The excitatory and inhibitory connections between neurons in the brain are continually refined through experience. To avoid hyper- or hypo excitability, homeostatic processes ensure that neuronal firing rates are returned an appropriate set-point after perturbation. One important way to preserve appropriate neuronal firing rates is through homeostatic regulation of the excitation-inhibition balance (E/I balance) within a circuit. Only slow cell-autonomous homeostatic processes been identified in vivo, but studies suggest that more rapid compensatory mechanisms are necessary to maintain stable firing in the face of rapid changes from Hebbian plasticity. Theoretical and experimental evidence suggests that dynamic balancing of E/I is necessary for networks to maintain stability, but this process has never been demonstrated in vivo. Thalamocortical (TC) axons send visual sensory information to the primary visual cortex, which mainly terminate in neocortical layer 4 (L4). TC axons directly excite star pyramidal (SP) neurons and PV+ fast-spiking (FS) interneurons. FS interneurons then provide disynaptic feedforward inhibition onto SP neurons. Preliminary data from the Turrigiano lab indicates that the thalamocortical feedforward E/I ratio to SP neurons is dynamically maintained. Interestingly, average firing rates (minutes to hours) of L4 SP neurons in visual cortex are not different across environmental or circadian states. I hypothesize that SP neuron firing rates are dynamically stabilized by scaling the strength of excitation to match the strength of feedforward inhibition across vastly different levels of sensory drive. I will test this in vivo using two paradigms: i) monocular visual deprivation (MD) and ii) modulation of PV+ FS firing rates using DREADDs. For each of these paradigms, I will record firing rates of FS and SP neurons in L4 in vivo using chronic electrode implants, and prepare cortical slices to probe for changes in synaptic properties at each synapse type. I expect that these experiments will elucidate basic principles about how neuronal firing rates are regulated in vivo. If successful, this would extend our understanding of neuronal homeostasis beyond slow cell-autonomous processes and reveal rapid, potentially network-level mechanisms that stabilize neuronal firing rates on shorter timescales.
Excitatory and inhibitory connections between neurons in the brain are continually refined by experience. In the face of these changes, homeostatic processes must be present to ensure that neuronal inputs have an appropriate excitation/inhibition balance. The proposed research will examine how these levels are balanced in thalamocortical microcircuits of the visual sensory system. It is important to uncover the mechanisms responsible for balancing excitation and inhibition because dysregulated excitation/inhibition balance and dysfunction of thalamocortical microcircuits are hallmarks of numerous pathologies, including epilepsy, schizophrenia, and autism.
