Bilal Haider - US grants

[unreadable] DESCRIPTION (provided by applicant): The interlaminar and horizontal connectivity of the neocortex segregates its neuronal elements into local networks. The cellular mechanisms underlying cortical network activity, and the impact of local cortical network activity during sensory processing remain largely unknown. In vivo, neurons of the neocortex exhibit rhythmic, spontaneous cycles of synaptically mediated depolarization, termed UP states, followed by cessation of synaptic activity, termed DOWN states. This proposal will specifically examine the cellular basis and functional consequences of spontaneous, persistent activity during UP states in the mammalian neocortex in vivo. The first aim of this proposal will characterize the contributions of excitation and inhibition during the spontaneous network activity of the UP state. This will be accomplished via single and paired intracellular recording, simultaneous with extracellular unit and local field potential recordings in anesthetized ferret prefrontal cortex. The second aim of this proposal will assess the effect of this ongoing network activity upon visual responsiveness of neurons in cat visual cortex, using methods described above. The proposed plan will provide insights into the dynamic operation of intact neocortical circuits. [unreadable] [unreadable]

Directly measuring synaptic and population coupling in cortex during perception The cerebral cortex is the defining brain structure of mammals and underlies our most complex sensory behaviors. A major need exists to identify how synaptic and network mechanisms in cortex lead to normal and impaired sensory perception and behavior. A prevailing model of cortical function postulates that synaptic excitation (E) and inhibition (I) exhibit a stable balance (E/I balance) that is disrupted during sensory impairments and neurodevelopmental diseases. Currently, there is no knowledge regarding synaptic E/I balance during sensory perception, nor its relationship to large-scale neural network activity. We are uniquely positioned to bridge this critical knowledge gap with an innovative combination of whole-cell patch-clamp and large-scale population recordings of defined excitatory and inhibitory neurons during visual perception in mice. This multi- scale approach will enable us to 1) Define how excitatory and inhibitory neuron populations spanning cortical layers predict the accuracy of visual perception 2) Reveal synaptic mechanisms that underlie visual perception 3) Define the relationship between excitatory and inhibitory population activity and synaptic mechanisms engaged by visual perception. SIGNIFICANCE. This project will meet a significant need to understand how excitatory and inhibitory activity in cortex is coordinated at the synaptic, network, and behavioral levels to support sensory perception. It is imperative to understand these processes in individual neurons, networks, and their synaptic inputs during behavior, so that we may better comprehend how to rectify sensory processing deficits characteristic of many neurological and neurodevelopmental disorders. INNOVATION. This project will provide innovative measurements and analysis of the relationship between single-neuron synaptic inputs and large-scale neural network activity during controlled perceptual behaviors. This combination of techniques will allow critical assessment of long-standing theories of cortical function (E/I balance) that require validation in relevant behavioral contexts. These results will provide conceptual innovation by detailing how inhibition sculpts and coordinates excitatory activity in cortex to orchestrate perceptual behaviors.

Sensory processing is a way to understand neural circuits and their functions during behavior. Behavioral context strongly affects sensory processing. For example, a brief visual stimulus is easier to detect if it appears in a predictable spatial location. Attention to visual space strongly enhances neural and behavioral responses to stimuli in those locations, but the detailed neural mechanisms producing these effects remain unknown. This is largely because we lack the ability to measure specific neurons, circuits, and synapses in real-time during behavior that elicits visual spatial attention. We are uniquely positioned to bridge this critical knowledge gap with an innovative combination of cell-type specific optogenetics, multi-site silicon electrode recordings, and whole-cell patch-clamp recordings in mouse primary visual cortex (V1) during a well-defined visual spatial attention behavior. This innovative combination of techniques will enable us to 1) determine response (gain) modulation in defined excitatory and inhibitory neurons during spatial attention; 2) determine gain modulation across cortical layers during spatial attention; 3) determine synaptic mechanisms of gain modulation during spatial attention SIGNIFICANCE. This project will meet a significant need to understand how an internal cognitive state?attention?exerts its effects across synaptic, cellular, network, and behavioral levels. Establishing a biophysical basis for attention and sensory processing will provide greater understanding of neurological disorders characterized by deficits of attention and sensory perception, such as schizophrenia and autism. INNOVATION. This work provides technical innovation by combining multiple scales of measurement from specific neural circuits during a well-controlled sensory behavior that elicits spatial attention. We will combine high-density local field potential and action potential measurements at population level, patch-clamp measurements from cortical and thalamic circuits at the synaptic level, and cell-type specific optogenetics. We provide conceptual innovation by defining how an internal cognitive factor like attention modulates sensory signals in defined circuits across network and synaptic levels.