Gina R. Poe, Ph.D. - US grants

DESCRIPTION (provided by applicant): We hypothesize that the absence of NE in the forebrain during REM sleep and the spindle-rich transition to REM sleep (TR) allows for synaptic depotentiation underlying normal assimilation of new memories into the global memory network schema. Post-traumatic stress disorder is one condition associated with abnormally high noradrenergic tone, intense dreaming and intrusive memories. We hypothesize that an abnormal presence of norepinephrine (NE) during sleep prevents the important depotentiation process of normal memory consolidation and thus prevents novel memories from being integrated with familiar memories in the neocortical memory network. We will record from the hippocampus and LC simultaneously to determine whether hippocampal reactivation during non-REM sleep occurs differently in the absence of NE (i.e. during spindle production). We will examine hippocampal reactivation events for changes indicative of plasticity, like burst spike attenuation changes, Causal Entropy and Functional Clustering. We will examine spike firing patterns in relation to local electrical field potentials and expect to see familiar, already consolidated memories activated differently than novel memories as we have seen during REM sleep, and that such replay will be phase specific during non-REM sleep spindles just as they are phase specific to theta in REM sleep. We hypothesize that LC silence is necessary to generate spindles in the first place as well as for the synaptic strengthening and weakening effects of spindle-phase associated firing. To test the necessity for NE to be absent we will stimulate the LC at sub-arousal levels (~3 Hz) during sleep whenever we see spindles in the cortex or hippocampus through to the next awakening. We expect a marked reduction in the number of spindles generated, a loss of the depotentiation that hippocampal replay in non-REM sleep produces, and impaired memory consolidation especially for reversal tasks. This research will have strong implications for the development of effective strategies to selectively downscale synaptic networks reactivated during the dreaming and spindle stages of sleep the overly strong retention of which is debilitating in those unable to normalize and integrate their traumatic memories.

[unreadable] DESCRIPTION (provided by applicant): The proposed experiments and simulation studies investigate one of the first feasible mechanisms for memory consolidation during sleep. The results will elucidate particular roles for the Schaffer Collateral and temporo-ammonic inputs to the hippocampal CA1 region in memory processing and how NE and 5-HT gate these pathways during waking and Rapid Eye Movement (REM) sleep. During REM sleep, we have found that reactivation of hippocampal cells changes over the course of several days as the animals became familiar with an environment. Cells with place fields in an initially novel environment switch from firing near the theta rhythm peaks to firing near the theta troughs during REM, while maintaining their theta peak activity during waking exploration. Theta trough firing during REM may uniquely facilitate depotentiation of intra-hippocampal synapses which are associated with now familiar, cortically-consolidated memories and allow for learning of new information and the integration of novel information with old memories. This proposal seeks to test the role of the uniquely REM-suppressed neurotransmitters norepinephrine (NE) and serotonin (5-HT) in theta phase reversal, potentiation of TA-CA1 inputs, depotentiation of SC-CA1 synapses and hippocampus-dependent learning and memory. Specifically, experimental and modeling studies are proposed to investigate the hypothesis that the absence of NE and 5-HT during REM reactivation provides an environment wherein TA-CA1 synapses may be strengthened and SC-CA1 synapses may be weakened, thus indicating a unique role for REM sleep in learning and memory. Understanding the mechanisms underlying memory consolidation during sleep should lead to sleep-specific treatments for learning disabled persons and the elderly. The results will also indicate effects of commonly prescribed anti-depressants, such as selective noradrenergic (SNRIs) and serotonergic (SSRIs) re-uptake inhibitors, on learning and memory. [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): SPECIFIC AIMS - Next-Generation Neuroscience Scholars Program Innovations and advances in neuroscience are greatly enhanced when the community of contributing scientists is diverse in perspectives, backgrounds, and experiences. Currently, however, racial/ethnic minorities and individuals with disabilities are not nearly as wel represented within neuroscience compared to their representation in society at large. Underrepresented minorities (URM) who enter the scientific career pipeline, including neuroscience, appear to be exiting at higher rates than their non-URM peers due to significant cultural, societal, and financial pressures, as well as limited access to role models and community support. Now, as the nation becomes increasingly more diverse, an important and exciting opportunity exists to bring an even wider range of voices to bear on neuroscience research and address barriers that may be keeping these important scientist contributors from participating as fully as possible. Helping to fix the leaky neuroscience career pipeline has been the focus of the Neuroscience Scholars Program (NSP), a long-standing, far-reaching NINDS-supported effort of the Society for Neuroscience (SfN). NSP has served nearly 600 URM scholars since 1982 and is now poised to broaden its impact while preserving its core service model. Building on NSP's historic successes in meeting short- and long-term performance metrics, this new application will strengthen NSP's activities for a core group of participants, significantly expose many more URM researchers to relevant content and valuable networks, and facilitate sustained research engagement within the greater URM neuroscience community. SfN brings to this effort broad access to neuroscience disciplines, strong commitment to diversity, deep-rooted volunteer engagement from among leaders in the field, valuable in-kind resources, and proven experience in implementing high-impact programs. As such, SfN is uniquely positioned to lead NSP through this next innovative, expansive phase with the affirmed goal of advancing careers and professional development of diverse neuroscience researchers. Evidence shows that former NSP participants have advanced in their neuroscience careers, overcoming challenges that could have led to an early exit from the scientific research career pipeline. SfN proposes to build on that strong foundation in the coming five years. Focusing particularly on graduate and postdoctoral neuroscience researchers from among racial/ethnic minorities and individuals with disabilities (collectively referred to as Underrepresented Neuroscience Researchers [UNRs]), NSP will achieve three specific aims: 1. Intensively guide and support more than 80 of the highest-achieving UNRs so they progress and thrive in their research careers through networking, mentoring, and career- advancement programming. Over five years, 12-15 of the highest-achieving UNRs will be selected annually to participate through the NSP Intensive Track as NSP Fellows. (Note: In addition to these new recruits, a cohort of 16 Scholars from the previous NSP funding cycle, currently in their first year, will complete their second year under the new Program). Fellows will receive formal mentoring, access to a comprehensive curriculum of professional and research-enhancement workshops and webinars, and special networking and financial-enrichment support. 2. Extensively engage 500 high-achieving UNRs to help them persist and succeed as neuroscientists through online professional enhancement programming and networking. Approximately 100 qualified NSP applicants will be formally invited annually to participate through the NSP Extensive Track as NSP Associates. Associates will receive special access to new and adapted webinars on neuroscience research and career-related topics, online diversity forums for discussion and learning, and a wealth of neuroscience community resources, as well as access to SfN's annual meeting networking events- when they choose to attend. 3. Motivate NSP alumni and diverse neuroscientists to stay engaged in neuroscience and garner long-term professional success by building community through online discussion and neuroscience career and community resources. NSP alumni, including former Fellows and Associates, as well as the broader community, will be actively encouraged to access archived webinars, take part in online discourse on diversity, and stay involved in online affinity networks.

Project Summary/Abstract The overall goal of the UCLA MARC program is to increase the number of undergraduates from underrepresented backgrounds who successfully enroll into graduate programs at highly selective, research- intensive institutions and subsequently complete a Ph.D. in biomedical fields. This application builds on a highly successful program that began at UCLA in 1996. Over the last 15 years, 97 students have completed UCLA?s MARC program and graduated. Of these 97, so far 68 (70%) have matriculated into PhD or MD/PhD programs (57 PhD, 11 MD/PhD). MARC trainees participate in a structured program that emphasizes research training with outstanding faculty, development of scientific writing and presentation skills, networking and mentoring. We propose to select 8 new junior level students per year to participate in this 2-year program, resulting in a total of 16 students in the program per year. The cumulative effect of the proposed MARC program will increase the pool of strong candidates from underrepresented backgrounds for PhD or MD/PhD programs. Specific aim 1 is to increase the social integration of MARC trainees to solidify their identity as scientists, to strengthen their motivation to persist in science, and to nurture their development as leaders in the scientific workforce. This aim will be achieved through outreach activities of MARC trainees and peer mentoring between the MARC program and pipeline programs. The measurable objectives are: 1) at least half of MARC trainees will participate in outreach activities; and 2) all MARC trainees will serve as peer mentors to two freshmen/sophomores each year. These activities will broaden the impact of the MARC program at UCLA. Specific aim 2 is to enhance the scientific and career knowledge, skills, and experience of MARC trainees to prepare them for biomedical PhD programs. This aim will be achieved through MARC research training, professional skills development, and close mentoring. The measurable objectives are: 1) all trainees will participate in research activities for the duration of their appointment in the MARC program; 2) all trainees will present their research at two or more conferences each year; 3) all trainees will write both NSF-style and NIH- style research proposals; and 4) within 3 years of graduating from UCLA, at least 80% of MARC trainees will enter PhD or MD/PhD programs.

Project Summary/Abstract Although several human studies suggest that sleep facilitates insight learning, the means by which this could occur is unknown. One hypothesis suggests that key elements in the environment necessary for insight are encoded in pieces during waking, then replayed during sleep, allowing the pieces to self assemble into insight. However, it is not clear which memories are selected for reactivation and processed in sleep versus allowed to be forgotten. We have developed a novel computational hypothesis called temporal scaffolding, which can serve as a platform to shed light on both questions. This hypothesis suggests that sleep replay should especially aid in gaining insight into temporal hidden patterns due to the unique compressed dynamics of memory replay occurring during non-rapid-eye- movement sleep (NREMS) and the learned sequences that are replayed in NREMS are those that were accompanied by bursts of activation from the Locus Coeruleus (LC) during the learning session, increasing the probability for replay. We developed a new task for animals that measures whether sleep facilitates insight into a hidden temporal order. We will use this task in combination with a measurements of activity from hundreds of neurons in the hippocampus simultaneously while animals are learning the task and assess activity from task-relevant neurons while animals train and assess activity from the same neurons again while they sleep, and once more when they are tested following sleep. In Aim 1 we will correlate the number of task-relevant hippocampal replay bursts during NREMS with measures of performance on the subsequent wake period that indicate whether the animals have gained insight into the hidden temporal order. Preliminary data show that a subset of unmanipulated animals can achieve insight into this task and that sleep boosts this gain of insight. In Aim 2 we will use an optogenetic approach to stimulate or silence LC neurons at critical choice points during initial task exposure and see whether such manipulation alters the density or type of replay events in subsequent sleep and influences the gain of insight. Sleep deprived and LC-silenced groups will serve as controls for the LC-stimulated animals. In Aim 3, the data gathered from the first two Aims will be entered into a computational model of hippocampal-neocortical networks to better estimate the parameters determining how temporal scaffolding occurs, which, in turn, will inform future mechanistic studies. Positive results in each aim will underscore the importance of memory replay in insight learning, the contribution of temporal scaffolding to this learning, and a learning mechanism (LC activity) modulating it. It will also provide a new handle by which to boost memory processing during sleep.

In the proposed renewal of the Neuroscience Scholars Program (NSP), the Society for Neuroscience (SfN) will build on the program?s history of enhancing career development and professional networking opportunities for graduate and postdoctoral neuroscience researchers from underrepresented racial and ethnic groups and individuals with disabilities (underrepresented neuroscience researchers, or UNRs). The 2019-2024 NSP will pursue three specific aims intended to achieve a diverse neuroscience workforce thriving in research and leadership positions: (1) provide intensive networking, mentoring, and career-building activities to at least 84 NSP Fellows by retaining successful programmatic elements while deepening mentoring, networking, and leadership-building activities; (2) round out current career-enhancing activities for up to 350 NSP Associates to include in-person and online professional development programming as well as new opportunities to travel to the SfN Annual Meeting; and (3) engage NSP Alumni as leaders and mentors in the NSP and broader neuroscience community to support their continued career trajectory and long-term professional success in neuroscience. SfN will continue NSP?s key strategies of providing mentoring, financial support, and social integration and community-building opportunities but will deepen the NSP experience for both Fellows and Associates by emphasizing leadership-building and lifelong mentoring in multiple ways. The renewal period will provide opportunities for NSP Fellows, Associates, and Alumni to lead NSP webinars and online discussions, serve as NSP class advisors and mentors, and organize a new biennial mid-year NSP Conference. These NSP activities seek to build the assets of knowledge, skills, and experience of underrepresented neuroscience researchers to optimally facilitate their progress and transition to more advanced research, education, and training activities. Since 1982, over 900 graduate students and postdoctoral UNRs have completed the NSP and become part of the career-long community of NSP Alumni. Evaluation studies consistently show that NSP Alumni continue along successful career trajectories, attain senior leadership positions in academia and industry, publish actively in peer-reviewed journals, attract grant funding for their research programs, serve as visible role models, and by their example and mentorship, influence the next generation of UNRs to contribute their diverse perspectives to furthering excellence in the field of neuroscience.