2018 Rutgers BHI-RUN-NJIT Pilot Grants in Neuroscience have been awarded
We received 21 applications in response to the RFA. Each application was reviewed by two members of an external scientific review committee. The results of the scientific review were used by the internal programmatic review committee to select 7 applications for funding. The investigator teams that were funded included-
(1) Travis Baker (RU-N; CMBN), Peter Cole (RBHS-RWJMS) and Miriam Rosenberg-Lee (RU-N; Psychology) (funded by RU-N)
Cognitive control deficits in childhood leukemia survivors: At the intersection of brain, behavior, and computation
Childhood acute lymphoblastic leukemia survivors (CLS) exhibit cognitive deficits at rates exceeding siblings and age-matched controls, negatively impacting school and occupational performance, and diminishing quality of life. The long-term goal of this research is to reduce the frequency and severity of cognitive control problems among CLS. Toward that end, this grant will foster a collaborative partnership between three investigators specializing in pediatric oncology (Dr. Peter Cole), cognitive computational neuroscience (Dr. Travis Baker), and learning disabilities in children (Dr. Miriam Rosenberg-Lee), with the aim to understand the pathophysiology underlying cognitive control dysfunction associated with CLS. Our specific objective is to evaluate the effects of chemotherapy on neural, computational, and behavioral assessments of cognitive control functioning (i.e. reward processing, decision making, and working memory), thereby providing a quantitative and precise understanding of how chemotherapy effects multiple aspects cognitive control functioning. Such an approach provides a promising new foundation for a neuroscientific understanding of cognitive deficits associated with CLS, and for specifying a predictive model to identify patients at risk for persistent treatment-induced cognitive dysfunction due to exposure to toxic therapy. This contribution is significant because defining the neurocognitive features underlying cognitive control deficits caused by leukemia treatment would guide the development of novel treatment strategies. The results are thus expected to have a positive impact because they will be a first step toward developing better targeted strategies to protect children with lymphoblastic leukemia against treatment-induced cognitive dysfunction, and further, to develop and tailor learning programs for the unique cognitive profiles of CLS.
(2) Ioana Carcea (RBHS-NJMS) and Gary Aston-Jones (BHI; RBHS-RWJMS) (funded by BHI)
Oxytocin neuromodulation and the hierarchy of needs
Maternal care is a rewarding behavior. Mammals prioritize caring for offspring over other needs, including other forms of reward, self-protection, and sometimes basic physiological needs. However, this behavior can break down when animals experience extreme conditions (abnormally high levels of stress, extreme hunger or thirst, etc). From human behavioral data, we know that drug addiction can also severely impair maternal care, as drug consumption becomes the first priority of the mother, to the expense of other needs and rewards. However, the converse is also true – in many cases, becoming a parent can protect against drug consumption and can even reverse the course of addiction. How does one drive gain priority over another drive at the behavioral and neurophysiological levels? We aim to address this question in rodent models, in the context of competing needs for drug use and for offering maternal care. In particular, we are interested in investigating the role of the maternal hormone oxytocin in motivating the choice for satisfying one of the two needs. Our collaborative research will rely on complementary expertise from the two labs to begin investigating the biological mechanisms for prioritizing between two strongly motivational behaviors, possibly opening new avenues for behavioral and medication-based interventions that would address the current drug epidemic in the United States and worldwide.
(3) Jeffrey Zahn (RU-NB; SOE), Zhiping Pang (RBHS-RWJMS) and Ronald Hart (RU-NB; SAS) (funded by the Office of the VCRI, RU-NB)
Micro-jigsaw puzzle to coordinate cellular interactions forming multi-neuron subtype mini neurocircuits
The goal of this project is to establish an in vitro model for human neural circuitry mimicking complex brain wiring using subtype specified human neurons. To achieve this “Neurocircuitry-on-Chip” model, we will fabricate interlocking structures (‘micro-jigsaw puzzle’ pieces) which can be independently seeded with different subtype (i.e., excitatory, inhibitory and dopaminergic (DA)) induced Neurons (iNs) derived from human induced pluripotent stem cells (iPS) with known genetic lineage. The ‘micro-jigsaw’ pieces will be designed such that when they are assembled they co-localize the distinct iN subtypes in close proximity to each other in order to allow synapse formation between the different the different iN subtypes to form in-vitro mini-neurocircuitry models consisting of multiple neuron subtype interactions. We will construct our micro-jigsaw puzzle to produce a neurocircuit model of the mesolimbic reward system (e.g., inhibitory→DA→inhibitory connections to mimic VTA local circuit of inhibitory neurons which regulate DA neurons and DA innervatation of Nucleus accumbens neurons or inhibitory→DA→excitatory connections to mimic VTA local circuitry and DA projections to the prefrontal cortex). Following construction of wildtype mini-neurocircuits we will validate our circuitry model by focusing on a well-studied genetic variant associated with increased alcohol consumption, nicotine and cocaine abuse, containing an altered μ-opioid receptor (MOR) sequence that alters intracellular signaling.
(4) Gary Aston-Jones (BHI; RBHS-RWJMS) and Kevin Pang (RBHS-NJMS) (funded by BHI)
The role of the orexin system in mild traumatic injury associated opioid addiction
Prescription opioid addiction is a chronic and relapsing disorder that has become a national epidemic. Individuals who suffer a mild traumatic brain injury (mTBI) are at greater risk for drug addiction including prescription opioid abuse. Despite the known link between mTBI and addiction, little is known about the underlying mechanism. However, increased risk of drug addiction following mTBI likely results from alterations in brain regions associated with addiction. Orexins (hypocretins) are a pair of neuropeptides exclusively produced in the hypothalamus that have been implicated in addiction. Preliminary data for this proposal indicates that in an animal model of mTBI, orexin neurons are increased post injury. This is consistent with recent findings showing that rats highly motivated for drug reward express a greater number of orexin-producing neurons compared to less motivated rats. Thus, it is possible that increased risk of drug addiction following mTBI results from results from changes in the orexin system. This collaborative pilot study between the Aston-Jones and Pang laboratories, will investigate the effects of mTBI on motivation for the prescription opioid oxycodone as well as determine the effects of mTBI on the orexin system. This proposal is timely given the current state of the opioid epidemic and the increased incidence of mTBI. The pilot data collected here will assist in subsequent grant proposals to the NIH, Department of Defense, and the NJ Commission on Traumatic Brain Injury to further investigate drug addiction following brain injury.
(5) Alexander Kusnecov (RU-NB; SAS), Huaye Zhang (RBHS-RWJMS), Lori Covey (RU-NB; SAS) and John Pintar (RBHS-RWJMS) (funded by the Office of the VCRI, RU-NB)
Maternal T Cell Activation During Pregnancy and Postnatal Neurobehavioral Development
Maternal immune activation (MIA) during pregnancy can produce neurobehavioral changes in the offspring. However, most MIA studies target innate immune cells, while markedly absent are studies on the neurobehavioral impact of maternal T-cells. Bacterial T cell superantigens, such as Staphylococcal Enterotoxin A (SEA), are microbial proteins that activate helper (CD4+) T cells and cause prominent T-cell proliferation and cytokine production. We published that offspring from pregnant mice challenged with SEA at embryonic day 12.5 (E12.5) displayed a modest reduction in social behavior, and showed an increase in anxiety-like behavior and increased locomotor behavior. In contrast, we also observed increased interest in a novel object, improved short-term spatial memory, and improved sensorimotor gating in the prepulse inhibition test. This dichotomy of negative and positive outcomes, may be due to the gestational timing of immune activation, as well as unique contributions of T cells to the developing embryo. In the current proposal, we wish to extend this research to a determination of whether SEA challenge at different gestational dates (viz., E9.5 and E14.5) produces alternate behavioral outcomes. Moreover, we will closely monitor the T cell proliferative response in the mother, and examine in the offspring, potential alterations in the resident immune cells of the brain, microglia, as well as dendritic spine structural plasticity. Overall, this project will provide important insights into the impact of the maternal T cell immune response on embryonic and/or postnatal behavioral development. This will provide a critical missing perspective on how the maternal immune system shapes neurodevelopment.
(6) Bonnie Firestein (RU-NB; SAS), Konstantinos Michmizos (RU-NB; SAS) and Zhiping Pang (RBHS-RWJMS) (funded by the Office of the VCRI, RU-NB)
We propose to explore the long-neglected functional roles of the non-neuronal brain cells and engraft them into biologically plausible models of Neural-Astrocytic Networks (NAN). To achieve our goal, we have formed an interdisciplinary team of principal investigators at Rutgers that balances pioneering and well-established experimental, computational and translational research. We will study how glial cells, astrocytes in particular, work independently and cooperatively with the neuronal brain. To do so, we will conduct experimental studies to explore the biological mechanisms that astrocytes exhibit in modulating neural synchronization and local plasticity, two fundamental components in brain network function and dysfunction. Our NAN models will, on the one hand, be informed by the experimental results and, on the other hand, expand the experimental evidence collected from cell recordings to the brain network level, where behavior, and its associated diseases, emerge. The anticipated new knowledge on astrocyte-neuron interaction will advance, if not transform, brain studies and related treatments. Overall, this and other efforts to harness and nurture the functional role of astrocytes into comprehensive computational models have the potential to shape a field that one may call “Computational Astrocyence.”
(7) Wise Young (RU-NB; SAS), KiBum Lee (RU-NB; SAS) and Yu-Ian Mary Ying (RBHS-NJMS) (funded by the Office of the VCRI, RU-NB)
Direct Cellular Programming of Reactive Astrocytes into Neurons for Enhanced CNS Repair
In this pilot proposal, we propose to make conceptual advances by providing the first evidence that non-viral delivery of artificial transcription factor to directly convert somatic cells into target cells, here neurons. The proposed NanoScript platform is a superior alternative that can efficiently generate target cells in a non-integrative approach. Our highly modular platform will not only significantly advance research efforts aimed at direct cellular programming, but also stem cell therapy, molecular imaging, and many other fields. Furthermore, this proposal outlines a paradigm-shifting technology to treat a disease that currently has no effective treatments and therefore is also a high-risk, high-reward research indication. While spinal cord injury (SCI) is the primary target of this proposal as a proof-of-concept, numerous diseases deal with reactive astrogliosis and general neuro-inflammation. Other injuries such as TBI, disorders such as Alzheimer’s, Stroke, Parkinson’s, and more, all deal with these phenomena and therefore our system can be broadly applicable to many different indications. By direct cell reprogramming, bypassing a stem or progenitor cell stage, our proposal fits perfectly with the vision and goal of the Brain Health Institute Pilot Grant to support highly innovative, high return, original, and unconventional research that will provide significant advances in biomedical and clinical research. We will utilize this BHI pilot grant to develop new collaborative, multidisciplinary research programs in neuroscience across Rutgers, BHI, and Rutgers-Newark (medical school). Additionally, this pilot grant will be used to generate the key data that facilitate the obtaining federal grants (e.g., NIH R01 and P grants).