2016 Rutgers BHI-RUN-NJIT Pilot Grants in Neuroscience have been awarded
We received 25 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 9 applications for funding. The investigator teams that were funded included-
(1) KiBum Lee (RU-NB; Chemistry & Chemical Biology), Kelvin Kwan (RU-NB; Cell Biology & Neuroscience and Mary Ying (RBHS-NJMS) (funded by BHI)
A Bio-Inspired Transcription Factor for Spiral Ganglion Neuron Regeneration
A major cause of sensorineural hearing loss is the death of spiral ganglion neurons (SGNs). Over a person’s lifetime, auditory neurons continually die from exposure to ototoxic drugs and loud sounds. An estimated 17% of adult Americans (36 million) (NIDCD) have some form of hearing loss. Use of stem cell replacement for auditory neuropathy holds great promise for clinical applications, but studies suggest that only a small percentage of stem cell derived-otic progenitors become neurons after transplantation. As such, there is a specific need to promote the efficient differentiation of otic progenitors into SGNs to promote otic neuronal regeneration. We identified Ascl1 as a transcription factor (TF) that can be repurposed for SGN regeneration. This proposal aims to develop a nanoparticle coupled to a synthetic Ascl1transcription factor (Ascl1-NanoScript) that is non-toxic, allow for efficiently delivery into cells and promote SGN differentiation. We hypothesize that the Ascl1-NanoScript will bind to the same promoter regions as endogenous Ascl1 TF to promote neuronal differentiation. Ascl1-NanoScript will be synthesized by coupling small molecules that mimic the DNA binding domain, activation domain, and the nuclear localization domain onto a magnetic nanoparticle. Next Ascl1-NanoScript transcriptional activity will be tested in vitro and in vivo. Finally, we will delivery Ascl1-NanoScript into stem cells by magenetofection and determine if efficient acquisition of neuronal morphology and function is achieved.
(2) Steve Levison & Teresa Wood (NJMS- Pharmacology, Physiology & Neuroscience), Cheryl Dreyfus (RWJMS- Neuroscience & Cell Biology) and Suhayl Dhib-Jalbut (NJMS/RWJMS-Neurology) (funded by BHI)
Delineating Oligodendrocyte Progenitor Subtypes and their Roles in CNS Remyelination
A persistent problem in treating Multiple Sclerosis (MS) patients is the lack of therapeutics to restore neurological function by promoting remyelination. Presently, none of the drugs administered to MS patients promote remyelination by stimulating the resident myelin-producing precursors known as oligodendrocyte precursor cells (OPCs). Therefore, the goal of this proposal is to gain a deeper understanding of the types of OPCs that reside in the adult brain and to understand the signals that stimulate them to produce new myelin subsequent to an MS attack. Our team is comprised of leaders in the area of cellular and molecular mechanisms of myelin repair and regeneration (Drs. Wood, Dreyfus, Levison) and an internationally recognized MS physician-scientist (Dhib-Jalbut), recognized for his clinical expertise and for his translational research using animal models to understand the mechanisms of action of MS therapies. We have proposed focused studies to establish whether there are 3 distinct subtypes of OPCs and whether they have disparate intracellular responses to growth factors known to promote myelination. The long-term goal of our studies is to identify treatments for those patients who have relapsing or progressive forms of MS who need myelin repair therapies. An immediate goal of our studies will be to reveal novel markers for subsets of OPCs. These markers will be indispensable in establishing whether one population of OPCs has greater potential to remyelinate MS lesions than another population. We also expect that our research will identify new biomarkers that will allow physicians to provide more personalized and effective treatments.
(3) Michael Lewis (RBHS-RWJMS) and Allan Leslie (RU-NB- RUCCS) (funded by BHI)
Intersenory Integration in Typically Developing and Children At-Risk for ASD
Autism Spectrum Disorders (ASDs) are characterized by atypical behavior in social interaction, social communication, and repetitive behaviors/interests. Atypical sensory integration abilities, however, have been recently added as a defining characteristic of ASDs. Given that our world multisensory and that children must learn to perceive audiovisual speech as a unified event, an inability to do so may contribute to cognitive and perceptual deficits in speech and language skills, cascading into the hallmark social deficits of ASD. This proposal suggests that by examining the development of the children’s audio-visual temporal binding window, or the minimum amount of time needed between two sensory inputs to perceive them as synchronous, we can better elucidate sensory integration abilities in at-risk and typically developing (TD) children younger than two years of age. This proposal seeks to gather pilot data so that a subsequent R01 can examine 4 key aims: 1) Investigate the development of TD children’s audio-visual temporal binding window, 2) Investigate the audio-visual temporal binding window in infants at-risk for ASD, 3) Investigate the relation between the audio-visual temporal binding window and later language development in TD and at-risk infants, and 4) Investigate the relation between the audio-visual temporal binding window and children’s ability to perform social word-object mapping. We hypothesize that differences in the size of children’s audiovisual temporal binding window will be present between TD and at-risk children that this ability will influence later language outcomes, and that word-object mapping in response to social cues will be affected.
(4) Rafael Benoliel (RBHS-SDM) and Gary Aston-Jones (RBHS/RU-NB/BHI) (funded by BHI)
Designer Receptors: A novel potential therapeutic for management of trigeminal neuropathic pain
Neuropathic pain often results from a lesion or disease affecting the somatosensory system, including the trigeminal system. Current management of painful traumatic trigeminal neuropathies (PTTN) relies on pharmacologic agents with severe side effects and low success rates. A new class of synthetic receptors termed DREADDs allows for localized suppression of neuronal excitability via viral expression of a Gi-coupled designer receptor known as hM4Di. The hM4Di receptor is activated by the otherwise inert ligand clozapine N-oxide (CNO). In our current year of BHI pilot funding, we successfully transfected trigeminal ganglion (TG) neurons with hM4Di-DREADDs under a general synapsin promotor and showed that activation of these receptors via CNO was analgesic in an acute formalin pain model. Here, we will extend these findings with a vector that selectively drives hM4Di expression in tachykinin/substance P neurons in TG, known to be primarily involved in pain, so as to minimize effects of hM4Diactivation on non-pain sensation. Using this novel vector, we will examine the effectiveness of DREADD-induced analgesia in established models of both acute and chronic trigeminal neuropathic pain. These studies have high translational potential, as they may lead to the development of a focused gene therapy for PTTN and other neuropathic pain disorders. This project is highly collaborative, involving laboratories from the RWJMS/Brain Health Institute (Piscataway) and Rutgers Dental School (Newark). Moreover, data from these studies will be important for a revised version of an NIH R21 application on this topic that was reviewed favorably earlier this year.
(5) Mark West (RU-NB) and Kevin Beck (RBHS-NJMS) (funded by BHI)
Determining the relationship between opioid use and avoidance susceptibility
A recent publication demonstrated that male patients actively enrolled in an opioid maintenance program (methadone therapy) demonstrated enhanced avoidance learning and extinction resistance using a novel task. Avoidance is a common symptom of anxiety disorders/post-traumatic stress disorder (PTSD) and predicts overall disorder severity. The human data suggests that opioid addiction may increase the risk for men to develop anxiety disorders or PTSD; the same was not true for women, suggesting that the relationship between opioid addiction and avoidance susceptibility is sex dependent. In order to determine if this is the case, controlled studies are needed to test this provocative hypothesis. Therefore, we plan to combine the expertise of the West lab in drug self-administration with the expertise of the Beck lab in avoidance learning to determine if opioid addiction can selectively increase the susceptibility of males to acquire avoidance. Male and female Sprague Dawley rats will be trained to self-administer fentanyl at the West lab in Piscataway. Once addictive behavior is well-established, the rats will be transferred to the East Orange VA Medical Center; there they will receive daily methadone maintenance treatments and be subsequently trained in avoidance learning, including avoidance extinction. The result is that this study will model the opioid addiction and subsequent therapy/behavioral assessment that occurred in the human study. In addition to testing the causal relationship between opioid addiction and avoidance, this study represents a new area of research focused on understanding how addiction to certain drugs selectively increases the risk for developing subsequent mental illness.
(6) Tracey Shors, Brandon Alderman and Steve Buyske (RU-SAS); Steven Silverstein (RBHS-RWJMS); Judy Thompson (RBHS-SHRP) and Sarah McMahon (RU-SSW) (funded by BHI)
It's About Time: Learning to Recover from Sexual Trauma in the Past
Sexual aggression and violence against women (VAM) are not only social problems; they are mental health problems (Shors and Millon, 2016). Women who experience sexual trauma often express disruptions in cognitive processes related to time and memory, which can lead to depression and post-traumatic stress disorder (PTSD). They also tend to ruminate, rehearsing autobiographical memories of the stressful event. We have developed an intervention that significantly reduces ruminative thoughts (Shors et al., 2014? Alderman et al., 2016). The intervention, known as MAP Training, was translated from laboratory studies on neurogenesis in the hippocampus, a brain region involved in the rehearsal of autobiographical memories (Shors, 2014). MAP Training combines “mental” training with focused-attention mediation and “physical” training through aerobic exercise. After 8-weeks of training, participants ruminated less while expressing more synchronized brain activity during processes of cognitive control (Shors et al., 2014, 2016; Alderman et al, 2016). In this proposal, we will provide MAP Training to women with a history of sexual trauma. It is hypothesized that trauma-exposed women who participate in MAP Training will ruminate less while expressing greater neurocognitive control than after meditation or aerobic exercise alone interventions. Secondly, it is hypothesized that MAP Training will increase neural processing of temporal information, which will relate to changes in time perspective from the past toward the present. Our goal is to establish MAP Training as an effective clinical intervention for women with a history of sexual trauma, while identifying neurocognitive and neurotemporal mechanisms involved in learning to recover.
(7) Namas Chandra (NJIT) and Viji Santhakumar (RBHS-NJMS) (funded by NJIT)
Biomechanical differences in injury rate determine neurological outcomes after blast and impact TBI
Blast-related traumatic brain injury (bTBI) is the signature injury of combat troops in recent wars and leads to long-term physical, mental and cognitive deficits. Blast TBI (bTBI) is defined as an injury due to “primary” blast wave exposure and impact TBI (iTBI) as injury due to “blunt-force or impact”. Although impact TBI is known to contribute to development of post traumatic epilepsy (PTE), the risk for PTE following blast injury is not known. The inherently distinct biomechanical characteristics of blast and impact injuries and the corresponding brain tissue responses suggest that the mechanisms and risk for PTE after blast may differ from those following impact injuries. A critical step towards offering both better diagnostic and treatment regiments is to characterize how blast exposure and blunt-force/impact TBI lead to the development of post traumatic epilepsy (PTE) under typical blast combat-relevant scenarios, and this is the main goal of this proposal. Using a field-validated shock tube and blast induced animal TBI model, we propose to identify the risk for post traumatic epilepsy and identify the mechanisms, early behavioral and cellular markers of blast TBI and long-term co-morbidity in memory function as a function of mild and moderate blast injury, based on electrophysiology, behavior and histology. The discovery of the specific risk for PTE after bTBI and the underlying mechanisms is a necessary first step towards improved diagnostic tools, follow up assessment and treatment regimens.
(8) Mark Gluck (CMBN, RU-Newark) and Daniel Schneider (RBHS-RWJMS) (funded by RU-Nwk)
Neurocognitive and Brain imaging Biomarkers that Track the Progression of Striatal Neurodegeneration in Early Prodromal Huntington’s Disease
In this proposal to the 2016 Rutgers BHI-RUN-NJIT Pilot Grants Program in Neuroscience, we seek to collect pilot data in an effort to understand the neurobiological and cognitive processes underlying prodromal cognitive and neurocognitive changes in Huntington’s disease (HD) gene carriers many years before symptom onset. HD is a hereditary, progressive neurodegenerative disease, caused by an expanded trinucleotide CAG sequence in the HD gene on chromosome 4. We will evaluate how CAG repeat length is correlated with (1) behavioral studies of learning from reward versus punishment as well as, (2) event-related brain activation and functional connectivity of the corresponding neural correlates during this task, and (3) how these behavioral and brain markers are modulated by striatal atrophy and neural degeneration. Successful pilot data from this project will allow us to submit next year a competitive R21 proposal to the NIH’s National Institute of Neurological Diseases and Stroke (NINDS), addressing the critical need for sensitive biomarkers that could be used in future drug evaluation studies to quickly and reliably assess the impact of early interventions that have potential to delay or reverse the progression towards debilitating symptom onset.
(9) Viji Santhakumar (RBHS-NJMS) and Tracy Tran (RU-Nwk) (funded by RU-Nwk)
Novel model targeting Semaphorin-Neuropilin Signaling in Inhibitory Circuit Development to examine mechanisms of Pediatric Epilepsy-Autism Comorbidity
The high comorbidity of epilepsy and autism spectrum disorders (ASD) has been suggested to result from shared pathological mechanisms involving abnormal development of inhibitory microcircuits. The goal of this study is to test the fundamental premise that deficits in establishment of normal inhibitory neuron networks during development underlies the shared outcome of epilepsy and autism. The experiments will determine the evolution of structural and functional changes to inhibitory neuron networks in a novel genetic model of autism-epilepsy syndrome to better understand the mechanistic logic underlying abnormal circuit features shared by both disorders and enable future therapeutic interventions. To achieve these goals, we will compare mice deficient in Neuropilin2 (Nrp2) a molecular cue important for establishing neuronal connections during development and is susceptible to epilepsy and autism. The study will use Nrp2 floxed mice with cell-type specific CreER animals to examine inhibitory and excitatory neuron structure and patterning in hippocampal circuits involved in seizure activity using quantitative anatomical techniques. Physiological characteristics of individual neurons and progressive alterations in overall circuit excitability and activity patterns over time will be evaluated to identify critical time windows and processes. The study will directly examine the development of epilepsy and autistic behaviors in models with selective inhibitory neuron deletion of Nrp2 or targeted suppression of inhibitory neuronal activity to resolve the principal trigger for circuit changes underlying epilepsy and autism. These studies will develop mechanistic insights into cellular, molecular, genetic and systems-level changes in interneuron circuits underlying childhood epilepsy autism comorbidity.