Laura Lee Colgin - US grants

DESCRIPTION (provided by applicant): Aberrant gamma rhythms are seen in Alzheimer's disease and schizophrenia and may relate to memory impairments in these disorders. It is thus imperative to understand gamma rhythms role in memory. Separate fast (~65-100 Hz) and slow (~25-55 Hz) gamma subtypes differentially route inputs to hippocampus, a brain region critical for memory. Fast gamma links the hippocampus to current sensory inputs from the medial entorhinal cortex (MEC). Slow gamma couples hippocampal subfield CA1 with CA3, a subfield essential for memory retrieval. Still, the functional relevance of slow and fast gamma with regard to memory processing remains largely unknown. The proposed work will test the hypothesis that slow and fast gamma perform distinct functions in the hippocampal network, with fast gamma promoting memory encoding and slow gamma mediating memory retrieval. The studies will employ multisite electrophysiological recordings of local field potentials and single unit activityin freely behaving rodents. Specific Aim 1 will test whether hippocampal 'place cells' and MEC 'grid cells' code locations differently during slow and fast gamma, as expected if slow and fast gamma are functionally distinct. Ensembles of place cells and grid cells will be recorded in rats running on a linear track. The track's one-dimensional nature will allow identical trajectories to be compared for slow and fast gamma periods. Bayesian decoding techniques will be applied to decipher neuronal ensemble activity for slow and fast gamma-associated trajectories. If fast gamma is involved in memory encoding, then place and grid cells should encode recent locations during fast gamma. If slow gamma is involved in memory retrieval, then place and grid cell codes should predict upcoming locations during slow gamma. Specific Aim 2 will test whether fast gamma promotes memory encoding using spatial memory tasks. The proposed studies will determine whether fast gamma correlates with memory encoding and also whether significant decreases in fast gamma during memory encoding are associated with error trials. Furthermore, Aim 2 will test whether fast gamma stimulation of the perforant path during encoding will improve memory in a mouse model of Alzheimer's disease (AD). Effects will be compared to slow gamma stimulation to determine whether fast gamma timing in particular facilitates memory encoding. Specific Aim 3 will test whether slow gamma promotes memory retrieval in the same spatial memory tasks. The studies will determine whether slow gamma correlates with memory retrieval and whether slow gamma is selectively enhanced during memory retrieval in correct, but not error, trials. This Aim will also test whether slow gamma stimulation of the Schaffer collaterals during memory retrieval improves memory in AD mice. Effects will be compared to fast gamma stimulation to determine if slow gamma timing is particularly well suited for memory retrieval. Discovering functional differences between slow and fast gamma is expected to change the field's concept of gamma rhythms and thereby lay the foundation for exciting future discoveries.

This project investigates the relation between brain rhythms during sleep and memory. The question of whether sleep serves a critical function in learning and memory remains strongly debated. There are two stages of sleep, rapid eye movement sleep (REM) and slow-wave sleep (SWS), and these different sleep stages may play unique roles in memory functions. This project tests the novel hypothesis that different types of brain waves, slow and fast gamma rhythms, occur during SWS and REM, respectively, and differentially regulate memory processing during these states. The project employs a state-of-the art approach that involves recording electrical signals from the brains of live animals and decoding the messages transmitted by these signals during wakeful learning and subsequent sleep. The studies are expected to reveal major insights about how memories may be strengthened during sleep. The results will also make progress toward successful decoding of conscious and unconscious brain activity. This is expected to promote the development of devices that advance human intelligence through brain signal translation. This project will also provide scientific training to students at various levels, from junior high to graduate school, and impart knowledge about brain signals to the general public.

This project will test whether distinct fast (~80 Hz) and slow (~40 Hz) gamma rhythms serve unique memory functions in the entorhinal-hippocampal network during different stages of sleep. The work has two objectives: 1) Test the hypothesis that slow gamma facilitates hippocampal output to the entorhinal cortex during SWS as part of the memory consolidation process, and 2) Test the hypothesis that fast gamma coordinates entorhinal input to the hippocampus during REM as a different step in the memory consolidation process. The proposal employs an innovative multi-technique approach combining single cell recordings, neuronal ensemble coding, network rhythms, and animal behavior. The proposed work has the potential to transform theories of memory processing during sleep. An influential theory of memory consolidation posits that memories are transferred from the hippocampus to the neocortex during sleep. Yet, it is unknown whether neurons in the entorhinal cortex, the gateway between the hippocampus and neocortex, respond to inputs from the hippocampus during sleep. If, instead, the hippocampus responds to inputs from the entorhinal cortex during sleep, conventional theories of memory consolidation during sleep would have to be revised.

Computational and quantitative approaches to the study of the brain and nervous system have been a part of neuroscience since its beginnings as a field. However, recent advances in the ability to collect large data sets, to create and run very large simulations, and in the development of new data analysis approaches may soon lead to an even more central role for computational thinking in this field. The goal of this meeting is to promote discussions and collaboration between experimental and computational neuroscientists. The meeting will highlight strategies for increasing the participation of historically under-represented groups in computational neuroscience.

The Principal Investigators and Co-Principal Investigators of grants supported through the NSF-NIH-ANR-BMBF-BSF-NICT-AEI-ISCIII Collaborative Research in Computational Neuroscience (CRCNS) program meet annually to report on projects; to discuss scientific, educational, and program-related issues; and to develop a cohesive investigator community representing many different approaches to computational neuroscience. This 15th meeting of CRCNS investigators brings together a broad spectrum of computational neuroscience researchers supported by the program, and includes plenary lectures, oral and poster presentations, and panel discussions. The meeting is scheduled for September 2-4, 2019 and is hosted by the University of Texas, Austin.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Project Summary/Abstract. Fragile X syndrome (FX) is a widespread type of inherited intellectual disability. Effective treatments that target mechanisms underlying FX are currently lacking. FX is the foremost monogenic cause of autism spectrum disorders, and thus many individuals with FX exhibit abnormal social behaviors. Individuals with FX also often engage in aberrant spatial behaviors such as ?elopement?, wandering off and getting lost. The hippocampus is a brain structure that is particularly vulnerable to FX. Much evidence suggests that hippocampal areas CA2 and CA1 are important for social behaviors and spatial memory, respectively. Yet, few studies have investigated whether disturbances in neurophysiological mechanisms of social and spatial memory functions in CA2 and CA1 underlie social behavioral and spatial memory impairments in FX. This project?s goal is to address this gap in knowledge by investigating the extent to which subcellular, cellular, circuit, and network mechanisms of social and spatial memory operations in the hippocampus are impaired in rodent models of FX. The studies will employ state-of-the-art in vivo and in vitro electrophysiological techniques. In vivo approaches will be used to assess whether aberrant cellular and network mechanisms are related to deficits in social exploration and spatial memory. In vitro experiments will uncover cellular mechanisms underlying altered intrinsic properties and plasticity in CA2 and aberrant inhibition in CA1. Models of FX in two species, specifically Fmr1 knockout (KO) rats and mice, will be used, allowing comparison of FX pathophysiology across species. Specific Aim 1 will assess whether the strength of inputs to CA2 neurons during exploration of social stimuli is weaker in Fmr1 KO rats than wildtype rats. This Aim will also use sophisticated behavioral tracking software to determine whether Fmr1 KO rats show aberrant behavioral patterns during social exploration. Specific Aim 2 will employ whole cell and patch clamp recordings, including recordings directly from dendrites, in hippocampal slices to test whether CA2 neurons in Fmr1 KO rats and mice show impaired synaptic plasticity and responses to the social neuropeptide, oxytocin. Specific Aim 3 will test whether coordination of spike sequences from ensembles of CA1 neurons, believed to be an important network mechanism of spatial memory processing, is disrupted in Fmr1 KO rats performing spatial memory tasks. Coordination of spiking across ensembles of hippocampal neurons requires properly timed activation of specific CA1 interneurons. Thus, disrupted coordination of CA1 spike sequences in FX may reflect disturbances in CA1 interneurons. Specific Aim 4 will employ whole cell recordings of specific classes of CA1 interneurons and inhibitory inputs to CA1 pyramidal cells to test the hypothesis that inhibitory circuits are disrupted in FX. Successful completion of these Aims will provide novel insights about specific mechanisms underlying aberrant social and spatial behaviors in FX. Gaining a deeper understanding of FX mechanisms is expected to suggest novel targets for intervention in FX.