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Byron Jones

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University of York

University of Washington

Massachusetts Institute of Technology (MIT)

Sergei Shchebetenko

National Research University “Higher School of Economics” (HSE), Moscow, Russia

Friederike Moltmann

Centre National de la Recherche Scientifique / French National Centre for Scientific Research

University of Belgrade

José Ignacio Pichardo Galán

Universidad Complutense de Madrid

University of Massachusetts Amherst

Caroline Humphrey

University of Cambridge

University of Salamanca

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Papers by Byron Jones

Dietary iron deficiency in BXD strain 40 mice causes diurnal‐dependent alterations in brain iron and activity

The FASEB Journal

Genetic Contribution to Initial and Progressive Alcohol Intake Among Recombinant Inbred Strains of Mice

Frontiers in genetics, 2018

We profiled individual differences in alcohol consumption upon initial exposure and during 5 week... more We profiled individual differences in alcohol consumption upon initial exposure and during 5 weeks of voluntary alcohol intake in female mice from 39 BXD recombinant inbred strains and parents using the drinking in the dark (DID) method. In this paradigm, a single bottle of 20% (v/v) alcohol was presented as the sole liquid source for 2 or 4 h starting 3 h into the dark cycle. For 3 consecutive days mice had access to alcohol for 2 h followed by a 4th day of 4 h access and 3 intervening days where alcohol was not offered. We followed this regime for 5 weeks. For most strains, 2 or 4 h alcohol intake increased over the 5-week period, with some strains demonstrating greatly increased intake. There was considerable and heritable genetic variation in alcohol consumption upon initial early and sustained weekly exposure. Two different mapping algorithms were used to identify QTLs associated with alcohol intake and only QTLs detected by both methods were considered further. Multiple sugges...

Integrating Genetic and Gene Co-expression Analysis Identifies Gene Networks Involved in Alcohol and Stress Responses

Frontiers in molecular neuroscience, 2018

Although the link between stress and alcohol is well recognized, the underlying mechanisms of how... more Although the link between stress and alcohol is well recognized, the underlying mechanisms of how they interplay at the molecular level remain unclear. The purpose of this study is to identify molecular networks underlying the effects of alcohol and stress responses, as well as their interaction on anxiety behaviors in the hippocampus of mice using a systems genetics approach. Here, we applied a gene co-expression network approach to transcriptomes of 41 BXD mouse strains under four conditions: stress, alcohol, stress-induced alcohol and control. The co-expression analysis identified 14 modules and characterized four expression patterns across the four conditions. The four expression patterns include up-regulation in no restraint stress and given an ethanol injection (NOE) but restoration in restraint stress followed by an ethanol injection (RSE; pattern 1), down-regulation in NOE but rescue in RSE (pattern 2), up-regulation in both restraint stress followed by a saline injection (R...

$Research paper thumbnail of {"__content__"=>"The genetic dissection ofgene expression in the retinas of BXD mice.", "i"=>{"__content__"=>"Myo7a"}}$

{"__content__"=>"The genetic dissection ofgene expression in the retinas of BXD mice.", "i"=>{"__content__"=>"Myo7a"}}

Molecular vision, 2018

Usher syndrome (US) is characterized by a loss of vision due to retinitis pigmentosa (RP) and dea... more Usher syndrome (US) is characterized by a loss of vision due to retinitis pigmentosa (RP) and deafness. US has three clinical subtypes, but even within each subtype, the severity varies. Myosin VIIA, coded by, has been identified as one of the causal genes of US. This study aims to identify pathways and other genes through whichinteracts to affect the presentation of US symptoms. In this study, we used the retinal tissue of BXD recombinant inbred (RI) mice to examine the expression ofand perform genetic mapping. Expression quantitative trait locus (eQTL), single nucleotide polymorphism (SNP), and gene correlation analysis were performed using GeneNetwork. Gene set enrichment analysis was performed using WebGestalt, and gene network construction was performed using the Gene Cohesion Analysis Tool. We foundto be-regulated, with varied levels of expression across BXD strains. Here, we propose a genetic network with 40 genes whose expression is highly correlated with. Among these genes,...

Lateralized Basal Ganglia Vulnerability to Pesticide Exposure in Asymptomatic Agricultural Workers

Toxicological Sciences

Pesticide exposure is linked to Parkinson's disease, a neurodegenerative disorder marked by dopam... more Pesticide exposure is linked to Parkinson's disease, a neurodegenerative disorder marked by dopamine cell loss in the substantia nigra of the basal ganglia (BG) that often presents asymmetrically. We previously reported that pesticideexposed agricultural workers (AW) have nigral diffusion tensor imaging (DTI) changes. The current study sought to confirm this finding, and explore its hemisphere and regional specificity within BG structures using an independent sample population. Pesticide exposure history, standard neurological exam, high-resolution magnetic resonance imaging (T1/T2weighted and DTI), and [ 123 I]ioflupane SPECT images (to quantify striatal dopamine transporters) were obtained from 20 AW with chronic pesticide exposure and 11 controls. Based on median cumulative days of pesticide exposure, AW were subdivided into high (AW Hi , n ¼ 10) and low (AW Lo , n ¼ 10) exposure groups. BG (nigra, putamen, caudate, and globus pallidus [GP]) fractional anisotropy (FA), mean diffusivity (MD), and striatal [ 123 I]ioflupane binding in each hemisphere were quantified, and compared across exposure groups using analysis of variance. Left, but not right, nigral and GP FA were significantly lower in AW compared with controls (p's < .029). None of the striatal (putamen and caudate) DTI or [ 123 I]ioflupane binding measurements differed between AW and controls. Subgroup analyses indicated that significant left nigral and GP DTI changes were present only in the AW Hi (p .037) but not the AW Lo subgroup. AW, especially those with higher pesticide exposure history, demonstrate lateralized microstructural changes in the nigra and GP, whereas striatal areas appear relatively unaffected. Future studies should elucidate how environmental toxicants cause differential lateralized-and regionally specific brain vulnerability.

Dissection of Z-disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach

World journal of cardiology, Jan 26, 2017

To investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in res... more To investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in restrictive cardiomyopathy (RCM). Gene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomics data were collected from Mypn knock-in and knock-out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify Mypn regulation, gene pathway and co-expression networks. A wide range of variation was found in expression of Mypn among BXD strains. We identified upstream genetic loci at chromosome 1 and 5 that modulate the expression of Mypn. Candidate genes within these loci include Ncoa2, Vcpip1, Sgk3, and Lgi2. We also identified 15 sarcomeric genes interacting with Mypn and constructed the gene network. Two novel members of this network (Syne1 and Myom1) have been confirmed at the protein level. Several members in this network are already known to r...

The effect of alcohol on the differential expression of cluster of differentiation 14 gene, associated pathways, and genetic network

PloS one, 2017

Alcohol consumption affects human health in part by compromising the immune system. In this study... more Alcohol consumption affects human health in part by compromising the immune system. In this study, we examined the expression of the Cd14 (cluster of differentiation 14) gene, which is involved in the immune system through a proinflammatory cascade. Expression was evaluated in BXD mice treated with saline or acute 1.8 g/kg i.p. ethanol (12.5% v/v). Hippocampal gene expression data were generated to examine differential expression and to perform systems genetics analyses. The Cd14 gene expression showed significant changes among the BXD strains after ethanol treatment, and eQTL mapping revealed that Cd14 is a cis-regulated gene. We also identified eighteen ethanol-related phenotypes correlated with Cd14 expression related to either ethanol responses or ethanol consumption. Pathway analysis was performed to identify possible biological pathways involved in the response to ethanol and Cd14. We also constructed a genetic network for Cd14 using the top 20 correlated genes and present sev...

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

Alcohol (Fayetteville, N.Y.), Jan 16, 2016

Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In t... more Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intraperitoneal (i.p.) injection of 1.8 g/kg ethanol or saline, and subsets of both groups were exposed to acute restraint stress for 15 min or controls. Gene expression in the hippocampus was examined using microarray analysis. Genes that were significantly (p < 0.05, q < 0.1) differentially expressed were further evaluated. Bioinformatic analyses were predominantly performed using tools available at GeneNetwork.org, and included gene ontology, presence of cis-regulation or polymorphisms, phenotype correlations, and principal component analyses. Comparisons of differential gene expression between groups showed little overlap. Gene Ontology demonstrated distinct biological processes in ea...

Nutrition for Brain Health and Cognitive Performance

Nutritional neuroscience, 2016

Preweaning iron deficiency increases non-contingent responding during cocaine self-administration in rats

Physiology & behavior, Dec 14, 2016

Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidenc... more Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidence that ID early in development (preweaning in rat) causes irreversible neurologic, behavioral, and motor development deficits. Many of these effects have been attributed to damage to dopamine systems, including ID-induced changes in transporter and receptor numbers in the striatum and nucleus accumbens. These mesolimbic dopaminergic neurons are, in part, responsible for mediating reward and thus play a key role in addiction. However, there has been relatively little investigation into the behavioral effects of ID on drug addiction. In 2002, we found that rats made ID from weaning (postnatal day 21) and throughout the experiment acquired cocaine self-administration significantly more slowly than controls and failed to increase responding when the dose of the drug was decreased. In the present study, we assessed addiction for self-administered cocaine in rats with a history of preweaning I...

Iron in the Brain

Nutr Rev, 2009

The results of our studies of iron in three brain structures, substantia nigra (SN), globus palli... more The results of our studies of iron in three brain structures, substantia nigra (SN), globus pallidus (GP), and hippocampus (Hip), are presented. Mössbauer spectroscopy, electron microscopy and ELISA (enzyme-linked immuno-absorbent assay) were applied. Mössbauer studies show that most of the iron in the brain is ferritin-like. The concentration of iron is similar in SN and GP, but less than half of this in Hip. ELISA studies showed that the H/L ratio of ferritin in SN and GP is also similar, but is about three times higher in Hip. These results suggest that the role of iron in SN and GP may be different from that in Hip. Electron microscopy shows that the diameters of the ferritin iron cores in the brain are smaller that in the liver (3.5 ± 0.5 nm vs. 6.0 ± 0.5 nm). Mössbauer studies yield the ratio between the concentration of iron in control and parkinsonian SN as 1.00 ± 0.13.

Dietary iron deficiency in strain 40 BXD mice causes diurnal-dependent alterations in brain iron and activity

The Faseb Journal, Mar 1, 2008

Ethanol Modulates Cocaine-Induced Behavioral Change in Inbred Mice

Pharmacology Biochemistry and Behavior, Mar 1, 1998

We recently conducted a study of the behavioral effects of combined cocaine and ethanol in geneti... more We recently conducted a study of the behavioral effects of combined cocaine and ethanol in genetically defined mice. Male and female C57BL/6 (B6) and DBA/2 (D2) were tested in an automated activity monitor on 2 consecutive days. On day 1, all animals received an IP injection of sterile saline and were placed into the activity monitor for 30 min. Behaviors measured were total distance traveled, stereotypy, nosepokes, and wall-seeking. On day 2, all animals were tested again for 15 min following injection of one of the following: saline, 10% v/v ethanol at 2.0 g kg(-1) or 2.0 g kg(-1) ethanol plus 5, 15, or 30 mg kg(-1) cocaine. Cocaine alone at the same doses was injected into separate groups of animals. For the B6 strain, the overall effect of ethanol was to reduce cocaine-induced locomotor stimulation; no consistent effect of ethanol on cocaine-induced locomotion was observed in D2 mice. Cocaine-induced inhibition of nosepokes in both strains and sexes was partially reversed by ethanol. Ethanol also partially reversed cocaine-elevated stereotypy in both strains and both sexes. In B6 mice, cocaine-increased wall seeking tended to be reversed by coadministration of ethanol, whereas no consistent pattern was observed in the D2s. Results from this study suggest that the several measures affected by cocaine (locomotor activity, stereotypy, exploration, thigmotaxis) were, in turn, differentially affected by concurrent treatment with ethanol. Furthermore, our results point to genetic-based differences in ethanol&#39;s effects on cocaine-related behaviors. We address the implications for combined ethanol and cocaine use in humans.

Pharmacogenetics of cocaine: a critical review

Pharmacogenetics, 1995

The development of genetic models to help explain individual differences in sensitivity to and su... more The development of genetic models to help explain individual differences in sensitivity to and susceptibility to misuse certain CNS active substances, like ethanol and psychostimulants, spans a brief, thirty-plus years. The first animal models involved inbred strains and selected lines of mice and rats and predicted genetic-based differential sensitivity to ethanol and its misuse in humans found a few years later. With drugs like cocaine, tracking genetic differences in sensitivity and misuse liability in humans is difficult because of legal problems. Genetically-defined animals, however, have shown most if not all of cocaine-related behavioural, neurophysiological and toxicological effects to evince wide variation with most effects being influenced by several genes. Thus, we argue that animal and human studies of individual differences in drug sensitivity be studied from both quantitative and molecular genetic approaches. For the former, new techniques involving recombinant inbred strains of rodents, genetic correlational analysis and quantitative trait loci analysis are particularly useful, especially as genetic synteny between rodents and humans becomes better described. Also, because drug effects are highly labile to environmental conditions as well as genetic-based individual differences, multivariate, systems level studies should be developed to provide more complete descriptive and mechanistic views of a multifaceted problem.

Behavioral effects of THC as a function of environment and prior drug experience

Pharmacology Biochemistry and Behavior, Jan 31, 1987

effects of THC as a function of environment and prior drug experience. PHARMACOL BIOCHEM BEHAV 26... more effects of THC as a function of environment and prior drug experience. PHARMACOL BIOCHEM BEHAV 26(1) 141-144, 1987.--Holtzman albino rats were divided into 4 groups, and on 5 consecutive days each group was exposed to one of 4 conditions. The drug-adapted group was given delta-9-tetrahydrocannabinol (THC) (0.0, 0.5, 2.5 or 5.0 mg/kg PO) in their home cages, while the environment-adapted group was given vehicle and placed for one hr in the chamber where they were later tested. The naive group was given vehicle in their home cages and the drug + environment adapted group was given THC and placed in the test chamber. One week later, all rats were given either 0.0, 0.5, 2.5, or 5.0 mg/kg THC and placed in the test chamber where standing, sitting, and behavioral activity were measured. The results showed that the behavioral effects of THC are a function of environmental familiarity in rats who are drug naive but not in rats given prior exposure to THC.

Abnormal rat brain monoamine metabolism in iron deficiency anemia

The Journal of Nutritional Biochemistry, Sep 1, 1995

iron deficiency in rats produces numerous alterations rn hrarn metabolism as assessed by in vitro... more iron deficiency in rats produces numerous alterations rn hrarn metabolism as assessed by in vitro techniques. We used a new method of in vivo microdlalvsis to stud\ the effect of acute iron deficiency anemia on rat brain monoamine metabolism. This method n,aS used to sample extracellular fluid from an implanted microdialysis probe in the caudate putamen from freely moving animals. Method validation experiments showed that steadystate levels of dopamine. norepinephrine, and their metabolites were obtained only after 5 to 7 days of surgical recovery and with prior perfusion of the brain region. Caudate putamen dopamine was significantly increased 30% and 400/c in fasted light-exposed and 2-hr-fed dark-exposed iron deficient anemic rats (hemoglobin <6 gldL), respectively. relative to control rats. Dihydroxyphenyl acetic acid and homovanillic acid concentrations were unaffected by iron deficiency in the fasted stare. These metabolites. along with dopamine, increased significantly (50 to 8270) in iron deficient rats with e.rposure to darkness andfood while control rats' metabolites did not change. The present stud! documents that iron deficiency is associated with altered in vivo brain monoamine metabolism tn the steady state and in response to the environmental stimuli of food and darkness. While these data are supportive of the previous in vitro demonstrations of down-regulation of dopamine D, receptors, the? also suggest that uptake and processing of monoammes is significantly perturbed by iron deficiency. (J. Nutr. Biochem. 6:48ti93. 199.5.)

Genetic�environment analysis of sensitivity and acute tolerance to ethanol in mice

Pharmacology Biochemistry and Behavior, Jul 1, 2001

The purpose of this study was to characterize initial sensitivity (IS), acute functional toleranc... more The purpose of this study was to characterize initial sensitivity (IS), acute functional tolerance (AFT), and rate of tolerance development to ethanol in lines of mice selected for aggression mice as well as to investigate the impact of isolate housing on these phenotypes. The results showed that for IS, there were no differences among treatment groups. For acute tolerance and rate of tolerance development, a Line x Sex x Housing interaction was present, with the response to housing being more pronounced in the low aggressive line than the high aggressive line, and the females being more affected than the males. Correlational analysis showed low to moderate associations between rate of tolerance development and IS, as well as between rate of tolerance and AFT. Housing condition significantly influenced female expression of ethanol phenotypes as compared to males. The line of the subject also influenced the magnitude of expression of these phenotypes. These findings suggest that environmental and genetic influences interact to influence acute tolerance and rate of tolerance development.

Ethanol and MDMA: a comment on the paper by Dumont et al

Psychopharmacologia, Aug 28, 2008

EEG and Behavioral Effects of A9-Tetrahydrocannabinol in Combination with Stimulant Drugs in Rabbits

Psychopharmacology, 1976

EEG and behavioral effects of ?9-Tetrahydrocannabinol in combination with stimulant drugs in rabbits

Psychopharmacology, 1976

Dietary iron deficiency in BXD strain 40 mice causes diurnal‐dependent alterations in brain iron and activity

The FASEB Journal

Genetic Contribution to Initial and Progressive Alcohol Intake Among Recombinant Inbred Strains of Mice

Frontiers in genetics, 2018

We profiled individual differences in alcohol consumption upon initial exposure and during 5 week... more We profiled individual differences in alcohol consumption upon initial exposure and during 5 weeks of voluntary alcohol intake in female mice from 39 BXD recombinant inbred strains and parents using the drinking in the dark (DID) method. In this paradigm, a single bottle of 20% (v/v) alcohol was presented as the sole liquid source for 2 or 4 h starting 3 h into the dark cycle. For 3 consecutive days mice had access to alcohol for 2 h followed by a 4th day of 4 h access and 3 intervening days where alcohol was not offered. We followed this regime for 5 weeks. For most strains, 2 or 4 h alcohol intake increased over the 5-week period, with some strains demonstrating greatly increased intake. There was considerable and heritable genetic variation in alcohol consumption upon initial early and sustained weekly exposure. Two different mapping algorithms were used to identify QTLs associated with alcohol intake and only QTLs detected by both methods were considered further. Multiple sugges...

Integrating Genetic and Gene Co-expression Analysis Identifies Gene Networks Involved in Alcohol and Stress Responses

Frontiers in molecular neuroscience, 2018

Although the link between stress and alcohol is well recognized, the underlying mechanisms of how... more Although the link between stress and alcohol is well recognized, the underlying mechanisms of how they interplay at the molecular level remain unclear. The purpose of this study is to identify molecular networks underlying the effects of alcohol and stress responses, as well as their interaction on anxiety behaviors in the hippocampus of mice using a systems genetics approach. Here, we applied a gene co-expression network approach to transcriptomes of 41 BXD mouse strains under four conditions: stress, alcohol, stress-induced alcohol and control. The co-expression analysis identified 14 modules and characterized four expression patterns across the four conditions. The four expression patterns include up-regulation in no restraint stress and given an ethanol injection (NOE) but restoration in restraint stress followed by an ethanol injection (RSE; pattern 1), down-regulation in NOE but rescue in RSE (pattern 2), up-regulation in both restraint stress followed by a saline injection (R...

$Research paper thumbnail of {"__content__"=>"The genetic dissection ofgene expression in the retinas of BXD mice.", "i"=>{"__content__"=>"Myo7a"}}$

{"__content__"=>"The genetic dissection ofgene expression in the retinas of BXD mice.", "i"=>{"__content__"=>"Myo7a"}}

Molecular vision, 2018

Usher syndrome (US) is characterized by a loss of vision due to retinitis pigmentosa (RP) and dea... more Usher syndrome (US) is characterized by a loss of vision due to retinitis pigmentosa (RP) and deafness. US has three clinical subtypes, but even within each subtype, the severity varies. Myosin VIIA, coded by, has been identified as one of the causal genes of US. This study aims to identify pathways and other genes through whichinteracts to affect the presentation of US symptoms. In this study, we used the retinal tissue of BXD recombinant inbred (RI) mice to examine the expression ofand perform genetic mapping. Expression quantitative trait locus (eQTL), single nucleotide polymorphism (SNP), and gene correlation analysis were performed using GeneNetwork. Gene set enrichment analysis was performed using WebGestalt, and gene network construction was performed using the Gene Cohesion Analysis Tool. We foundto be-regulated, with varied levels of expression across BXD strains. Here, we propose a genetic network with 40 genes whose expression is highly correlated with. Among these genes,...

Lateralized Basal Ganglia Vulnerability to Pesticide Exposure in Asymptomatic Agricultural Workers

Toxicological Sciences

Pesticide exposure is linked to Parkinson's disease, a neurodegenerative disorder marked by dopam... more Pesticide exposure is linked to Parkinson's disease, a neurodegenerative disorder marked by dopamine cell loss in the substantia nigra of the basal ganglia (BG) that often presents asymmetrically. We previously reported that pesticideexposed agricultural workers (AW) have nigral diffusion tensor imaging (DTI) changes. The current study sought to confirm this finding, and explore its hemisphere and regional specificity within BG structures using an independent sample population. Pesticide exposure history, standard neurological exam, high-resolution magnetic resonance imaging (T1/T2weighted and DTI), and [ 123 I]ioflupane SPECT images (to quantify striatal dopamine transporters) were obtained from 20 AW with chronic pesticide exposure and 11 controls. Based on median cumulative days of pesticide exposure, AW were subdivided into high (AW Hi , n ¼ 10) and low (AW Lo , n ¼ 10) exposure groups. BG (nigra, putamen, caudate, and globus pallidus [GP]) fractional anisotropy (FA), mean diffusivity (MD), and striatal [ 123 I]ioflupane binding in each hemisphere were quantified, and compared across exposure groups using analysis of variance. Left, but not right, nigral and GP FA were significantly lower in AW compared with controls (p's < .029). None of the striatal (putamen and caudate) DTI or [ 123 I]ioflupane binding measurements differed between AW and controls. Subgroup analyses indicated that significant left nigral and GP DTI changes were present only in the AW Hi (p .037) but not the AW Lo subgroup. AW, especially those with higher pesticide exposure history, demonstrate lateralized microstructural changes in the nigra and GP, whereas striatal areas appear relatively unaffected. Future studies should elucidate how environmental toxicants cause differential lateralized-and regionally specific brain vulnerability.

Dissection of Z-disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach

World journal of cardiology, Jan 26, 2017

To investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in res... more To investigate the regulation of Myopalladin (Mypn) and identify its gene network involved in restrictive cardiomyopathy (RCM). Gene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomics data were collected from Mypn knock-in and knock-out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify Mypn regulation, gene pathway and co-expression networks. A wide range of variation was found in expression of Mypn among BXD strains. We identified upstream genetic loci at chromosome 1 and 5 that modulate the expression of Mypn. Candidate genes within these loci include Ncoa2, Vcpip1, Sgk3, and Lgi2. We also identified 15 sarcomeric genes interacting with Mypn and constructed the gene network. Two novel members of this network (Syne1 and Myom1) have been confirmed at the protein level. Several members in this network are already known to r...

The effect of alcohol on the differential expression of cluster of differentiation 14 gene, associated pathways, and genetic network

PloS one, 2017

Alcohol consumption affects human health in part by compromising the immune system. In this study... more Alcohol consumption affects human health in part by compromising the immune system. In this study, we examined the expression of the Cd14 (cluster of differentiation 14) gene, which is involved in the immune system through a proinflammatory cascade. Expression was evaluated in BXD mice treated with saline or acute 1.8 g/kg i.p. ethanol (12.5% v/v). Hippocampal gene expression data were generated to examine differential expression and to perform systems genetics analyses. The Cd14 gene expression showed significant changes among the BXD strains after ethanol treatment, and eQTL mapping revealed that Cd14 is a cis-regulated gene. We also identified eighteen ethanol-related phenotypes correlated with Cd14 expression related to either ethanol responses or ethanol consumption. Pathway analysis was performed to identify possible biological pathways involved in the response to ethanol and Cd14. We also constructed a genetic network for Cd14 using the top 20 correlated genes and present sev...

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

Alcohol (Fayetteville, N.Y.), Jan 16, 2016

Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In t... more Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intraperitoneal (i.p.) injection of 1.8 g/kg ethanol or saline, and subsets of both groups were exposed to acute restraint stress for 15 min or controls. Gene expression in the hippocampus was examined using microarray analysis. Genes that were significantly (p < 0.05, q < 0.1) differentially expressed were further evaluated. Bioinformatic analyses were predominantly performed using tools available at GeneNetwork.org, and included gene ontology, presence of cis-regulation or polymorphisms, phenotype correlations, and principal component analyses. Comparisons of differential gene expression between groups showed little overlap. Gene Ontology demonstrated distinct biological processes in ea...

Nutrition for Brain Health and Cognitive Performance

Nutritional neuroscience, 2016

Preweaning iron deficiency increases non-contingent responding during cocaine self-administration in rats

Physiology & behavior, Dec 14, 2016

Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidenc... more Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidence that ID early in development (preweaning in rat) causes irreversible neurologic, behavioral, and motor development deficits. Many of these effects have been attributed to damage to dopamine systems, including ID-induced changes in transporter and receptor numbers in the striatum and nucleus accumbens. These mesolimbic dopaminergic neurons are, in part, responsible for mediating reward and thus play a key role in addiction. However, there has been relatively little investigation into the behavioral effects of ID on drug addiction. In 2002, we found that rats made ID from weaning (postnatal day 21) and throughout the experiment acquired cocaine self-administration significantly more slowly than controls and failed to increase responding when the dose of the drug was decreased. In the present study, we assessed addiction for self-administered cocaine in rats with a history of preweaning I...

Iron in the Brain

Nutr Rev, 2009

The results of our studies of iron in three brain structures, substantia nigra (SN), globus palli... more The results of our studies of iron in three brain structures, substantia nigra (SN), globus pallidus (GP), and hippocampus (Hip), are presented. Mössbauer spectroscopy, electron microscopy and ELISA (enzyme-linked immuno-absorbent assay) were applied. Mössbauer studies show that most of the iron in the brain is ferritin-like. The concentration of iron is similar in SN and GP, but less than half of this in Hip. ELISA studies showed that the H/L ratio of ferritin in SN and GP is also similar, but is about three times higher in Hip. These results suggest that the role of iron in SN and GP may be different from that in Hip. Electron microscopy shows that the diameters of the ferritin iron cores in the brain are smaller that in the liver (3.5 ± 0.5 nm vs. 6.0 ± 0.5 nm). Mössbauer studies yield the ratio between the concentration of iron in control and parkinsonian SN as 1.00 ± 0.13.

Dietary iron deficiency in strain 40 BXD mice causes diurnal-dependent alterations in brain iron and activity

The Faseb Journal, Mar 1, 2008

Ethanol Modulates Cocaine-Induced Behavioral Change in Inbred Mice

Pharmacology Biochemistry and Behavior, Mar 1, 1998

We recently conducted a study of the behavioral effects of combined cocaine and ethanol in geneti... more We recently conducted a study of the behavioral effects of combined cocaine and ethanol in genetically defined mice. Male and female C57BL/6 (B6) and DBA/2 (D2) were tested in an automated activity monitor on 2 consecutive days. On day 1, all animals received an IP injection of sterile saline and were placed into the activity monitor for 30 min. Behaviors measured were total distance traveled, stereotypy, nosepokes, and wall-seeking. On day 2, all animals were tested again for 15 min following injection of one of the following: saline, 10% v/v ethanol at 2.0 g kg(-1) or 2.0 g kg(-1) ethanol plus 5, 15, or 30 mg kg(-1) cocaine. Cocaine alone at the same doses was injected into separate groups of animals. For the B6 strain, the overall effect of ethanol was to reduce cocaine-induced locomotor stimulation; no consistent effect of ethanol on cocaine-induced locomotion was observed in D2 mice. Cocaine-induced inhibition of nosepokes in both strains and sexes was partially reversed by ethanol. Ethanol also partially reversed cocaine-elevated stereotypy in both strains and both sexes. In B6 mice, cocaine-increased wall seeking tended to be reversed by coadministration of ethanol, whereas no consistent pattern was observed in the D2s. Results from this study suggest that the several measures affected by cocaine (locomotor activity, stereotypy, exploration, thigmotaxis) were, in turn, differentially affected by concurrent treatment with ethanol. Furthermore, our results point to genetic-based differences in ethanol&#39;s effects on cocaine-related behaviors. We address the implications for combined ethanol and cocaine use in humans.

Pharmacogenetics of cocaine: a critical review

Pharmacogenetics, 1995

The development of genetic models to help explain individual differences in sensitivity to and su... more The development of genetic models to help explain individual differences in sensitivity to and susceptibility to misuse certain CNS active substances, like ethanol and psychostimulants, spans a brief, thirty-plus years. The first animal models involved inbred strains and selected lines of mice and rats and predicted genetic-based differential sensitivity to ethanol and its misuse in humans found a few years later. With drugs like cocaine, tracking genetic differences in sensitivity and misuse liability in humans is difficult because of legal problems. Genetically-defined animals, however, have shown most if not all of cocaine-related behavioural, neurophysiological and toxicological effects to evince wide variation with most effects being influenced by several genes. Thus, we argue that animal and human studies of individual differences in drug sensitivity be studied from both quantitative and molecular genetic approaches. For the former, new techniques involving recombinant inbred strains of rodents, genetic correlational analysis and quantitative trait loci analysis are particularly useful, especially as genetic synteny between rodents and humans becomes better described. Also, because drug effects are highly labile to environmental conditions as well as genetic-based individual differences, multivariate, systems level studies should be developed to provide more complete descriptive and mechanistic views of a multifaceted problem.

Behavioral effects of THC as a function of environment and prior drug experience

Pharmacology Biochemistry and Behavior, Jan 31, 1987

effects of THC as a function of environment and prior drug experience. PHARMACOL BIOCHEM BEHAV 26... more effects of THC as a function of environment and prior drug experience. PHARMACOL BIOCHEM BEHAV 26(1) 141-144, 1987.--Holtzman albino rats were divided into 4 groups, and on 5 consecutive days each group was exposed to one of 4 conditions. The drug-adapted group was given delta-9-tetrahydrocannabinol (THC) (0.0, 0.5, 2.5 or 5.0 mg/kg PO) in their home cages, while the environment-adapted group was given vehicle and placed for one hr in the chamber where they were later tested. The naive group was given vehicle in their home cages and the drug + environment adapted group was given THC and placed in the test chamber. One week later, all rats were given either 0.0, 0.5, 2.5, or 5.0 mg/kg THC and placed in the test chamber where standing, sitting, and behavioral activity were measured. The results showed that the behavioral effects of THC are a function of environmental familiarity in rats who are drug naive but not in rats given prior exposure to THC.

Abnormal rat brain monoamine metabolism in iron deficiency anemia

The Journal of Nutritional Biochemistry, Sep 1, 1995

iron deficiency in rats produces numerous alterations rn hrarn metabolism as assessed by in vitro... more iron deficiency in rats produces numerous alterations rn hrarn metabolism as assessed by in vitro techniques. We used a new method of in vivo microdlalvsis to stud\ the effect of acute iron deficiency anemia on rat brain monoamine metabolism. This method n,aS used to sample extracellular fluid from an implanted microdialysis probe in the caudate putamen from freely moving animals. Method validation experiments showed that steadystate levels of dopamine. norepinephrine, and their metabolites were obtained only after 5 to 7 days of surgical recovery and with prior perfusion of the brain region. Caudate putamen dopamine was significantly increased 30% and 400/c in fasted light-exposed and 2-hr-fed dark-exposed iron deficient anemic rats (hemoglobin <6 gldL), respectively. relative to control rats. Dihydroxyphenyl acetic acid and homovanillic acid concentrations were unaffected by iron deficiency in the fasted stare. These metabolites. along with dopamine, increased significantly (50 to 8270) in iron deficient rats with e.rposure to darkness andfood while control rats' metabolites did not change. The present stud! documents that iron deficiency is associated with altered in vivo brain monoamine metabolism tn the steady state and in response to the environmental stimuli of food and darkness. While these data are supportive of the previous in vitro demonstrations of down-regulation of dopamine D, receptors, the? also suggest that uptake and processing of monoammes is significantly perturbed by iron deficiency. (J. Nutr. Biochem. 6:48ti93. 199.5.)

Genetic�environment analysis of sensitivity and acute tolerance to ethanol in mice

Pharmacology Biochemistry and Behavior, Jul 1, 2001

The purpose of this study was to characterize initial sensitivity (IS), acute functional toleranc... more The purpose of this study was to characterize initial sensitivity (IS), acute functional tolerance (AFT), and rate of tolerance development to ethanol in lines of mice selected for aggression mice as well as to investigate the impact of isolate housing on these phenotypes. The results showed that for IS, there were no differences among treatment groups. For acute tolerance and rate of tolerance development, a Line x Sex x Housing interaction was present, with the response to housing being more pronounced in the low aggressive line than the high aggressive line, and the females being more affected than the males. Correlational analysis showed low to moderate associations between rate of tolerance development and IS, as well as between rate of tolerance and AFT. Housing condition significantly influenced female expression of ethanol phenotypes as compared to males. The line of the subject also influenced the magnitude of expression of these phenotypes. These findings suggest that environmental and genetic influences interact to influence acute tolerance and rate of tolerance development.

Ethanol and MDMA: a comment on the paper by Dumont et al

Psychopharmacologia, Aug 28, 2008

EEG and Behavioral Effects of A9-Tetrahydrocannabinol in Combination with Stimulant Drugs in Rabbits

Psychopharmacology, 1976

EEG and behavioral effects of ?9-Tetrahydrocannabinol in combination with stimulant drugs in rabbits

Psychopharmacology, 1976