individual VIP-INs, as well as the necessity of VIP-INs for modulation of visual cortex activity by brain state.
Aim 2 will then dissect the roles of specific sources of input to VIP-INs across development. These studies will be performed in vivo in awake, behaving mice, during rest and visual stimulation, using wide- field and two-photon calcium imaging, optogenetics, chemogenetics, and pharmacological manipulations. Brain state will be measured using multiple validated measures of arousal. With a mechanistic understanding of the role for VIP-INs in the development of this circuitry, it will then be possible to interrogate how circuit-level dysfunction arises in various neurodevelopmental disorders.
Deficits in the modulation of cortical function by brain state are a hallmark clinical finding in patients diagnosed with a wide range of neurodevelopmental disorders. This study will examine the role for vasoactive intestinal peptide-expressing neurons in instructing the development of the circuitry underlying modulation of rodent visual cortex by brain state. A comprehensive understanding of this developmental process is necessary for further work to understand how it may be disrupted in neurodevelopmental disorders and to identify therapeutic strategies to reverse or overcome the deficits that arise from these disorders.
