Benjamin R. Arenkiel, PhD - US grants

DESCRIPTION (provided by applicant): The mammalian brain shows a remarkable capacity for continued neurogenesis throughout life. This feature normally occurs in two brain regions, the dentate gyrus of the hippocampus and in the olfactory system. Interestingly, it has been found that multiple forms of neural activity affect the rates of proliferation, survival, and synape formation of newborn neurons. Exercise, learning, and exposure to enriched sensory environments promote continued neurogenesis and circuit formation, whereas stress, sensory deprivation, and certain neuropathologies negatively influence neuronal division, circuit integration, and survival. Although much has been learned about the environmental and molecular factors that influence continued neurogenesis in the mammalian brain, key information regarding the cellular origins and distinct types of inputs that are made onto newborn neurons during periods of circuit formation is lacking. Neural activity is conferred through the repertoire of inputs that newborn neurons receive during their development. To date, the exact patterns of synaptic connectivity, timing of synapse formation, identity of the cel types that provide presynaptic input, and the nature of the synaptic cues onto postnatal-born neurons remain unknown. Revealing the identity and nature of these inputs is essential if we are to harness the mechanisms of continued neurogenesis for adult brain repair. The Specific Aims of this research proposal are to: 1) determine the identity and signaling nature of cells that provide presynaptic input to newborn neurons, and 2) determine the effect of enhanced presynaptic input on newborn neuron circuit integration. This proposal outlines experimentation that will combine novel molecular genetic approaches to mark, map, and manipulate the presynaptic inputs that are made onto newborn neurons in the mouse olfactory system, asking: what are the cellular origins and nature of activity cues that facilitate and promote continued circuit formation in the mammalian brain? The main objective of this proposal is to identify the cell types that provide presynaptic input onto postnatal- born neurons, and to determine their function in guiding synapse and circuit formation. Long-term, elucidating the molecular factors critical for integration of newborn neurons into circuits will significantly enhance our mechanisti knowledge of the programs that guide adult brain wiring, providing novel insights into possible avenues for cell or circuit-based brain repair.

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Abstract/Project Summary Obesity-associated diseases such as diabetes and cardiovascular disease together account for the leading cause of death in the United States. Roughly one-third of the U.S. population is obese, and it is estimated that nearly half of the population will be obese within the next two decades. To date, studies investigating the neural contribution to body weight control have focused largely on neuropeptidergic signaling in the hypothalamus, a key brain region involved in feeding behavior. However, signaling from extra-hypothalamic brain regions has also been implicated in regulating nutrient metabolism, appetite, and satiety. We recently uncovered a novel mechanism by which cholinergic signaling in the basal forebrain strongly influences body weight control. This discovery provides intriguing evidence that specific cholinergic signaling pathways in the brain critically regulate feeding behavior and body weight homeostasis. To elucidate the mechanisms by which forebrain cholinergic signaling influences body weight management, feeding behaviors, and metabolism, we will test the hypothesis that cholinergic signaling modulates metabolic and appetitive programs to regulate body weight. Using a combination conditional genetic targeting, optogenetic manipulations, electrophysiology, and behavioral analysis, we will set out to determine the role for basal forebrain cholinergic signaling in body weight control and obesity.

A key problem in neuroscience is to uncover fundamental principles and algorithms that allow neuronal networks to perform the complex calculations that underlie normal behavior effectively and efficiently. Our goal in this project is to develop a powerful team approach to understand the mechanisms and principles underlying the processing of odorant information by the olfactory system. In Project 1, we will develop the experimental and computational methods to characterize the processing of olfactory information by the olfactory bulb, and to examine how that processing changes with learning or changes in neuronal excitability. In Project 2, we will develop real time approaches to the analyses developed in Project 1 to improve our ability to test hypotheses of information encoding in the olfactory bulb, and the roles of specific neurons in this encoding. In Project 3, we will perform neural network modeling of the olfactory bulb circuit in a way that allows rapid and global optimization of parameters that have biophysical relevance for understanding bulb circuitry function. In Project 4, we will develop dual in vivo imaging of cortex and olfactory bulb to better understand the transfer of olfactory information to the cortex and how this changes with learning. In Project 5, we will examine the cortical feedback to the bulb to understand how this feedback helps shape olfactory odorant responses and direct the appropriate changes in bulb circuitry during learning that will preserve odor information. The technical innovation of this proposal is driven by a multilevel experimental approach that leverages expertise from an investigative team with diverse backgrounds. We expect this approach to uncover valuable insights into principles of neural circuit organization and algorithmic function that underlie olfactory system function and plasticity. Our studies will have a broad impact on our understanding of how neuronal circuits implement effective algorithms, and will likely provide important insights into the function of other circuits in the central nervous system. In addition, our work may reveal previously unrecognized computational algorithms that will have a broad impact on computer science.

Intellectual and developmental disabilities (IDDs) manifest as dysfunction in neural circuits. Thus, understanding and ultimately treating IDDs requires directly and precisely interfacing with neural circuits in animal models and the human brain. The goal of the Circuit Analysis & Modulation (CAM) Core is to provide a set of techniques and approaches for BCM IDDRC investigators, and the broader scientific community, which provide a path from hypothesis to pre-clinical readiness regarding neural circuit dysfunction in IDDs. The CAM Core is comprised of three sub-cores. The Tool Generation & Characterization sub-core will develop neurotropic viruses tailored to the particular needs of IDDRC neural circuit studies, and provide assistance applying the tools to their experiments. We will focus on lenti- and adeno-associated viral vectors that are engineered to drive gene expression in desired cell types. In particular, constructed viruses will allow investigators to target mainstay and emerging powerful optogenetic proteins to individual neurons, neuronal subsets, or desired lineages to suit their experimental design. These viral vectors afford the spatial and temporal flexibility of stereotaxic targeting, and provide a time- and cost-efficient alternative to transgenic mouse design. These tools provide valuable information about neuronal firing properties or patterns of connectivity, or provide a means to synthetically perturb function, facilitating study of normal circuit function or disease. The Circuit Assessment sub-core will provide assessment of sensory and neuromodulatory systems in mice and humans, both of which feature prominently in many IDDs. Prepulse inhibition (PPI) of acoustics startle is at the intersection of sensory and neuromodulatory functions, and PPI deficits are observed in many IDDs. We offer use of our novel human ?brain state and cognition? testing suite, which uses pupillometry to extract multiple indicators of neuromodulatory function in sensory recognition and sensorimotor gating, as well as an analogous high-throughput mouse system to IDDRC members. We also offer sophisticated attention tasks that tap into broader circuits, and two-photon imaging of circuit function in the PPI and attention tasks. The Circuit Modulation sub-core will perform in vivo neural recordings and targeted brain stimulation for IDDRC investigators. Combining optogenetic and chemogenetic methods with neurophysiological recordings allows testing circuit mechanisms with ground truth electrical readouts. In addition, targeted chronic deep brain stimulation has been increasingly applied to function- specific neuronal assemblies or pathways in preclinical studies of various neurological diseases, including IDDs. Thus we will provide assistance, design, and service towards testing targeted electrophysiological recordings or stimulation of nervous tissue in rodent models of IDD. In sum, the CAM core as a whole will provide powerful viral tools, electrical and optical recording and stimulation approaches, and cross-species non-invasive circuit assessment, in order to translate hypotheses about neural circuit dysfunction into pre-clinical readiness for IDD treatments.

Abstract/Project Summary Obesity-associated diseases such as diabetes and cardiovascular disease together account for the leading cause of death in the United States. Roughly one-third of the U.S. population is obese, and it is estimated that nearly half of the population will be obese within the next two decades. To date, studies investigating the neural contribution to body weight control have focused largely on neuropeptidergic signaling in the hypothalamus, a key brain region involved in feeding behavior. However, signaling from extra-hypothalamic brain regions has also been implicated in regulating nutrient metabolism, appetite, and satiety. We have recently uncovered a novel mechanism by which glutamatergic signaling in the basal forebrain strongly influences feeding and body weight control. This discovery provides intriguing evidence that specific glutamatergic signaling pathways in the brain critically regulate feeding behavior and body weight homeostasis. To elucidate the mechanisms by which forebrain glutamatergic signaling influences body weight management, feeding behaviors, and metabolism, we will test the hypothesis that glutamatergic basal forebrain circuits modulate metabolic and appetitive programs to regulate body weight. Using a combination conditional genetic targeting, optogenetic manipulations, electrophysiology, and behavioral analysis, we will set out to determine the role for basal forebrain glutamatergic signaling in body weight control and obesity.

PROJECT SUMMARY Alzheimer?s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the United States. Primary pharmaceutical interventions for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, are capable of temporarily improving cognitive function, but no current treatments exist to halt or reverse AD progression. Several histopathological hallmarks manifest in AD patients, including formation of extracellular A? plaques, neurofibrillary tangles, and accelerated degeneration of basal forebrain cholinergic neurons (BFCNs). This marked BFCN degeneration is believed to be a major underlying cause of the cognitive deficits observed in human AD patients throughout disease progression. This supplemental application proposes to utilize tools and information garnered through current research being conducted the parent award ?Genetically dissecting cholinergic signaling in body weight control? (R01DK109934), where we have selectively targeted basal forebrain cholinergic neurons for genetic manipulations and biological analysis, to elucidate either their involvement in AD. We will specifically investigate if BFCNs contribute to AD progression with their loss, or provide potential neuroprotective avenues with activation.