Michael Goard, Ph.D - US grants

[unreadable] DESCRIPTION (provided by applicant): The cholinergic system of basal forebrain (nucleus basalis, NB) has been implicated in important cognitive functions such as arousal, attention, and memory, yet little is known of how this system affects cortical processing. Previous studies have shown that NB stimulation causes bi-directional changes in the overall firing rate of cortical neurons. Additionally, the laminar distributions of different subtypes of acetylcholine (ACh) receptors suggest that ACh can selectively boost feedforward thalamocortical inputs while suppressing recurrent intracortical interactions. Thus, although cortical cholinergic input does not carry sensory information, it may act to modulate neural excitability and effective connectivity in the cortex. These changes in the cortical circuit may in turn affect visual processing by dynamically altering cortical receptive field (RF) properties. I have generated a series of hypotheses on the effect of NB stimulation on visual cortical RFs. In the proposed project, I will test these hypotheses by stimulating the NB while making multielectrode recordings from neurons in the adult rat visual cortex. Specifically, I will characterize the effects of NB stimulation on (i) V1 orientation tuning, direction selectivity, and spatiotemporal receptive field (STRF) properties (ii) spatial phase sensitivity of visual responses (which differs between simple and complex cells), and (iii) response characteristics to natural scenes. Determining the effects of NB stimulation on cortical RFs will provide important insights into the modulation of ongoing sensory processing that potentially underlies higher-level cognitive processes. PUBLIC HEALTH RELEVANCE Nucleus Basalis is one of the first and most severely damaged areas affected by Alzheimer's disease. Thus, understanding what effect it has on sensory processing represents an important step in understanding the pathologies associated with Alzheimer's disease. The proposed research will elucidate the receptor types involved in specific changes to sensory processing as well as suggest potential treatment strategies using pharmacological agents. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Two individuals presented with similar sensory input may process the incoming material in very different ways depending on their level of engagement with the presented information. However, it is not understood how engagement (defined as non-selective attention to sensory input) exerts such a strong influence on neural processing. The goal of the proposed research is to investigate the influence of engagement on cortical processing of visual input using a mouse model. First, we will establish an experimental preparation for measuring the activity of primary visual cortical (V1) neurons in awake, head-fixed mice performing a behavioral task (Aim 1). Neural activity will be measured by 2-photon imaging of visual cortical neurons expressing a virally delivered genetically encoded calcium indicator (GCaMP5) while the mouse performs a demanding orientation discrimination task. The response apparatus will be withdrawn in alternating blocks, allowing comparison of responses during engaged versus passive viewing. Next, we will characterize the effects of engagement on different classes of neurons in V1 using transgenic mouse lines that express red fluorescent protein (TdTomato) in cell types of interest (specifically, parvalbumin-positive and somatostatin- positive interneurons; Aim 2). Genetic identification of interneuron subtypes will allow us to dissect the effect of engagement on specific components of the cortical circuitry. Finally, we will investigate the impact of engagement on sensory processing in higher visual cortical regions beyond V1 (Aim 3). For these experiments, secondary visual areas LM (lateromedial), AL (anterolateral), and PM (posteromedial) will be identified using anterograde tracers and imaged using GCaMP5. Responses in secondary visual areas will be imaged to determine whether engagement enhances the propagation of sensory information more broadly throughout the visual cortical hierarchy. Taken together, this work will have important implications for understanding the influence of behavioral engagement on sensory processing in the neocortex, and reveal fundamental mechanisms underlying disorders of cognition that afflict engagement and attention.

DESCRIPTION (provided by applicant): Short-term memory, the ability to hold information in mind over short timescales, is a fundamental cognitive process underlying an array of complex abilities. In contrast to long-term memory, which involves modification of synaptic connections, short-term memory is associated with sustained neural activity in cortical and subcortical structures. In particular, recent studies have suggested that the posterior parietal cortex plays a key role in maintaining mnemonic traces. However, it is not understood how the neural activity in these regions supports the maintenance of short-term memory. The goal of this project is to develop a short-term memory task for head-fixed mice and to leverage recent advances in 2-photon calcium imaging and optogenetics to dissect the neural circuits underlying short-term memory. This goal will be undertaken with the following aims: (Aim 1) Develop a short-term memory task for mice, and measure the neural signature of short-term memory in visual and parietal cortices using 2-photon calcium imaging. (Aim 2) Determine the necessity and time course of sustained activity in specific cortical regions using targeted optogenetic inactivation. (Aim 3a) Investigate the role of norepinephrine on sustained cortical activity during the short-term memory task by optogenetic modulation of noradrenergic tone. (Aim 3b) Determine whether the duration and accuracy of short-term memory maintenance can be improved by optogenetic modulation of norepinephrine release. Developing a systems-level understanding of short-term memory will yield critical insights into how the brain represents and maintains information, and may have translational implications for treating deficits in short-term memory commonly observed in normal aging and psychiatric disorders.