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LIN - Section on Behavioral Science and Genetics (BSG)

 

Andrew Holmes, Ph.D., Section Chief, Principal Investigator

 

National Institute on Alcohol Abuse and Alcoholism

National Institutes of Health

5625 Fishers Lane, Room 2N09

Rockville MD 20852-9411

telephone: +1 301 402 3519

fax: +1 301 480 1952

e-mail: holmesan@mail.nih.gov

 

 

Mission Statement

 

We are utilizing animal models to determine how exposure to stress and emotional trauma can subsequently impair an individual’s capacity for high-level cognitive and so-called executive functions.  Executive functions include the ability to inhibit inappropriate behaviors such as aggression and excessive fear, and the capacity for controlling and avoiding potentially self-destructive activities as often occurs in drug and alcohol addiction.  One goal of this research is to uncover the genes that increase a person’s susceptibility to these detrimental effects of stress in order to identify individuals who are particularly at-risk.  Another objective is to elucidate the neural systems and molecules that are compromised by stress as a first step to developing new medications for stress-related neuropsychiatric diseases ranging from post-traumatic stress disorder to alcoholism.

 

 

Current staff

 


Elizabeth Kirby; Secretary; kirbye@mail.nih.gov

 


Jonathan Brigman, PhD, Post-doctoral fellow, brigmanj@mail.nih.gov

 

Current projects: Neural basis of cognitive flexibility; the role of NMDA receptors.

Jonathan Brigman 

 

 

Marguerite Camp, PhD, Post-doctoral fellow, campmc@mail.nih.gov

 

Current projects: Role of glutamate signaling in ethanol dependence and addiction.

 

Marguerite Camp

 

 

 

Paul Fitzgerald, PhD, Post-doctoral fellow, Post-doctoral fellow, paulfj@mail.nih.gov

 

Current projects: Neurophysiology of affect and addiction.

 

Paul Fitzgerald

 

 

 

Carolyn Grabeal, BSc, Graduate student (Brown University - NIH Graduate Partnerships Pogram) graybealc@od.nih.gov

 

Current projects: Effects of stress on executive function.

 

 Carolyn Grabeal

 

 

 

Rose-Marie Karlsson, MSc, Graduate student (Laboratory of Clinical and Translational Studies and Karolinska Institute-NIAAA graduate program) karlssonr@mail.nih.gov

 

Current projects: Role of the glutamate system in modulating anxiety stress and alcohol-related behaviors.

 

Rose-Marie Karlsson

 

 

 

Michael Feyder, BSc, Post-baccalaureate fellow, feyderm@mail.nih.gov

 

Current projects: Role of intracellular glutamate signaling molecules in behavior and drug-seeking behaviors.

 

Michael Feyder

 

 

 
Section alumni

 

Alicia Izquierdo, PhD, currently Assistant Professor, Department of Psychology, California State University, Los Angeles AIzquie@calstatela.edu

 

Janel Boyce-Rustay, PhD, currently Senior Research Pharmacologist, Abbott Laboratories

 

Rachel Millstein, BA, currently at Harvard University

 

Lisa Wiedholz, BA, currently Reserch Pharmacologist, Abbott Laboratories

 

Rebecca Yang, BA, currently at Emory University

 

Kathryn Hefner, BA, currently at University Wisconsin-Madison

 

Poonam Mathur, BA, currently at Nova Southeastern University

 

Benjamin Palachick, BSc, currently at Drexel University

 

 

Collaborators

 

Dr. Timothy J. Bussey and Dr. Lisa M. Saksida, Department of Experimental Psychology, University of Cambridge; Weblink

 

Dr. Heather Cameron, Unit on Neuroplasticity, NIMH; Weblink

 

Dr. Lynette C. Daws, Department of Physiology, The University of Texas Health Science Center; Weblink

 

Dr. Seth Grant, Wellcome Trust Sanger Institute; Weblink

 

Dr. Markus Heilig, Laboratory of Clinical and Translational Studies, NIAAA; Weblink

 

Dr. Kazutoshi Nakazawa, Unit on Genetics of Cognition and Behavior, NIMH; Weblink

 

Dr. David Lovinger, Dr. Rui Costa, Dr. Veronica Alvarez, Dr. Margaret Davis, Laboratory for Integrative Neuroscience, NIAAA; Weblink

 

Dr. Cara Wellman, Department of Psychology, Indiana University; Weblink

 

Dr. Danny Winder, Department of Pharmacology, Vanderbilt University Medical Center; Weblink

 

Dr. Ted Usdin, Laboratory of Genetics, NIMH; Weblink

 

 

Recent key publications

 

 

Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein RA, Lesch K-P, Murphy DL, and Holmes A  (2007) Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knockout mice. The Journal of Neuroscience, 27:684-691. Pubmed

 

Yang RJ, Mozhui K, Karlsson R-M, Cameron HA, Williams RW, Holmes A (2008) Genetically-driven variation in mouse basolateral amygdala volume predicts differences in fear learning and stress-reactivity.  Neuropsychopharmacology.  Pubmed

 

Izquierdo A, Wellman CL and Holmes A (2006) Stress causes rapid dendritic retraction in infralimbic cortex and impairs fear extinction in mice. The Journal of Neuroscience 26: 5733-5738.  Pubmed

 

Hariri AR and Holmes A (2006) The serotonin transporter and the genetics of affect regulation. Trends in Cognitive Sciences 10: 182-191.  Pubmed

 

Daws LC, Montañez S, Munn JL, Owens WA, Baganz NL, Boyce-Rustay JM, Millstein RA, Wiedholz LM, Murphy DL and Holmes A (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. The Journal of Neuroscience 26: 6431-6438.  Pubmed

 

Esaki T, Cook M, Shimoji K, Murphy DL, Sokoloff L and Holmes A (2005) Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice.  Proceedings of the National Academy of Sciences USA 102: 5582-5587.  Pubmed

 

Cryan, JF and Holmes A (2005) The ascent of mouse: advances in modeling human depression and anxiety. Nature Reviews Drug Discovery 4: 775-790.  Pubmed

 

Izquierdo A, Wiedholz LM, Millstein, RA, Yang, RJ, Bussey TJ, Saksida LM, and Holmes A (2006) Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice. Behavioral Brain Research, 171:181-188.  Pubmed

 

 

 

 

Additional publications 

 


Parker CC, Ponicsan H, Spencer RL, Holmes A, Johnson TE. Restraint stress and exogenous corticosterone differentially alter sensitivity to the sedative-hypnotic effects of ethanol in ILS and ISS mice.  Alcohol in press

Holmes A Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease.  Neuroscience & Biobehavioral Reviews in press

Palachick B, Chen Y-C, Enoch AJ, Karlsson RM, Sprengel R, Mishina M, Holmes A MK-801 potentiation of ethanol intoxication is not dependent upon major NMDAR or AMPA receptor subunits.  Alcoholism: Clinical and Experimental Research in press

Karlsson RM, Hefner KM, Sibley DR, Holmes A Constitutive loss of dopamine D1, but not D5, receptor prevents locomotor sensitization to cocaine in mice.  Psychopharmacology in press

Adamec RA, Holmes A, Blundell J Vulnerability to lasting anxiogenic effects of brief exposure to predator stimuli: sex, serotonin and other factors - relevance to PTSD.  Neuroscience & Biobehavioral Reviews in press


Karlsson RM, Heilig, MA, Holmes A Loss of mouse GLAST (EAAT1) mediated glutamate reuptake causes locomotor hyperactivity and exaggerated responses to psychotomimetics in mice. Biological Psychiatry in press

Brigman J, Mathur P, Lu L, Williams RW, Holmes, A Genetic relationship between fear- and anxiety-related behaviors in BXD recombinant inbred mice.  Behavioural Pharmacology in press


Feyder M, Wiedholz LM, Sprengel R, Holmes A (2008) Impaired associative fear learning following complete or partial loss of AMPA GluR1 receptors in mice.  Frontiers in Behavioral Neuroscience 1:4.  Journal website

 

Brigman J, Feyder M, Saksida LM, Bussey TJ, Mishina M, Holmes A (2008) Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit.  Learning and Memory 15:50-54.  Pubmed

 

Karlsson RM, Holmes A, Crawley, JN, Heilig, MA (2008) The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like but not antidepressant-like effects of neuropeptide Y.  Psychopharmacology 195:547-557.  Pubmed

 

Boyce-Rustay JM, Janos A, Holmes A (2008) Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice. Behavioural Brain Research 188: 133-137. Pubmed

 

Fox MA, Andrews AM, Wendland JR, Lesch KP, Holmes A, Murphy DL (2008) A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. Psychopharmacology.  Pubmed

 

Holmes A, Stein, MB and Steckler T (2008) Modeling anxiety in mice. In Animal and translational models of psychiatric disorders.  RA McArthur and F Borsini (Eds). Elsevier, London.

 

Millstein RA, and Holmes A (2007) Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains.  Neuroscience & Biobehavioral Reviews 31:3-17. Pubmed

 

Wiedholz LM, Owens WA, Horton RE, Feyder M, Hefner KR, Sprengel R, Celikel T, Daws LC, Holmes A (2007) Mice lacking the AMPA GluR1 receptor exhibit hyperdopaminergia and schizophrenia-related behaviors. Molecular Psychiatry, in press.  Pubmed

 

Hefner KM and Holmes A (2007) Changes in the pharmacodynamic and pharmacokinetic effects of ethanol across adolescence in mice. Psychopharmacology, 191:311-322. Pubmed

 

Holmes A (2007) Mouse models of anxiety. In Handbook of Behavioral Genetics of the Mouse. WE Crusio, F Sluyter, RT Gerlai (Eds). Cambridge University Press, Cambridge.

 

Caldwell HK, Stewart S, Wiedholz LM, Millstein RA, Holmes A, Young SW, and Wersinger S (2007) The acute intoxicating effects of ethanol are not dependent on the vasopressin 1a or 1b receptors. Neuropeptides 40:325-337. Pubmed

 

Tonelli LH, Holmes A, Postlache TT (2008) Intranasal immune challenge induces sex-dependent depressive-like behavior and cytokine expression in the brain. Neuropsychopharmacology. Pubmed

 

Hefner KM and Holmes A (2007) Ontogeny of fear-, anxiety- and depression-related behavior across mouse adolescence. Behavioral Brain Research 176:210-215. Pubmed

 

Carroll J, Boyce-Rustay JM, Izquierdo A, Millstein RA, Yang RJ, Wiedholz LM, Murphy DL and Holmes A (2007) Effects of mild early life stress on abnormal emotional behaviors in 5-HTT knockout mice. Behavior Genetics, 37:214-222.  Pubmed

 

Mozhui K, Hamre K, Holmes A, Lu, L, and Williams RW (2007) Genetic and structural analysis of the mouse basolateral amygdala complex.  Behavior Genetics, 37:223-243.  Pubmed

 

Boyce-Rustay JM, Cameron HA, and Holmes A (2007) Chronic swim stress alters sensitivity to acute behavioral effects of ethanol in mice. Physiology & Behavior, 91:77-86. Pubmed

 

Holmes A and Griebel G (2007) The pharmacology of anxiety. In Handbook of Anxiety and Fear.  R Blanchard, DC Blanchard, DJ Nutt (Eds). Elsevier, London.

 

Hasnie FS, Wallace V, Hefner KM, Holmes A, and Rice ASC (2007) Mechanical and cold allodynia in nerve-injured mice is not associated with anxiety- and depression-related behaviours.  British Journal of Anaesthesia, 98:816-822.3. Pubmed

 

Holmes A (2007) The pharmacology of anxiety. In Handbook of Anxiety and Fear.  R Blanchard, DC Blanchard, DJ Nutt (Eds). Elsevier, London.

 

Hefner KM and Holmes A (2007) Short-term and long-term effects of exposure to an unfamiliar male in C57BL/6J mice. Behavioural Brain Research, in press. Pubmed

 

Holmes A and Picciotto M (2006) Galanin; a novel target system for stress-related disorders and addiction? Current Drug Targets – CNS & Neurological Disorders 5: 225-232.  Pubmed

 

Boyce-Rustay JM and Holmes A (2006) Genetic inactivation of the NMDA NR2A subunit has anxiolytic- and antidepressant-like effects in mice.  Neuropsychopharmacology, 31: 2405-1414. Pubmed

 

Adamec, RA, Burton, P, Blundell, J, Murphy, DL and Holmes A (2006) Vulnerability to mild predator stress in serotonin transporter knockout mice. Behavioral Brain Research 170: 126-140. Pubmed

 

Millstein RA, Ralph RJ, Yang RJ and Holmes A (2006) Effects of repeated maternal separation on prepulse inhibition of startle across inbred mouse strains. Genes, Brain & Behavior 5: 346-354. Pubmed

 

Boyce-Rustay JM and Holmes A (2006) Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit. Psychopharmacology, 187: 455-466. Pubmed

 

Holmes A and Cryan JF (2006) Measuring anxiety- and depression-related behaviors in the mouse. In Transgenic and Knockout Models of Neuropsychiatric Disorders. GS Fisch and J Flint (Eds). Humana Press, New Jersey.

 

Karlsson R and Holmes A (2006) Galanin; a modulator of stress and emotion.  Amino Acids, in press. Pubmed

 

Wrenn C.C. and Holmes, A. Galanin; a novel target for stress-related disorders. Drug News and Perspectives, 26: 753-778. Pubmed

 

Ren-Patterson R, Cochran LW, Holmes A, Lesch K-P, Lu B, and Murphy DL (2006) Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies.  Molecular and Cellular Biology in press. Pubmed

 

Boyce-Rustay JM, Wiedholz LM, Millstein RA, Carroll J, Murphy DL, Daws LC, and Holmes A (2006) Behavioral responses to ethanol in serotonin transporter knockout mice.  Alcohol: Clinical and Experimental Research 30:1957-1965. Pubmed

 

Holmes A, Li Q, Koenig EA, Gold E, Stephenson D, Yang RY and Crawley JN (2005) Assessment of galanin modulation of the acute behavioral effects of antidepressants in mice. Psychopharmacology 178: 276-285. Pubmed

 

Karlsson, R-M, Holmes A, Heilig M and Crawley JN (2005) Comparative profiles of centrally-administered neuropeptide Y and galanin in mouse tasks for fear and anxiety-related behaviors. Pharmacology, Biochemistry and Behavior 80: 427-436. Pubmed


Holmes A, le Guisquet A-M, Vogel E, Millstein RA, Leman S and Belzung C (2005) Early life genetic, epigenetic and environmental factors shaping emotionality in rodents. Neuroscience & Biobehavioral Reviews 29: 1335-1346.  Pubmed

Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang S-J, Tolliver T, Lesch, K-P, Lu B and Murphy DL (2005) Loss of BDNF gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. Journal of Neuroscience Research 79: 756-771. Pubmed

 

Boyce-Rustay JM and Holmes A (2005) Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice. Synapse 56: 222-225. Pubmed

 

Rustay NR, Wrenn CC, Kinney JW, Holmes A, Bailey KR, Sullivan T, Harris AP, Long KC, Saavedra MC, Starosta G, Innerfield CE, Yang RJ, Dreiling JL and Crawley JN (2005) Galanin impairs performance on learning and memory tasks:  findings from galanin transgenic and GAL-R1 knockout mice. Neuropeptides 39: 237-241. Pubmed

 

Kim D-K, Tolliver TJ, Huang SJ, Martin BJ, Andrews AM, Wichems C, Holmes A, Lesch K-P, and Murphy DL (2005) Altered serotonin synthesis, turnover and dynamic regulation regions of mice lacking the serotonin transporter.  Neuropharmacology 49: 798-810. Pubmed

 

Zhao S, Edwards J, Carroll J, Wiedholz L, Millstein RA, Murphy DL, Lanthorn TH and Holmes A (2005) Mutant mice reveal an essential functional role for the C-terminus of the 5-HT transporter. Neuroscience 140: 321-334. Pubmed

 

Wrenn CC, Kinney JW, Marriott LK, Holmes A, Harris AP, Saavedra MC, Innerfield CE, Jacoby AS, Shine J, Wenk G, Iismaa TP and Crawley JN (2004) Learning and memory performance in GAL-R1 null mutant mice.  European Journal of Neuroscience 19: 1384-1396. Pubmed

 

Holmes A, Lachowicz JE, and Sibley DR (2004) Functional specificity of dopamine receptor subtypes; recent evidence from knockout mice. Neuropharmacology 47: 1117-1134. Pubmed

 

Li Q, Holmes A, Ma L and Murphy DL (2004) Medial hypothalamic 5-HT1A receptors may be involved in the regulation of defensive behaviors, but not exploratory anxiety-like behaviors in mice. The Journal of Neuroscience 24: 10868-10877. Pubmed

 

Holmes A, Heilig M, Rupniak, NMJ, Steckler T and Griebel G (2003) Neuropeptides as novel therapeutic targets for stress-related disorders; recent developments. Trends in Pharmacological Sciences 24: 580-558. Pubmed

 

Holmes A, Li Q, Murphy DL, Gold E and Crawley JN (2003) Abnormal anxiety-related behavior in serotonin transporter null mutant mice; the influence of genetic background. Genes, Brain and Behavior 2: 365-380. Pubmed

 

Holmes A, Murphy DL and Crawley JN (2003) Behavioral phenotypes of serotonin transporter knockout mice; parallels with human anxiety and depression. Biological Psychiatry 54: 953-959. Pubmed

 

Holmes A and Hariri AR (2003) Editorial: Genetic variation in serotonin transporter function and negative emotionality; placing single gene effects in the context of genetic background and environment. Genes, Brain and Behavior 2: 332-335. Pubmed

 

Holmes A, Kinney JW, Wrenn CC, Li Q, Yang RJ, Ma L, Vishwanath J, Saveedra MC, Innerfield CE, Jacoby AS, Shine J, Iismaa TP and Crawley JN (2003) Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze test. Neuropsychopharmacology 28: 1031-1044. Pubmed

 

Holmes A and Rodgers RJ (2003) Prior exposure to the elevated plus-maze sensitizes mice to the acute behavioral effects of phenelzine and fluoxetine. European Journal of Pharmacology 459: 221-230. Pubmed

 

Holmes A, Yang RJ, Lesch KP, Crawley JN and Murphy DL (2003) Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in anxiety-like and exploratory behavior. Neuropsychopharmacology 28: 2077-2088. Pubmed