Lindsey L. Glickfeld - US grants

[unreadable] DESCRIPTION (provided by applicant): Synaptic inhibition shapes the activity of neuronal populations in space and time. Basket cells, a class of inhibitory interneurons which synapse specifically on the somata of principal cells, provide strong local inhibition to balance afferent excitation. However, the specific means by which they control the activity of their target neurons is poorly understood. This proposal addresses the role of a unique population of basket cells: cannabinoid sensitive basket cells. Our preliminary data suggest that cannabinoid sensitivity defines a distinct network of hippocampal basket cells with unique functional properties. Cannabinoid sensitive basket cells are only weakly and transiently excited such that, under basal conditions, they are responsible for only a minority of inhibition in the hippocampus. However, application of neuromodulators such as opioids can shift the balance of inhibition in favor of cannabinoid sensitive interneurons. Thus, an understanding of the role of these interneurons will help to elucidate how both cannabinoids and opioids modulate network activity. Further, a deeper insight into how a balance between excitation and inhibition is dynamically maintained may contribute to the development of therapies aimed at preventing epileptogenesis in cortical areas. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The main purpose of the central nervous system is to enable animals to generate appropriate behavioral outputs. In order to be appropriate, the animal must take into account both external (sensory) inputs as well as internal (motivational) states. Recent observations suggest that neuronal representations of these internal states are present at relatively early stages in sensory processing. Moreover, these internal states may fundamentally change the way that sensory information is processed by modulating the functional properties of cortical circuits. Yet, the synaptic and circuit mechanisms underlying thi context-dependent processing of sensory information are not known. Moreover, since these changes occur on rapid time scales, standard in vitro methods for investigating the cellular mechanisms of plasticity are not appropriate. Instead, this question requires new approaches for monitoring synaptic connectivity and strength in the awake, behaving animal. Thus, we will develop new strategies, and combine existing ones, to address how cortical circuits are dynamically reconfigured by internal state. In particular, newly developed visually-guided behaviors for headfixed rodents have made the mouse visual system a useful model to study this problem. This proposal builds on these behavioral advances, and combines them with other modern methods including in vivo two-photon calcium imaging, single-cell juxtacellular stimulation, and whole-cell electrophysiology to directly measure how neuronal networks in primary visual cortex are modified during behavior. This novel combination of techniques will reveal how engagement in tasks which rely on the detection of distinct visual features alter the functional connectivity within visual cortex. In addition, we will use newly developed approaches to image the sensory responses in cortico-cortical axonal projections to determine how behavioral context impacts the transmission of sensory information to the higher visual areas. These experiments will identify synaptic and circuit mechanisms that underlie context-dependent changes in network activity, thereby achieving a fundamentally new level of understanding of sensory processing in the actively working brain.

Abstract Adaptation is a fundamental feature of sensory processing whereby recent sensory experience shapes responses to current input. This phenomenon has been observed across species, sensory systems, and stages of processing and has been shown to engage mechanisms that are induced across a range of time-scales from milliseconds to hours. In the visual system, rapid eye and head movements make shorter time-scales of adaptation particularly relevant for determining sensory encoding during ongoing behavior. We have recently identified a form of rapid, stimulus-specific adaptation in the awake mouse primary visual cortex (V1) that is engaged on the scale of milliseconds and persists for seconds. Importantly, adaptation on this time-scale is important for sensory processing as it dramatically impairs performance on an orientation discrimination task. Thus, our goal here is to determine the mechanisms that underlie the magnitude, time-course and stimulus specificity adaptation with the aim of determining how adaptation shapes sensory processing across the visual hierarchy and behavioral states. In particular, we will test the hypothesis that adaptation is largely determined by cortico-cortical short-term synaptic depression and is under the specific control of behavioral context. In Aim 1, we will use intra- and extracellular recordings in combination with opto- and chemogenetic manipulations to determine the contribution of depression at cortico-cortical synapses to adaptation. We will also test the contribution of other mechanisms including activation of intrinsic conductances, recruitment of suppressive mechanisms, and changes in the balance of excitation and inhibition. In Aim 2, we will use extracellular recordings to measure the magnitude, time-course and specificity of adaptation in excitatory and inhibitory neurons in V1 and the higher visual areas. This will reveal how adaptation accumulates along the visual cortical hierarchy, with a particular focus on the ventral stream which is thought to support object recognition through adaptation. In Aim 3, we will investigate the impact of behavioral context on adaptation. Our preliminary data reveal that the specificity of adaptation is different in naïve mice and those mice performing an orientation discrimination task. We will determine the specific behavioral contexts (task engagement versus training) that control adaptation, and investigate the circuit mechanisms that support this plasticity. Together, these experiments will reveal how rapid adaptation shapes, and potentially enriches, sensory processing across visual areas and behavioral contexts. We expect that these results will reveal general principles underlying adaptation across sensory areas, as well as mechanisms that are specialized to support visual processing and perception.