2015 Rutgers BHI-RUN-NJIT Pilot Grants in Neuroscience have been awarded
We received 27 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) Bin Tian (RBHS-NJMS) and Zhiping Pang (RBHS-RWJMS) (funded by BHI)
Post-transcriptional gene regulation in normal and diseased neurons
Trisomy 21 (TS21, a.k.a. Down syndrome) is the most common genetic form of intellectual disability, and is caused by inheriting three copies of chromosome 21 (HSA21). HSA21 codes 161 known coding sequences and 5 miRNAs (miR-99a, let-7c, miR-125b-2, miR-155 and miR-802), resulting in extra copy of each gene in TS21 individuals. As such, misregulation of gene expression at the post-transcriptional level is expected in TS21 neurons. However, this has never been examined. As first reported by the Tian lab about ten years ago, the 3’ untranslated regions (3’UTRs) of mRNAs are significantly longer in neuronal cells than in other cell types. This is due to alternative cleavage and polyadenylation (APA), an RNA processing step in which different cleavage and polyadenylation sites (pAs) are chosen to generate mRNA isoforms. However, the biological mechanism(s) of APA leading to long 3’UTRs in neuronal cells is not known, nor is its consequences for neuronal functions. Most mRNAs are regulated by cis elements in their 3’UTRs, including sites targeted by microRNAs (miRNAs) and bound by RNA-binding proteins (RBPs). The objectives of this project are to 1) examine how 3’UTR isoforms are expressed during neurogenesis of normal and TS21 cells; and 2) how post-transcriptional regulation is executed in normal and TS21 neurons.
(2) John Pintar (RBHS-RWJMS) and Alexander Kusnecov (RU-NB) (funded by BHI)
A novel ligand receptor system for treatment of chronic stress
We have obtained preliminary evidence from gene targeted mice produced in house that the orphanin FQ peptide, one of the opioid family of peptides, limits detrimental cytokine responses that accompany chronic stress. Thus agonists for this peptide may represent novel treatments for this condition. In this pilot grant, we propose two aims that will confirm and extend our preliminary data and provide information needed for a successful NIH application. In the first aim, we will determine whether there are genotype (OFQ ligand vs. OFQ receptor KO), sex, and (if time permits) mouse strain background effects on the increased IL-1? levels initially found to accompany OFQ deletion in C57Bl6/J OFQ male mice when subjected to chronic unpredictable stress. In addition, we will investigate a potential cellular basis for this response by producing mice with microglia labeled with eGFP and then beginning to compare the responses of these eGFP-labelled microglia (a likely site of action of OFQ effects) from WT and OFQ receptor KO mice. In the second aim, similar cohorts of mice will be bred, exposed to unpredictable stress and then used for a focused sequential battery of behavioral tests to evaluate learning and memory and anxiety including the Y-maze, the Morris water maze, elevated plus maze, and light-dark box Together these experiments are expected to provide critical information regarding the role of the OFQ system in response to chronic stress and to identify the most promising approaches for future grant applications when additional cytokines, microglia responses, and behaviors can be evaluated in conjunction with OFQ system agonists and antagonists.
(3) Vanessa Routh (RBHS-NJMS) and Nicholas Bello (RU-NB) (funded by BHI)
The role of orexin in binge eating behavior and ventral tegmental glutamate plasticity
Binge eating remains a major obstacle in the effective treatment for bulimia nervosa and binge eating disorder. Unlike simple overeating, bingeing is accompanied by a sense of a “loss of control” over how much is eaten. The underlying mechanisms of binge eating are poorly understood, but strongly resemble the compulsive intake
demonstrated with the ingestion of drugs of abuse and alcohol. Although bulimia nervosa and binge eating disorder are different psychiatric disorders, several risk factors and triggers have been associated with binge eating. Of these, repeated episodes of prolonged calorie restriction (i.e. bouts of fasting) for bulimia nervosa or intermittent dieting for binge eating disorder have been strongly associated with the entrainment of binge eating. Our goal is to specifically determine how repeated intermittent caloric restriction contributes to the sustained neurological changes that promote the binge eating of sugary fat pleasurable foods.
(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 (NP) is a common disease that arises as a direct consequence of a lesion or disease affecting the somatosensory system. It is most often associated with an injury or a disease affecting peripheral nerve fibers. Prominent features in the pathophysiology of neuropathic pain are ectopic and increased neuronal activity. Currently there are no effective NP treatments available. The management of painful traumatic trigeminal neuropathies (PTTN) relies on pharmacologic agents with severe side effects and very low success rates. An attractive therapeutic possibility is the transfection of a new class of receptors termed DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). This chemogenetic approach has been used to achieve localized inhibition and suppression of neuronal excitability via viral expression of the synthetic Gi-coupled GPCR receptor known as hM4Di. The hM4Di receptor is activated by the otherwise inert ligand clozapine N-oxide (CNO). Most importantly, hM4Di is essentially insensitive to acetylcholine or other brain chemicals, and thus exhibits no effects in the absence of its selective agonist (CNO). The ability to target and transiently suppress neuronal excitability, without permanently altering other neuronal properties, via the systemic delivery of a small molecule inhibitor makes the hM4Di DREADD an attractive focused gene therapy approach for neuropathic pain. Therefore, this research aims to investigate the potential of hM4Di expressing DREADDs as therapeutic agent for trigeminal neuropathic pain.
(5) Joshua Berlin (RBHS-NJMS) and Bryan Pfister (NJIT) (funded by NJIT)
Novel cellular approach to study acute neuronal hyperexcitability in TBI
This project explores mechanisms underlying development of seizures in the immediate aftermath of traumatic brain injury (TBI). Early onset seizures are among the most serious morbidities with traumatic TBI. Yet our understanding of the mechanisms that precipitate early seizures is quite incomplete. To address this gap in our understanding, we modified an in vitro TBI stretch injury model using networks of cultured cortical neurons in which injury is confined to a localized area, but neuron electrical activity can be measured almost immediately. Our novel finding is that hyperexcitability, i.e. dramatically increased spontaneous action potential and bursting activity, is observed within minutes after stretch injury, but only in “non-injured” neurons located away from the injury site. This hyperexcitability in the non-injured neurons is analogous to activity patterns in in vivo models of TBI where hyperexcitability is thought to precipitate seizure-like discharges. Because hyperexcitability is observed in non-injured neurons only, we hypothesize that reduced inhibitory neurotransmission from injured neurons disinhibits electrical activity in surrounding non-injured neurons. To test this hypothesis, (1) we will determine whether acute hyperexcitability is due to changes in excitatory or inhibitory neurotransmission from injured neurons or due to intrinsic changes in non-injured neurons using electrophysiologic and histologic approaches; (2) we will determine how acute hyperexcitability in non-injured neurons arises from altered dynamics of adjoining injured neurons using genetically-encoded membrane potential sensors and high speed imaging to map spatiotemporal changes in electrical activity in physically and functionally defined neurons.
(6) Radek Dobrowolski (RU-Nwk) and Hieronim Jakubowski (RBHS-NJMS) (funded by RU-Nwk)
mTOR Signaling and Homocysteine in the Brain
Sporadic Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with aging, which is characterized by a systemic decline of metabolic processes, including homocysteine (Hcy) metabolism. Indeed, patients with elevated total plasma Hcy levels are at high risk of developing Alzheimer’s disease. Despite its established impact on human health and disease, the molecular mechanisms facilitated by HHcy are largely unknown. Our preliminary data suggests that one of the major cellular kinases, the mechanistic target of Rapamycin complex 1 (mTORC1), is up-regulated by Hcy. We propose to investigate this molecular pathway (Hcy ==> mTOR --| clearance/autophagy ==| protein aggregation ==> neurodegeneration) in vivo, in Cbs-KO mice, and in vitro, using induced pluripotent stem cells (iPSCs)-derived human neurons, a promising new tool to study dementia.
(7) Viji Santhakumar (RBHS-NJMS) and Tracy Tran (RU-Nwk) (funded by RU-Nwk)
Role of Semaphorin-Neuropilin Signaling in Hippocampal Interneurons and Epilepsy
Diverse GABAergic interneurons are essential for information processing and maintaining optimal network excitability1. Developmental and acquired deficits in inhibitory neuron diversity, connectivity and function lead to multiple neurological disorders which are collectively termed as interneuronopathies and include childhood epilepsies and autism spectrum disorders (ASD) which show significant co-morbidity. Interactions between semaphorins (Semas), a class of secreted and membrane-associated proteins, and their multimeric receptors, including Neuropilins (Nrps), are essential for patterning neural circuits and influence cell shape, differentiation, motility and survival. Specifically, Neuropilin (Nrp)2 is expressed in and regulated by the transcription factor Nkx2.1 which is present in inhibitory neuron precursor cells in the median ganglionic eminence (MGE). Here we focus on hippocampal and dentate circuits, which show structural and functional plasticity in epilepsy and ASD, to examine how Sema/Nrp signaling impacts network inhibition. The proposed studies will fill a critical knowledge gap concerning developmental role of Sema/Nrp signaling in the establishment of interneuron morphology and networks and their role in interneuronopathies relevant to epilepsy/ASD syndromes.
(8) David Margolis (RU-NB) and James Tepper (RU-Nwk) (funded by RU-Nwk)
Role of Sensory Cortex in Behavioral Response Inhibition
Beyond its traditional role as an early-stage relay of tactile information, the primary somatosensory cortex (S1) has an increasingly appreciated role in sensorimotor behavior and motor control. Our proposed experiments explore the hypothesis that S1 is involved in sensory-driven behavioral response inhibition via differential connectivity with neural circuits of the striatum. Response inhibition, the ability to stop a goal-directed behavior in the appropriate context, is fundamental for the cognitive control of behavior. Impaired response inhibition underlies impulsive behaviors present across many neurological and neuropsychiatric disorders, such as Tourette’s syndrome, attention-deficit hyperactivity disorder (ADHD), and addiction disorders. While current thinking holds that signaling from prefrontal cortex to striatum mediates response inhibition, this idea may be too simplistic; other cortical areas including S1 provide massive projections to the dorsal striatum (DStr) that could play important functional roles, especially during specific behavioral contexts. The proposed research will investigate the functional circuitry of S1-mediated response inhibition using an integrative experimental approach including optogenetics, mouse behavior and electrophysiology. The results have the potential not only to change current thinking about the role of S1-DStr projections in behavioral control, but could also identify S1-DStr signaling as a potential therapeutic target in disorders involving impulsive behaviors.
(9) Bart Krekelberg (RU-Nwk) and Brian Keane (RBHS-UBHC) (funded by RU-Nwk)
Therapeutic effects of transcranial alternating current stimulation in schizophrenia
Schizophrenia (Sz) is a severe and disabling brain disorder that affects approximately 1% of the population. Even though the psychotic symptoms of schizophrenia are better known, patients display significant cognitive deficits; these are stable throughout the course of the disease, better prodromal indicators of disease progression than many traditional neuropsychological tests, and promising biomarkers for drug development. In the current proposal we focus on visual cognitive deficits such as the reduced integration of spatial context (e.g. reduced contour integration) or temporal context (e.g. reduced orientation-contingent color aftereffects). These behavioral phenomena are reliable indicators of neural processing deficits, and they can be measured repeatedly and quantitatively. Moreover, these visual cognitive deficits are associated with aberrant neural dynamics –predominantly in the gamma range– in visual cortex. Our innovative proposal is to use transcranial current stimulation to target these aberrant neural dynamics for therapeutic purposes.