Andre A. Fenton, Ph.D. - US grants

Brains represent information in the patterns of electrical discharge that are distributed across vast networks of brain cells to signal what we are experiencing, planning and thinking. Traces of this activity are stored and reactivated during diverse mental phenomena including perception, learning, recollection, planning and thought. It is unknown how the brain encodes and reads the information out of this dynamic activity and how different streams of information are coordinated in the electrical discharge patterns. In the effort to understand the fundamental neural code, we will record electrical activity within two networks of brain cells from freely moving rats that are using two streams of information to locate themselves on a rotating carousel-like arena. The activity in one network of cells, the hippocampus, alternates between representing the rat's position in the stable room and the position on the rotating floor. Electrical activity in a second related network, the medial entorhinal cortex, may or may not fluctuate between representing the two spatial frameworks of position information. To identify the rules of how information is coded and exchanged between brain networks, we will investigate how the activity in the hippocampus and the medial entorhinal cortex is organized and coordinated to signal the rat's location. In additional to scientific training, student members of the laboratory will receive professional training in communicating science to a lay audience. Across the year, each lab member will pay several visits to a high school science class to communicate the merits and progress of their research effort. Thus, this project will train the next generation of scientists in cutting-edge research and how to be effective communicators and provide a rare opportunity for high school students to learn about scientific research as a process of enquiry and creative problem solving.

DESCRIPTION (provided by applicant): In the mammalian adult brain, there are two regions where stem cells continuously give rise to new neurons, a process termed neurogenesis: the subventricular zone and the subgranular zone of the dentate gyrus. The dentate gyrus has been proposed to play a role in pattern separation, a process by which similar experiences or events are transformed into discrete non-overlapping representations (Leutgeb et al., 2007; Treves et al., 2008). Recent studies have found pattern separation deficits in humans during normal aging and in patients with Mild Cognitive Impairment (Toner et al., 2009; Yassa et al., 2011). We have shown that hippocampal neurogenesis is required for specific forms of learning such as context discrimination learning that may involve pattern separation (Sahay et al., 2011a). We are proposing to test the hypothesis that pharmacological strategies aimed at stimulating adult hippocampal neurogenesis, may have therapeutic potential for reversing impairments in pattern separation such as those seen during normal aging and in patients with Mild Cognitive Impairment. Specifically, we will use mice where the Bax pro-apoptotic gene has been deleted specifically from adult-born granule cells, as well as pharmacological strategies to increase neurogenesis in the dentate gyrus of aged mice and test whether such manipulations improve both cognitive discrimination and pattern separation.

DESCRIPTION (provided by applicant): The synthesis of proteins in synapto-dendritic domains is tightly regulated but in fragile X mental retardation (FXS) and related cases of autism, translation at dendrites is dysregulated due to the loss of at least one regulatory mechanism, the fragile X mental retardation protein (FMRP). How this dysregulation of translation contributes to the clinical expression of impaired cognition in FXS and autism is unknown. An important clue and departure point for formulating our central hypothesis is the fact that loss of FMRP promotes hyperexcitability of neural circuits through overstimulation of group I metabotropic glutamate receptors (mGluR). Group I mGluR-dependent responses increase neuronal excitability and are a necessary determinant of the gamma band (30-100 Hz) electrical oscillations that coordinate action potential discharge throughout the vast networks of excitatory and inhibitory neurons that is the substrate for cognition. Our central discoordination hypothesis is that dysregulated translation causes cognitive impairments in FXS and autism because dysregulated translation leads to exaggerated group I mGluR responses that produce inappropriately coordinated synchronization and desynchronization of the electrical activity in the networks of neurons that mediate cognitive information processing in the mammalian brain. This hypothesis is based on advances in the basic science of cognition and the recognition that abnormal neural synchrony is emerging as the core pathophysiology underlying cognitive impairments in mental disorders, including schizophrenia, depression, FXS, and autism. We propose to characterize neural synchrony and cognition in five mutant mouse models of dysregulated RNA translation. In three Specific Aims, we examine neural synchrony in mice lacking the FMRP gene Fmr1, mice lacking BC1 RNA, a second repressor of translation in the brain, and mice lacking both FMRP and BC1 RNA. To confirm that abnormalities arise from acute loss of translation repressors (as predicted by the discoordination hypothesis) and not due to developmental effects, we will use a conditional Fmr1 knockout mutant mouse model that has lost FMRP only in adulthood as well as an inducible knock-in Fmr1 mutant mouse model in which Fmr1 is restored in adulthood under experimental control. First, we investigate abnormalities in the cortical EEG of the mice and determine the dependence on group I mGluR, M1 and 5-HT2 signaling. Second, we investigate neural coordination abnormalities in hippocampus and their synapse-specific origins using linear arrays of electrodes and pharmacological manipulations. Third, we identify which abnormalities coincide with cognitive impairments in the mutant mice. It is our overall goal to determine how translational dysregulation contributes to associated abnormalities in neural synchrony and cognition in fragile X mental retardation and autism.

Sleep is a major problem for parents of young children. This is demonstrated by the large number of best-selling books on "sleep training" geared toward new parents, and by the numerous courses offered to new parents focusing on helping them get a better handle on their infant's sleep. But despite the attention given to educating parents about how to teach their children to sleep, getting a good night sleep remains one of the most anxiety-provoking aspects of parenting. There are a large number of baby monitors currently on the market, but none provide direct information about sleep. The majority of devices provide an audio monitor so that parents can hear whether their baby is crying. But sound is a poor proxy for sleep. The proposed project will solve this problem by developing the high-fidelity baby sleep monitor for use at home by parents.

This I-Corps team will develop a consumer product that will provide better and more direct information about sleep. The team will leverage recent developments in both hardware and software to make measuring and monitoring sleep simple and cost effective, so that parents will be able to monitor their infant's sleep. The team will develop a product that provides parents with useful information about their baby?s sleep by comparing measurements from their baby with the rest of the database. The team intends to apply the technology in a wide range of neurometric consumer products including self-monitoring of sleep throughout the lifespan, monitoring arousal/vigilance of professional drivers (e.g.,truck drivers) and pilots, and monitoring arousal/vigilance of security personnel (e.g.,TSA).

The broader impact/commercial potential of this I-Corps project arises from objective cognitive assessment aided by electroencephalography (EEG) technology. Stress, anxiety, irritability, lack of focus, emotional reactivity and problems with relationships amongst coworkers all impact productivity. Stress alone is responsible for up substantial healthcare costs in the U.S. Similarly, good mental health is associated with improved creativity, inspiration and mental clarity, improved relationships and reduced anxiety, improved collaboration and increased employee loyalty. This project aims to explore the commercial potential of including objective cognitive assessment as part of healthcare and wellness programs. Users would be monitored for signs of psychological distress and if detected, an intervention such as therapy, coaching or training would be suggested in order to minimize the impact of distress in its early stages. Objective cognitive assessment can have an impact on the overall productivity of employees and is likely to increase the mental capital of the organization.

This I-Corps project is based on electroencephalography (EEG) aided assessment of cognitive function and builds on decades of cognitive evaluation research, recent developments of biomedical signal acquisition and processing, and expertise in statistical analyses, data science, and machine learning. The proposed technology expands prior developments of both research and clinical devices for recording brain activity in diverse settings including emergency rooms, sports fields, military and aerospace. The technology also directly builds on experience with quantifying cognitive state of a person in a wide range of settings such as exercise, cognitive processing, and communication. Furthermore, it builds on a decade long efforts in cognitive assessment in animal models of epilepsy, schizophrenia, intellectual disability and autism.

ABSTRACT Full mutation of the FMR1 gene causes loss of the fragile X mental retardation protein (FMRP) and fragile X syndrome (FXS) characterized by intellectual disability with devastating cognitive consequences and features of autism. Study of Fmr1 knockout (KO) mouse models of the FXS genetic defect identified that loss of FMRP dysregulates translation at synapses, leading to synaptic dysfunction, for example excessive synaptic depression in response to group 1 mGluR stimulation. Unfortunately, despite substantial knowledge of the molecular consequences of FMR1 alteration, how the molecular changes lead to the clinical, cognitive manifestations is unknown. We consider a systems level analysis and use the hippocampus as a model cognitive system. We propose that impaired cognition in Fmr1 KO mice is due to the inability of information-carrying hippocampus principal cell spike trains to represent distinct streams of information because of the dysregulation of synaptic transmission. As a result, cognitive deficits primarily manifest when FXS model mice are challenged to generate distinctive neural representations in situations that are inconsistent with the information they have previously learned. Preliminary findings from analysis of temporal coordination amongst hippocampal place cell spike trains, local field potentials (LFPs), and conjoint action potential and LFP (spike-field) coordination provide substantial evidence in support of the central ?excitation-inhibition discoordination? hypothesis of this work. The hypothesis asserts that cognitive deficits in FXS arise because dysregulated learning-induced changes of synaptic network function cause discoordinated discharge within networks of excitatory and inhibitory neurons. We test the hypothesis by comparing FXS model and control mice in a variety of memory discrimination tasks. We will examine conventional Fmr1 KO mice in which the gene is mutated in all cells, as well as mice in which the mutation is restricted to excitatory (Fmr1 KOe) or inhibitory (Fmr1 KOi) neurons to learn whether dysfunction in one cell class is sufficient to cause cognitive dysfunction. We will also measure how memory training changes synaptic function within the hippocampus circuit by recording evoked potentials across the somatodendritic synaptic compartments of dorsal hippocampus in freely-behaving mice. Finally, we will investigate abnormalities in how memory-related Fmr1 place cell ensemble discharge is controlled by oscillations in the LFP that arise from inputs at distinctive dendritic compartments and causally test whether the abnormality contributes to memory discrimination impairment using chemogenetic manipulations of the inputs. These studies evaluate a novel, circuit-driven neuromodulatory therapeutic concept for reducing cognitive disability in FXS and perhaps other disorders.