2019 Rutgers BHI-RUNB Pilot Grants in Neuroscience have been awarded
We received 11 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 4 applications for funding. The investigator teams that were funded included-
(1) Mladen-Roko Rasin (RBHS-RWJMS), Wei Dai (RU-NB-SAS) and Jason Kaelber (RU-NB-SAS) (funded by Office of the VCRI, RU-NB)
Architecture of ribosome heterogeneity in developing neocortex under the control of RNA binding proteins
Formation of initial synapses within a prenatal neocortex lays the foundation for complex circuits to form. When mature, these circuits encode complex behaviors specific to the neocortex. Thus, forming the correct initial synapses is essential for the successful establishment of later complex central nervous system functions. First synapses are formed within the prenatal neocortices of both mice and human in two specialized zones, the marginal zone and subplate. However, we do not fully understand molecular and cellular mechanisms for these unique synapses to form in either of the two zones. Here, we hypothesize that an RNA binding protein Celf4 dictates the formation of first neocortical synapses in marginal zone and subplate through regulation of the mRNA translation and ribosome heterogeneity. To test this hypothesis, we will use powerful combination of mouse genetics, polysome fractionation and CryoEM analysis.
(2) David Barker (RU-NB-SAS; BHI) and Ping-Yue Pan (RBHS-RWJMS) (funded by Office of the VCRI, RU-NB)
Genetic predisposition to cocaine tolerance
Substance use disorder is characterized by uncontrollable drug seeking behavior and plastic changes in the mesolimbic dopamine system. One of the most highly abused drugs, Cocaine, acts by preventing the reuptake of dopamine at the synapse by blocking the dopamine transporter (DAT). The chronic blockade of DAT often leads to altered DAT expression / activity as well as upregulation of mTOR. Accordingly, inherent genetic differences that affect levels of DAT or mTOR may change an individual’s susceptibility to cocaine abuse. Defining such molecular underpinnings may provide new avenues for revelation of druggable targets. In the present study, we propose to investigate the SYNJ1 gene, which is implicated in multiple dopamine-related disorders including bipolar disorder, schizophrenia and Parkinsonism. In our preliminary studies of the SYNJ1 +/- mice, we found striatal dopamine depletion accompanied by increased levels of brain mTOR and DAT, suggesting a profoundly altered dopaminergic system. As elevated levels of mTOR and DAT are essential neuroadaptations following chronic drug use, the goal of the present study is to determine what role SYNJ1 plays in altering mesolimbic function, motivated behavior, and drug abuse susceptibility. We hypothesize that SYNJ1 deficiency causes elevated basal levels of mTOR and DAT within the mesolimbic dopamine system and that these changes are associated with a blunted dopaminergic response that may ultimately modulate reward valence and produce cocaine tolerance. We will test this hypothesis using behavioral and cellular / biochemical strategies aiming to gain molecular insight in genetic predisposition in reward processing and cocaine drug addiction.
(3) Christopher Pierce (RBHS-RWJMS/BHI) and Zhiping Pang (RBHS-RWJMS) (funded by BHI)
Deep Brain Stimulation as an Anti-Cocaine Craving Therapeutic
This grant will exploit recent methodological advances in order to examine the mechanisms underlying the ability of nucleus accumbens deep brain stimulation (DBS) to attenuate the reinstatement of cocaine seeking, an animal model of relapse. We will assess the behavioral and neuronal effects of DBS-like stimulation induced by light activation of channelrhodopsin expressed in specific neuronal subtypes. Neuronal specificity in the optogenetic experiments will be achieved through the use of transgenic rat lines that express Cre recombinase selectively in D1 dopamine receptor (D1DR)- or D2DR-expressing medium spiny neurons (MSNs) in the nucleus accumbens. DBS will be mimicked with optogenetic activation of D1DR- or D2DR-expressing neurons in the accumbens shell. Field and patch clamp recordings from shell neurons will assess the effects of increasing frequencies on neuronal activity. Parallel behavioral experiments will assess the effects of DBS-like optogenetic stimulation on cocaine priming-induced reinstatement of cocaine seeking in male and female rats. The results of pilot priming-induced reinstatement experiments indicate that DBS-like optogenetic stimulation of D2DR-containing, but not D1DR-expressing, accumbens neurons attenuates drug seeking by suppressing activity in these neurons. Identifying the specific mechanisms by which DBS influences cocaine reinstatement will provide critical new information that will lay for the groundwork for future targeted therapeutics for cocaine addiction.
(4) John Pintar (RBHS-RWJMS) and Patricia Soteropoulos (RBHS-NJMS) (funded by BHI)
Genetic studies of opioid system function
We propose to continue discovery-based studies to characterize a novel analgesic system that, quite unexpectedly, is upregulated or unmasked in a mouse strain-dependent manner following genetic ablation of the delta opioid receptor (DOR-1). This novel analgesic system was initially observed during analysis of DOR- 1 KO mice produced in our laboratory. Surprisingly, traditional delta agonists such as DPDPE still retained analgesic potency in these DOR-1 KO mice that were initially studied while on an outbred genetic background. In addition, atypical opioid agonists such as the non-peptide BW-373U86, which had no analgesic potency in wild type mice, produced robust analgesia reaching cut-off in single and combinatorial mouse genotypes lacking DOR-1 KO but not in mice lacking other opioid receptors. We then produced DOR-1 KO mice isogenic/congenic on both the C57Bl6 and 129S6 backgrounds. Remarkably, we have found that the novel analgesic system, assayed by BW363U86 analgesia, is differentially expressed in these two background strains of DOR-1 KO mice. The robust strain difference in sensitivity to BW-373U86 suggested that QTL mapping should potentially allow us to identify the chromosomal region/s (and ultimately the genes) comprising or regulating this novel analgesic system. Preliminary data support this possibility and lead us to propose the following aims for this BHI Pilot Grant application:
1. To identify chromosomal loci required for expression of this novel delta-like analgesic system.
2. To begin to identify and characterize the genes responsible for the novel analgesic system.
We expect results from these pilot studies will identify specific candidate genes relevant to the delta-like analgesic system that can be basis for subsequent, direct experimental tests in subsequent applications.