Full Text PA-96-057 QTL MAPPING OF ALCOHOL-RELATED BEHAVIORAL TRAITS IN RODENTS NIH GUIDE, Volume 25, Number 18, June 7, 1996 PA NUMBER: PA-96-057 P.T. 34 Keywords: Alcohol/Alcoholism Behavioral/Experimental Psychology 0755044 National Institute on Alcohol Abuse and Alcoholism PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant applications to map quantitative trait loci (QTL) influencing rat and mouse behavioral traits that model human behavioral traits predisposing to alcoholism. Mapping of such QTL will permit subsequent testing of human homologues of these genes for linkage to alcoholism in human pedigrees. Such a test will help to establish which animal behavioral traits are most relevant to human alcoholism. Mapping of the QTL will also serve as a prologue to the isolation of the relevant genes and the identification of the products they encode. This approach can provide a novel route to elucidating the physiological mechanisms for predisposition to alcoholism and to developing intervention strategies to diminish harmful effects of alcohol. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2000," a PHS-led national activity for setting priority areas. This Program Announcement, QTL Mapping of Alcohol-Related Behavioral Traits in Rodents, is related to the priority areas of alcohol abuse reduction and alcoholism treatment. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) Awards (R29). Regular research grant applications (R01) from foreign institutions are limited to three years. MECHANISM OF SUPPORT Research support may be obtained through applications for a research project grant (R01) or First Independent Research Support and Transition (FIRST) Award (R29). Applicants may also submit Investigator-Initiated Interactive Research Project Grants (IRPG) under this program announcement. Interactive Research Project Grants require the coordinated submission of related regular research project grant applications and, to a limited extent, FIRST Award applications from investigators who wish to collaborate on research, but do not require extensive shared physical resources. Further information on the IRPG mechanism is available in program announcement PA-96-001, NIH Guide for Grants and Contracts, Vol. 24, No. 35, October 6, 1995. RESEARCH OBJECTIVES Genetic Basis of Alcoholism Alcoholism has been recognized for over a century as a familially transmitted condition. Over the past 25 years, considerable evidence from family, twin, and adoption studies supports important roles for both genes and environment in its etiology in both men (Cloninger, et al., 1981; Merikangas, 1990; McGue, et al., 1992) and women (Kendler, et al., 1992). The specific etiological factors underlying susceptibility to alcoholism remain, however, unknown. Ongoing efforts to discover genes linked to alcoholism in human pedigrees are challenged by the heterogeneous, polygenic nature of alcoholism, along with the incompletely understood role of the environment in its etiology (Aston and Hill, 1990). These efforts could be greatly bolstered by a strategy taking advantage of powerful genetic methods permitting identification of genes influencing ethanol-related behavior in experimental animals (Zeng, 1994; Jansen and Stam, 1994; Crabbe, et al., 1994a). Human homologues of these genes could then be tested directly for linkage to alcoholism in human pedigrees. The recent large increase in the density of markers on the mouse genetic map (Dietrich, et al., 1995), along with the development of new and more powerful methods of data analysis (Zeng, 1994; Jansen and Stam, 1994), have now made it possible to map individual quantitative trait loci (QTL), the genes contributing jointly to the determination of genetically complex traits (such as behavior) (Crabbe, et al., 1994a). Since mapped genes can be isolated and their encoded products characterized, QTL mapping offers a powerful reductionistic approach for dissecting the complex physiological bases of alcohol-related behavior. A detailed human-mouse synteny map can accurately predict the map location of potential human homologues of mouse genes (Nadeau, et al., 1992), so that these predicted loci can then be tested for linkage to alcoholism in human alcoholic pedigrees. This strategy would permit the direct application of knowledge gained from an animal behavior genetic study, for which behavioral measures are precisely defined and powerful genetic techniques can be brought to bear, to a human genetic study of alcoholism. A finding of linkage would, moreover, provide additional evidence for the relevance of the animal behavior under study to human alcoholism. Human Behavioral Indicators of Predisposition to Alcoholism Because family history of alcoholism is a significant risk factor for alcoholism (Cotton, 1979), researchers have examined psychological, biological, and behavioral characteristics that distinguish children of alcoholics from children of non-alcoholics as a means of identifying indicators of vulnerability to alcoholism. The most prominent theories of vulnerability to alcoholism have centered on temperament, baseline sensitivity, and acute tolerance to alcohol. Temperament models of vulnerability to alcoholism propose that deviations in dispositional traits mediate transmission of alcoholism (Tarter, 1991; Cloninger, 1987). According to Tarter, who used Rowe and Plomin's (1977) six dimensions of temperament, children at high risk for developing alcoholism have traits such as high behavioral activity, low attention span and persistence, low soothability, high emotionality, and low sociability. These disturbances of temperament in children of alcoholics are attributed to neurological dysfunction in the prefrontal, limbic, and midbrain areas. This theory is supported by observations of a number of differences between children of alcoholics and children of nonalcoholics, including increased incidence of psychopathology (attention deficit hyperactivity disorder, childhood conduct disorder, anxiety disorders and depression, antisocial personality disorder), behavioral disturbances (impulsiveness, aggression, emotionality), neuropsychological deficits (abstraction/ conceptualization, verbal ability), and neurophysiological variations (reduced amplitude of the P3 component of event-related potentials) (see Tarter, 1991; Sher, 1991 for reviews). In a similar vein, Cloninger's model of Type 1 and Type 2 alcoholism (Cloninger, 1987) is based on temperamental differences (novelty seeking, harm avoidance, reward dependence), which are related to selective neurological substrates and predispose an individual to certain types of alcoholism. For example, Type 2 alcoholics are high in novelty seeking, associated with impulsiveness, distractibility, and positively motivated drinking. Variation in novelty seeking has recently been associated with variants of the gene encoding the dopamine D4 receptor (Benjamin, et al., 1996). Type 1 alcoholics, on the other hand, are high in harm avoidance and reward dependence associated with anxiety, shyness, emotional dependence, and negatively motivated drinking (i.e., escape from dysphoric feelings). The sensitivity hypothesis of vulnerability to alcoholism, first elaborated by Schuckit and his colleagues in the early 1980s, postulated that children of alcoholics are less sensitive to the subjective intoxicating effects of alcohol, and therefore, are susceptible to drinking excessively (Schuckit, 1980, 1984). However, subsequent studies designed to test this hypothesis demonstrated opposite effects, i.e., children of alcoholics were more sensitive to the reinforcing effects of alcohol as measured by muscle relaxing, stress-dampening, electroencephalographic and mood effects (see Sher, 1991 for review). A recent interpretation proposed by Newlin and Thomson (1990) may resolve this conflict. Compared to sons of nonalcoholic fathers, sons of alcoholic fathers show greater acute sensitivity to the reinforcing effects of alcohol (euphoria, muscle relaxation, stress-response dampening) on the ascending limb of the blood alcohol curve, and less sensitivity (greater acute tolerance) to the aversive effects of alcohol (nausea, dysphoria) on the descending limb of the blood alcohol curve. Measuring Animal Behaviors Related to Human Traits Predicting Alcoholism Investigators are now mapping QTL influencing various ethanol-related behaviors in mice, including preference for drinking, sensitivity to sedation, locomotor activation, hypothermia, and withdrawal severity (for review, see Crabbe, et al., 1994a). More recently, they have begun mapping genes influencing more complex behaviors, such as acute functional tolerance to ataxia (Crabbe, et al., 1994a) and hypothermia (Crabbe, et al., 1994b), conditioned place preference (a measure of reinforcement) (Cunningham, 1995), and conditioned taste aversion (a measure of aversive effects) (Risinger and Cunningham, 1994). Aspects of more complex rodent behaviors could conceivably be homologous to human traits predisposing to alcoholism. Some of the corresponding assays could, in principle, be adapted for QTL mapping. Examples are given below. (These examples are for illustrative purposes only, and are not intended to exclude other behavioral tests from this RFA.) Tests that assess intrinsic traits of temperament or personality predisposing humans to alcoholism, such as impulsiveness, novelty seeking, aggression, hyperactivity, emotionality, anxiety, and stress reactivity, can be administered to rodents. Impulsiveness in individuals at risk for alcoholism has been attributed to prefrontal- limbic brain dysfunction (Tarter, 1991) and is comparable to difficulties in response inhibition observed in rodents with prefrontal lesions (see Kolb, 1984 for review). Evidence of impaired response inhibition in rodents has been measured by reversal learning tasks (i.e., the animal first learns to respond to a particular stimulus or location for a reward, and then must reverse its response to a different place or stimulus), tests of response extinction (a previously rewarded response is no longer rewarded), or go/no go tasks (reward is presented for responding to a stimulus on "go" trials, and for not responding on "no go" trials) (Kolb, 1984; Sakurai and Sugimoto, 1985). Animals with deficits in response inhibition have difficulty shifting responses on reversal tasks, continue responding when rewards are no longer presented, and fail to suppress responding on "no go" trials. Research on alcohol and aggression in humans and animals has focused on whether alcohol consumption increases violent/aggressive behavior toward family members, peers, or rivals (see Miczek, et al., 1993 for review). However, whether a history of antisocial personality or aggressive behavior predisposes a person to excessive alcohol consumption has received little study. Measures of aggressive behavior in rodents that might reflect aspects of human antisocial behavior include social interaction/social conflict paradigms, such as isolation-induced aggression between male pairs, resident-intruder encounters, and possibly frustration-induced aggression (omission of reward) (Cairns, et al., 1983; Miczek, et al., 1993; Brain, et al., 1993). Measures of other traits potentially serving as markers of human alcoholism, such as anxiety, emotionality, activity level, and novelty- seeking, could be applied to rodents. Novelty or "sensation-seeking" can be measured by nose-poke or hole-board behavior in which the animal places its nose or head into a board with equally spaced holes. Activity level can easily be measured with activity wheels or by the number of boxes crossed in an open field. Hole-board behavior and exploratory open field activity, along with number of defecations and rearings in the open field, have also been used to quantitate levels of anxiety and emotionality. Other experimental paradigms for measuring anxiety include conflict paradigms, acoustic startle response, and elevated plus-maze (see Crawley, 1985; Shepard, 1986; Heilig, et al., 1994; Stout and Weiss, 1994 for reviews of all of these paradigms). A further related behavior is stress reactivity, which could be measured by responses to various stressors (social stress, isolation, early weaning), such as changes in vocalization pattern, disruption of circadian rhythms, or autonomic responses such as changes in blood pressure or heart rate (see Pohorecky, 1990; Brown, et al., 1991 for reviews). Acute behavioral tolerance to a single challenge dose of alcohol can be demonstrated in animals by comparing the extent of functional impairment at a given blood alcohol concentration on the ascending limb of the blood alcohol curve with the extent of impairment when the same alcohol concentration is reached on the descending limb. The development of acute tolerance within a single session to alcohol's effects such as motor impairment, hypothermia, and operant responding has been shown by several studies (LeBlanc, et al., 1975; Crabbe, et al., 1994b; Le, et al., 1992; Hiltunen and Jarbe, 1992). Finally, because frequency and amount of alcohol consumed are significant discriminators of alcoholic subtypes (Babor, et al., 1992; Morley and Skinner, 1986), measures of temporal patterns of alcohol consumption in rodents may be informative behavioral markers. Using operant techniques, distinctive temporal patterns of alcohol consumption have been demonstrated in the selectively bred alcohol-preferring and - nonpreferring rats (Schwarz-Stevens, et al., 1991). Such techniques could possibly be adapted to permit QTL mapping. Methodological Considerations Most QTL mapping of behavioral traits has been done in mice because of the well-developed genetic map available for this species. However, the rat genome map is now undergoing rapid development (Jacob, et al., 1995) and has already proven suitable for QTL mapping (Brown, et al., 1996; Galli, et al., 1996; Gauguier, et al., 1996). Because many interesting behavioral paradigms have been developed in rats to study ethanol- related behaviors, NIAAA encourages investigators studying rat behavior to respond to this RFA. While the choice of animal strains for study is an important feature of experimental design, applicants are encouraged to consider using any of a wide variety of strains, rather than confining their attention only to those already used extensively in alcohol research. While recombinant inbred (RI) strains have been used extensively to map QTL influencing behavioral traits (Crabbe et al., 1994a), applicants should consider carefully whether the small size of most extant batteries of RI strains (<25 strains) affords sufficient statistical power to detect QTL of modest to moderate effect size. Applicants are encouraged (when cost and experimental considerations permit) to test more than one behavioral paradigm on the same group of animals. Applicants may also wish to consider neurochemical measurements (e.g., receptor binding studies, in situ hybridization, other histological measurements) on the same group of animals. Such studies offer the prospect of a rigorous determination of genetic correlations among multiple behaviors and neurochemical parameters, as well as mapping of the genes responsible for those correlations. Some behavioral paradigms of great potential interest may be so complex as to preclude measurements on the hundreds of animals required for QTL mapping. Investigators working with such paradigms are strongly encouraged to attempt modifying them so as to permit measurements on hundreds of animals, without degrading their informativeness about the principal aspect of the behavior under study. SPECIAL REQUIREMENTS This program announcement is intended to publicize NIAAA's interest in the genetic analysis of animal behaviors not previously analyzed, in the hope that these behaviors may usefully model human traits related to predisposition to alcoholism. Investigators wishing to obtain support for such research who lack expertise in genetic analysis should seek collaboration with investigators experienced in QTL mapping, insofar as such experience will prove essential for proper study design and data analysis. Investigators desiring to establish such collaborations are encouraged to contact one of the individuals mentioned under INQUIRIES, below. Awardees will be expected to attend one joint meeting per year in or near Washington, DC, in order to review progress, and should request sufficient funds in their budgets to support such attendance. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0715, Email: asknih@odrockm1.od.nih.gov. The title and number of the program announcement must be typed in section 2 on the face page of the application. Applications for the FIRST award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) REVIEW CONSIDERATIONS Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria Criteria to be used in the scientific and technical merit review of alcohol research grant applications will include the following: 1. The scientific, technical, or medical significance and originality of the proposed research. 2. The appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research. 3. The adequacy of the qualifications (including level of education and training) and relevant research experience of the principal investigator and key research personnel. 4. The availability of adequate facilities, general environment for the conduct of the proposed research, other resources, and collaborative arrangements necessary for the research. 5. The reasonableness of budget estimates and duration in relation to the proposed research. 6. Where applicable, the adequacy of procedures to protect or minimize effects on animal and human subjects and the environment. The review criteria for FIRST Awards (R29) are contained in the FIRST program announcement (revised February 1994). AWARD CRITERIA Applicatons will compete for available funds with all other approved applications. The following will be considered in making funding decisions: quality of the proposed project as etermined by peer review, availability of funds, and program priority. Applications assigned to the National Advisory Council on Alcohol Abuse and Alcoholism will be considered for funding on the basis of the overall scientific and technical merit of the application as determined by peer review, NIAAA programmatic needs and balance, and the availability of funds. Priority will be given to applications analyzing behavioral and neurochemical traits not yet subject to QTL analysis. Applicants desiring further information about funding priorities are encouraged to contact one of the persons listed under INQUIRIES. INQUIRIES The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding genetic aspects of proposed research to: Robert W. Karp, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 402 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4223 FAX: (301) 594-0673 Email: rkarp@willco.niaaa.nih.gov Direct inquiries regarding behavioral aspects of proposed research to: Ellen Witt, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 402 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4223 FAX: (301) 594-0673 Email: ewitt@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Linda Hilley Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 504 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4703 FAX: (301) 443-3891 Email: lhilley@willco.niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.273. Awards are made under the authorization of the Public Health Service Act, Sections 301 and 464H, and administered under the PHS policies and Federal Regulations at Title 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency Review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. 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