Biology subjects

Bryant, C. D.

Publications and source records attributed to Bryant, C. D..

4 recordsLinked to original sources

bioRxiv2018

C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception

Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freunds Adjuvant (CFA) model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic nerve constriction injury (CCI), a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-CCI. We replicated the enhanced thermal nociception in the 52.5{degrees}C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J x B6N-F2 cross (N=164), we mapped a major quantitative trait locus (QTL) underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (LOD=3.81, p<0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression QTLs (eQTLs) associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (FDR < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.

genetics↗

bioRxiv2018

Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation

RNA binding proteins are a diverse class of proteins that regulate all aspects of RNA metabolism. Accumulating studies indicate that heterogeneous nuclear ribonucleoproteins are associated with cellular adaptations in response to drugs of abuse. We recently mapped and validated heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1) as a quantitative trait gene underlying differential behavioral sensitivity to methamphetamine. The molecular mechanisms by which hnRNP H1 alters methamphetamine behaviors are unknown but could involve preand/or post-synaptic changes in protein localization and function. Methamphetamine initiates post-synaptic D1 dopamine receptor signaling indirectly by binding to pre-synaptic dopamine transporters and vesicular monoamine transporters of midbrain dopaminergic neurons which triggers revers e transport and accumulation of dopamine at the synapse. Here, we examined changes in neuronal localization of hnRNP H in primary rat cortical neurons that express dopamine receptors that can be modulated by the D1 or D2 dopamine receptor agonists SKF38393 and (-)-Quinpirole HCl, respectively. Basal immunostaining of hnRNP H was localized primarily to the nucleus. D1 dopamine receptor activation induced an increase in hnRNP H nuclear immunostaining as detected by immunocytochemistry with a C-domain directed antibody containing epitope near the glycine-rich domain but not with an N-domain specific antibody. Although there was no change in hnRNP H protein in the nucleus or cytoplasm, there was a decrease in Hnrnph1 transcript following D1 receptor stimulation. Taken together, these results suggest that D1 receptor activation increases availability of the hnRNP H C-terminal epitope, which could potentially reflect changes in protein-protein interactions. Thus, D1 receptor signaling could represent a key molecular post-synaptic event linking Hnrnph1 polymorphisms to drug-induced behavior.\n\nHighlightsO_LIWe investigated immunofluorescence and localization of hnRNP H following dopamine receptor activation in primary rat cortical neurons.\nC_LIO_LIActivation of D1 dopamine receptor increased nuclear immunofluorescence of the C-terminal domain but not the N-terminal domain of hnRNP H with no change in either nuclear or cytoplasmic levels of hnRNP H protein.\nC_LIO_LID1 dopamine signaling could alter interaction of hnRNP H with other proteins.\nC_LI

neuroscience↗

bioRxiv2018

Cyfip1 haploinsufficiency increases compulsive-like behavior and paternally inherited palatable food intake: Implications for Prader-Willi Syndrome

Binge eating (BE) is a heritable trait associated with eating disorders and involves rapid consumption of large quantities of food. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 - one of four paternally-deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance premorbid compulsive-like behavior and palatable food (PF) intake in a parent-of-origin-selective manner. We tested Cyfip1+/- mice on a C57BL/6N (N) background that were homozygous for the BE-associated missense mutation in Cyfip2 (S968F) as well as mice that we backcrossed to homozygosity for the C57BL/6J (J) allele at Cyfip2 (Cyfip2J/J). Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds, increased PF consumption on the Cyfip2N/N background in a paternally-enhanced manner, and decreased PF consumption in male Cyfip1+/- mice on the Cyfip2J/J background in a maternally selective manner. In the hypothalamus, there was a maternally-enhanced reduction of Cyfip1 transcription, but a paternally-enhanced reduction in CYFIP1 protein. In the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Together, increased compulsive-like behavior, parent-of-origin-, and genetic background-dependent effects of Cyfip1 haploinsufficiency on PF consumption implicate CYFIP1 in behaviors in neurodevelopmental disorders involving reduced expression of CYFIP1, including PWS, Fragile X Syndrome, and 15q11.2 Microdeletion Syndrome.

genetics↗

bioRxiv2017

Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains

Binge eating (BE) is a heritable symptom of eating disorders associated with anxiety, depression, malnutrition, and obesity. Genetic analysis of BE could facilitate therapeutic discovery. We used an intermittent, limited access BE paradigm involving sweetened palatable food (PF) to examine genetic differences in BE, conditioned food reward, and compulsive-like eating between C57BL/6J (B6J) and DBA/2J (D2J) inbred mouse strains. D2J mice showed a robust escalation in intake and conditioned place preference for the PF-paired side. D2J mice also showed a unique style of compulsive-like eating in the light/dark conflict test where they rapidly hoarded and consumed PF in the preferred unlit environment. BE and compulsive-like eating exhibited narrow-sense heritability estimates between 56 and 73 percent. To gain insight into the genetic basis, we phenotyped and genotyped a small cohort of 133 B6J x D2J-F2 mice at the peak location of three quantitative trait loci (QTL) previously identified in F2 mice for sweet taste (chromosome 4: 156 Mb), bitter taste (chromosome 6: 133 Mb) and behavioral sensitivity to drugs of abuse (chromosome 11: 50 Mb). The D2J allele on chromosome 6 was associated with greater PF intake on training days and greater compulsive-like PF intake, but only in males, suggesting that decreased bitter taste may increase BE in males. The D2J allele on chromosome 11 was associated with an increase in final PF intake and slope of escalation across days. Future studies employing larger crosses and genetic reference panels comprising B6J and D2J alleles will identify causal genes and neurobiological mechanisms.

animal behavior and cognition↗