Yingxi Lin - US grants

DESCRIPTION (provided by applicant): GABAergic synapses are the major inhibitory connections in the brain and likely play an important role in all brain functions, including learning and memory. A deficit in GABAergic synapses is often implicated in devastating disorders such as autism, schizophrenia, and epilepsy. Despite their importance, many fundamental questions regarding the regulation and function of GABAergic synapses remain unanswered. Our long-term goal is to explore the cellular and molecular mechanisms by which neuronal activity is coupled to modification of GABAergic synapses during behavioral experience and to understand how disruption of this form of GABAergic synaptic plasticity leads to cognitive deficits. Towards this goal, we have recently identified the activity-regulated bHLH-PAS transcription factor Npas4 as a key regulator of GABAergic synapses. Npas4 is rapidly induced by excitatory synaptic activity and its level determines the number of GABAergic synapses formed on excitatory neurons. These findings suggest that Npas4 is the molecular link between neuronal excitation and GABAergic synapses. By investigating Npas4's role in regulating activity-dependent modulation of GABAergic synapses and regulating behavioral output of neural circuits, the research plan outlined here will yield new insights into the etiology of many neurological disorders. PUBLIC HEALTH RELEVANCE: The research described in this proposal will explore the role of GABAergic synaptic plasticity in important neural circuit functions such as learning and memory. A deficit in GABAergic synapses is often implicated in devastating neurological disorders such as autism, schizophrenia, and epilepsy, most of which often involve profound psychiatric and cognitive deficits in afflicted individuals. Our proposed study will shed light on the pathology and etiology of these neurological diseases.

DESCRIPTION (provided by applicant): The way in which sensory experience is captured and converted into long lasting changes in the brain is critical for adaptive behaviors. A deficit in sensory information processing is a pronounced feature shared by many devastating neuropsychiatric disorders such autism, schizophrenia and depression. Each experience activates a unique set of neurons within specific regions of the brain. While we now know in many cases the brain regions that are associated with particular types of sensory experience, we know very little about the identity of specific ensembles of neurons that are responsible for the encoding of specific sensory information, let alone the underlying molecular and cellular mechanisms. The goal of this proposed study is to fill this gap in our knowledge by developing a versatile system that allows for the identification and manipulation of ensembles of neurons as they participate in the processing of the influx of sensory information. Using this system, our long term goal is to explore the cellular and molecular mechanisms by which sensory experience is coupled to modification of the synaptic properties of neural networks and to understand how disruption of this process leads to cognitive deficits.

? DESCRIPTION (provided by applicant): In the mammalian brain, early sensory areas are organized as stereotyped maps of stimulus qualities. The anatomical features of these sensory maps underlie the neuronal computations and information processing that are essential to generate appropriate perceptual experiences and behaviors. In the mammalian olfactory bulb (OB), the most striking anatomical feature of this sensory map is the convergent axonal input from primary olfactory sensory neurons (OSNs); specifically, each insular glomerular structure in the OB receives axons exclusively from OSNs expressing the same odorant receptor. Moreover, OB projection neurons, the mitral/tufted cells, also project their primary dendrites exclusively into a single glomerulus. However, it is not well understood how this strict pattern of convergence and segregation contributes materially to the processing of olfactory information and odor-driven behaviors. In this project, we establish a multi-disciplinary approach to determine the contribution of this strict anatomical mapping to odor representation and perception. Specifically, we will genetically manipulate the projection patterns of OSN populations to perturb the anatomical map in the olfactory bulb, and perform a battery of automated behavioral assays probing odor discrimination and recognition. We then will integrate mathematical models based on OB circuitry with electrophysiological and optical imaging studies to elucidate the basis for these response differences in wildtype and mutant mice. By combining genetics, behavior, electrophysiological, and imaging approaches, we will determine the impact of genetically altered glomerular maps on odor perception under both naïve and learned conditions. RELEVANCE: Precise neuronal connectivity in the nervous system is essential for its proper function. Cognitive deficits in many psychiatric disorders arise from disruptions in neural connectivity, including disruptions within sensory circuits. The proposed study investigates the role of a specialized, anatomical neuronal connectivity pattern in regulating sensory information processing and perceptual experience. Results from this study will reveal how brain function can deteriorate because of disruptions in the normal connection patterns among neurons.

Learning and memory defines how animals interact with their environment. This process relies on experience-driven changes in synaptic connections, a phenomenon known as synaptic plasticity; disruption of this process is believed to underlie several cognitive and psychiatric disorders. Although synaptic plasticity is critical for learning and memory, the mechanisms by which memory is formed and stored in neural circuits remains poorly understood. The proposed studies address this knowledge gap by focusing on synaptic mechanisms by which contextual memory is encoded in CA3 pyramidal neurons of the hippocampus, a brain region with a central role in learning and memory. Among the excitatory inputs converging onto CA3 pyramidal neurons, the mossy fiber (MF) input from dentate gyrus granule cells is known to be required for the encoding of contextual memory. We propose to identify molecular pathways that selectively modulate MF-CA3 synapses in the mouse hippocampus. Using genetic tools recently developed by us, we seek to identify the specific group of CA3 neurons activated by contextual learning, and pinpoint the specific learning- dependent synaptic modifications that are key to forming new memories in these neurons. The proposed research has the potential to generate conceptual breakthroughs in our molecular and cellular understanding of memory formation, and ultimately provide insights into mechanisms underlying cognitive and psychiatric impairments.

Learning and memory defines how animals interact with their environment. This process relies on experience-driven changes in synaptic connections, a phenomenon known as synaptic plasticity; disruption of this process is believed to underlie several cognitive and psychiatric disorders. Although synaptic plasticity is critical for learning and memory, the mechanisms by which memory is formed and stored in neural circuits remains poorly understood. The proposed studies address this knowledge gap by focusing on synaptic mechanisms by which contextual memory is encoded in CA3 pyramidal neurons of the hippocampus, a brain region with a central role in learning and memory. Among the excitatory inputs converging onto CA3 pyramidal neurons, the mossy fiber (MF) input from dentate gyrus granule cells is known to be required for the encoding of contextual memory. Using genetic tools recently developed by us, we were able to identify the specific group of CA3 neurons activated by contextual learning, and identified a learning-dependent synaptic modifications associated with these neurons. We hypothesize that this newly identified synaptic plasticity plays a critical role in contextual memory formation. This hypothesis will be tested using a combination of molecular, cellular, electrophysiological and behavioral approaches in mice. We will also identify molecular pathways that selectively modulate MF-CA3 synapses in the mouse hippocampus. The proposed research has the potential to generate conceptual breakthroughs in our molecular and cellular understanding of memory formation, and ultimately provide insights into mechanisms underlying cognitive and psychiatric impairments.

PROJECT SUMMARY The ability of the brain to utilize information from past experiences to guide future decisions, termed adaptive behavior, is critical for survival. To effectively adapt behaviors, the brain applies stored memory to new but similar situations (generalization), while also maintaining the capacity to distinguish unique stimuli (discrimination). When these critical processes (memory generalization or discrimination) go awry, it can lead to maladaptive disorders such as post-traumatic stress disorder (PTSD) and panic disorder. Despite their importance, mechanisms underlying memory discrimination and generalization remain largely unknown. This proposal will investigate the dynamic processes that underlie the utilization of an encoded memory to guide future behaviors, in particular the molecular, synaptic, and circuit mechanisms that govern the balance between discrimination and generalization. We have collected very exciting preliminary data showing that individual contextual fear memories are represented in the dentate gyrus (DG) by multiple functionally distinct neuronal ensembles defined by different activity-dependent transcriptional pathways, and that these ensembles bi-directionally regulate the discrimination-generalization balance. Based on these exciting findings, we hypothesize that the activity- dependent pathways target specific synaptic inputs on DG granule cells to differentially control memory discrimination and generalization. We aim to (1) uncover novel forms of learning-induced synaptic plasticity; (2) reveal underlying circuit mechanisms for memory discrimination and generalization; and (3) identify the molecular players important for this experience-dependent behavioral adaptation. The proposed research is both conceptually and technically innovative. It will experimentally demonstrate for the first time functionally distinct active neuronal ensembles coexisting within the memory engram, shed light on the synaptic and circuit mechanisms by which encoded memories directly drive experience-dependent behavioral outputs, and may lead to new treatment strategies for neuropsychiatric disorders, such as PTSD and panic disorder, which are caused by the imbalance between memory discrimination and generalization.