GENETIC BASIS OF COMPLEX BEHAVIORS

Release Date: August 5, 1998

PA NUMBER:  PA-98-097

P.T.

National Institute of Mental Health
National Institute on Alcohol Abuse and Alcoholism
National Institute of Child Health and Human Development
National Institute of Dental Research
National Institute on Drug Abuse
National Institute of General Medical Sciences
National Institute of Neurological Disorders and Stroke

PURPOSE

The purpose of this program announcement (PA) is to solicit applications for
multidisciplinary, methodologically rigorous programs of neuroscience research
that will use advanced techniques for statistical and molecular genetic
analysis in human and animal populations to elucidate the genetic basis of
complex behaviors.  This PA is issued in response to the growing evidence that
complex behaviors of relevance to human health and disease show varying
degrees of genetic influence.  Examples include complex behaviors associated
with memory, activity level, harm avoidance, reward dependence, emotionality,
contextual fear conditioning, sensorimotor gating, drug seeking, pain
perception and reactivity, and analgesic response.  The goals of this PA are
to quantify genetic and environmental effects and gene-environment
interactions and to locate and characterize genes affecting complex behaviors
in humans and animals.

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 PA, Genetic Basis of Complex
Behaviors, is related to the priority area of genetics and medicine. 
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 foreign and domestic, 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.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) individual research
project grant (R01) mechanism.  Responsibility for the planning, direction,
and execution of the proposed project will be solely that of the applicant. 
Awards will be administered under PHS grants policy as stated in the Public
Health Service Grants Policy Statement.  Because the scope of the research
proposed in response to this PA encompasses the interests of several NIH
Institutes, applications may receive dual assignments based on the established
PHS guidelines.  The total project period for an application submitted in
response to this PA may not exceed five years.

An applicant planning to submit a new (Type 1) investigator-initiated grant
application requesting $500,000 or more in direct costs for any year is
advised that he or she must contact Institute program staff (see INQUIRIES,
below) before submitting the application, i.e, as plans for the study are
being developed.  Furthermore, the applicant must obtain agreement from
Institute staff that the Institute will accept the application for
consideration for award.  Finally, the applicant must identify, in the cover
letter that is sent with the application, the staff member and Institute who
agreed to accept assignment of the application.

RESEARCH OBJECTIVES

Extensive scientific evidence supports a substantial genetic contribution to
complex behaviors in humans and animals, but the nature of that contribution
is still poorly understood.  Recently, preliminary evidence has been presented
for the chromosomal localization of genes for learning, emotionality, and
abnormal sensorimotor gating in mice.  This success provides further impetus
to the search for the genes and mechanisms that contribute to normal and
abnormal complex behaviors in animals and to complex behaviors of relevance to
human health and disease.  Through identification of genes underlying complex
behavioral traits that are also expressed in mental disorders, further insight
into the genetic basis of mental disorders as well as of complex behaviors may
be obtained.

To identify specific genes underlying complex behavioral traits, more research
is needed on the role of quantitative trait loci (QTLs) as well as of single
genes of major effect and the environmental factors that correlate or interact
with them.  Genetic technologies have progressed rapidly, permitting a
parallel expansion of research.  Our increasing ability to manipulate the
genome in experimental organisms has created new scientific opportunities to
understand the development of the genetics of complex behavior.  One important
approach in experimental organisms is random mutagenesis followed by screening
for impairments in behavioral phenotypes.  Another important approach is the
generation of null mutations or "knock-outs" using gene targeting technologies
with the goal of identification of novel behavioral mutations.  Ongoing
refinements of transgenic techniques for turning genes on or off in vivo (in
specific cell types and/or stages of development) as well as technological
refinements in measuring how these genetic alterations affect function in vivo
are creating new opportunities to investigate interactions between genes,
brain, and behavior.  However, progress in behavioral genetic research in
animals is impeded by many technical barriers which need to be addressed.  For
example, in the mouse, genetic mutations are being created in a limited number
of strains (those whose embryonic stem (ES) cells can be easily propagated in
germ line), some of which have atypical, if not aberrant, neurobehavioral
phenotypes.  The effects of many of the mutations being created are
developmentally and regionally nonspecific and therefore difficult to
interpret.

In the area of human behavioral genetics, statistical advances now allow
measured environmental risk factors to be actively incorporated into genetic
modeling to help understand the developmental cascades that underlie the
etiologic pathways to complex behaviors of particular relevance to human
health and disease.  Model fitting combined with new data collection
strategies such as studying twins and their parents using twin-family models
and the study of twins in a longitudinal or developmental framework has
increased the power to clarify the mechanisms of the cross-generational
transmission of complex behaviors.  Allelic association analyses allow QTLs
for human complex behaviors to be identified.  Much of this type of research
requires a prospective design to avoid the methodological limitations of
retrospectively gathered information such as recall bias, reduced power to
detect environmental effects, and confusion about the direction of effects in
attempting to relate environmental variables to complex behaviors.  Studies of
particular interest to the participating institutes would be those that
examine behavioral traits in young children, adolescents, and adults.

In addition to ongoing development of molecular genetic and statistical
techniques, advancement of the field of behavioral genetics will require
ongoing development of validated and reliable quantification of phenotypes. 
Quantification of phenotypes may include use of neuroanatomical and
physiological measures as well as of behavioral measures.  Behavioral measures
and equipment for analyzing complex behaviors must be validated and
operationalized so that valid and reliable criteria can be easily distributed
to the wider scientific community.

The following are examples of topics that would be of interest.  This list is
meant to be illustrative, not comprehensive. (Human research projects that
focus on the genetics of complex behaviors that are a component of human
behavioral disorders are encouraged under this PA; however, human research
projects that focus on the genetics of the comprehensive behavioral disorder
phenotype are not considered within the scope of this PA.)

o  Mapping and identification of genes influencing complex behavioral traits
in mice or rats using experimental designs such as congenic, recombinant
congenic, consomic, or transgenic strains.

o  Mapping and identification of genes influencing complex behavioral traits
in species other than the mouse or rat such as nonhuman primates, C. elegans,
Drosophila, zebrafish, or honeybees.

o  Mapping and identification of genes influencing complex behavioral traits
of relevance to human health and disease using methods such as allelic
association analyses in population samples employing within-family controls.

o  Identification of genes influencing complex behavioral traits in
experimental organisms using random mutagenesis (e.g., employing N-ethyl-N-
nitrosourea, chlorambucil, or x-rays).

o  Identification of genes influencing complex behavioral traits in
experimental organisms using transgenic methods of spatially and temporally
targeted misexpression of individual genes or using site-specific
recombination systems in transgenic animals.

o  Identification of QTLs influencing complex behaviors in animals, using
backcross, intercross, recombinant inbred strains or other experimental
designs for an initial genome scan, interval mapping or its variations to
estimate QTL map location, and single-QTL-oriented fine mapping using
strategies such as selective phenotyping or genetic chromosome dissection.

o  Identification of nontransmissable biological factors (including stochastic
DNA events such as genomic imprinting and unstable DNA sequences) that
regulate the expression of genes influencing complex behaviors, and estimation
of the relative contributions of genetic and environmental effects and
interactions.

o  Analyses to investigate the effects and interactions of genes and
environment on the development - over time - of complex behavioral traits.

o  Development and characterization of new ES cell lines from strains deemed
particularly useful for behavioral studies and/or with behavioral traits
potentially relevant to mental health research.

o  Development of new technologies relevant to the genetic analysis of complex
behaviors to manipulate and analyze gene expression in the brain in
developmentally and regionally specific manners.

o  Development of new and powerful quantitative methods for QTL mapping of
complex behaviors in experimental organisms, which are implemented in
efficient and well-documented computer programs distributed to the wider
scientific community.

Of particular interest to the NIMH are human and animal studies of complex
behaviors of relevance to the understanding of mental disorders.  Phenotypes
include a wide range of cognitive, emotional, affective, motor, social, and
other complex behaviors.

Of particular interest to the NIAAA are studies of complex behaviors of
relevance to the understanding of alcoholism and alcohol abuse.

Of particular interest to the NICHD are the following topics:

o  Studies that seek to identify linkages of distinct reading related
cognitive and linguistic processes to specific chromosomal loci in
longitudinal samples of individuals with reading disabilities.

o  Studies that elucidate genetically-based differences in response to well
defined interventions for the development of basic reading skills in
individuals with reading disabilities.

o  Studies to identify specific relationships between relevant chromosome
markers for reading-related cognitive and linguistic processes and specific
patterns of neural activation derived from fMRI studies of children and adults
with reading disabilities.

Of particular interest to the NIDR are the following topics:

o  Studies that clarify mechanisms underlying interactions between genetic and
environmental factors contributing to behaviors seen in individuals with
developmental disorders, such as cleft lip/cleft palate, disorders or rarer
craniofacial anomalies.

Of particular interest to the NIDA are the following topics:

o  Studies elucidating the molecular and genetic mechanisms of vulnerability
to addiction, dependence, tolerance, and sensitization to drugs of abuse
(nicotine, cocaine, heroin, amphetamine, cannabinoids, benzodiazepines,
barbiturates, LSD, etc.)

o  Studies elucidating genetically-based differences in vulnerability to
addiction and dependence following administration of analgesics.

Of particular interest to the NINDS are the following topics:

o  Identification of genes influencing presence of motor compulsions or motor
stereotypies in animal models.

o  Quantification of genetic, environmental, and gene-environment interaction
effects on problem solving behavior in humans and animals.

o  Identification of genetic contributions to individual differences in
recovery following injury from trauma or stroke.

Of particular interest to the NIDA, NIDR, and NINDS are topics related to the
study of pain:

o  Studies elucidating genetically-based differences in response to pain and
to analgesics.  Such differences can be studied in human and animal models and
may underlie differences seen in vulnerability to the development of
neuropathic pain following injury and differential risks for chronic pain
conditions.  Also of interest are genetic factors and genetic-environmental
interactions underlying hypervigilance to either nociceptive or other sensory
stimuli.  Genetic differences in the efficacy of various analgesics.  Further,
the use of genetic techniques to alter pain sensory processing.

SPECIAL REQUIREMENTS

Data and Biological Materials Dissemination

The sharing of materials, data, and software in a timely manner has been an
essential element in the rapid progress that has been made in genome research. 
Although PHS policy requires that investigators make unique research
resources, including DNA sequences and mapping information, readily available
when they have been published (PHS Grants Policy Statement, April 1, 1994, pp.
8-25 to 8-26), the advisors to the NIH and the Department of Energy (DOE)
genome programs have encouraged more rapid sharing.  This has, in fact, become
the norm in the genome community.

To address the joint interests of the government in the availability of, and
access to, the results of publicly funded research and in the opportunity for
economic development based on those results, NIH requires applicants who
respond to this PA to develop and propose a detailed plan and timetable for
sharing the data, materials, phenotyping tools, and software generated through
the grant.  Applications submitted in response to this PA that propose to
develop new animal models, may, for example, include a plan (and a request for
funds) for cryopreservation of embryos or sperm for storage and dissemination
of strains developed through the grant.  Applications submitted in response to
this PA to develop new statistical methods must include a detailed plan and
timetable for rapidly developing and widely distributing new computer programs
that implement the proposed methods to the scientific community of biomedical
researchers studying the genetics of complex behaviors in experimental
organisms.  The preferred mode of distribution for data on map locations and
DNA sequences and for new computer programs will be through a well-publicized
World Wide Web site.  It is strongly encouraged that this site provides an
opportunity for users to direct questions to the developer about new analytic
methods and software.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 12)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address:  http://www.nih.gov/grants/guide/notice-files/not98-024.html

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 Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267; fax: (301) 480-0525 Email: GrantsInfo@NIH.GOV.  The title and number of
the program announcement must be typed in Section 2 on the face page of the
application.

The completed original application and five legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (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 may undergo a process in
which only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written review, comments on the following aspects of the application will
be made in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria
will be addressed and considered in the assignment of the overall score:

(1) Significance
Does this study address an important problem? If the aims of the application
are achieved, how will scientific knowledge be advanced? What will be the
effect of these studies on the concepts or methods that drive this field?

(2) Approach
Are the conceptual framework, design, methods, and analyses adequately
developed, well integrated, and appropriate to the aims of the project? Does
the applicant acknowledge potential problem areas and consider alternative
tactics?

(3) Innovation
Does the project employ novel concepts, approaches or method? Are the aims
original and innovative? Does the project challenge existing paradigms or
develop new methodologies or technologies?

(4) Investigator
Is the investigator appropriately trained and well suited to carry out this
work? Is the work proposed appropriate to the experience level of the
principal investigator and other researchers (if any)?

(5) Environment
Does the scientific environment in which the work will be done contribute to
the probability of success? Do the proposed experiments take advantage of
unique features of the scientific environment or employ useful collaborative
arrangements? Is there evidence of institutional support?

The initial review group will also examine the provisions for the protection
of human and animal subjects, the safety of the research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities
as Subjects in Clinical Research.  The reviewers will also be instructed to
address the adequacy of plans for including children as appropriate for the
scientific goals of the research, or justification for exclusion.

In addition, for this Program Announcement the review will also assess:

o  Scalability:  For technology development, what is the likelihood that the
technology or approach will be able to be used efficiently at a full
production level in a timely manner?

o  Exportability and accessibility: If applicable, will the quantitative
methods developed in the research project be implemented and documented in
software that runs efficiently in a variety of computer environments and
operating systems?

o  Data and biological materials dissemination: Are there adequate plans for
making the data, materials, phenotyping tools, and software generated through
the grant highly accessible to the biomedical research community?

For applications dealing with data, the initial review group will comment on
the proposed plan for sharing and data release.  The adequacy of this plan
will also be considered by NIH staff as one of the criteria for award.  The
proposed sharing plan, after negotiation with the applicant when necessary,
will be made a condition of the award.  Evaluation of renewal applications
will include assessment of the effectiveness of data, material, and software
release.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  Factors that will be used to make award decisions are as
follows:

o  Quality of the proposed project as determined by rigorous scientific peer
review;

o  Cost effectiveness of the proposed strategy;

o  Adequacy of plans to make data, materials, phenotyping tools, and software
generated through the grant highly accessible to the biomedical research
community;

o  Adequacy of plans to phenotype subjects in a valid and replicable way;

o  Availability of funds.

INQUIRIES

Written, telephone, and e-mail inquiries concerning this PA are encouraged. 
The opportunity to clarify any issues or questions from potential applicants
is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Mary E. Farmer
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857
Telephone:  (301) 443-1411
FAX:  (301) 443-9890
Email:  mary_farmer@nih.gov

Dr. Robert W. Karp
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  rkarp@willco.niaaa.nih.gov

Dr. Patricia S. Bryant
Behavior, Health Promotion, and Environment Program
National Institute of Dental Research
45 Center Drive, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2095
FAX:  (301) 480-8318
Email:  bryantp@de45.nidr.nih.gov

Dr. Jonathan D. Pollock
Division of Basic Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A19
Rockville, MD  20857
Telephone:  (301) 594-6300
FAX:  (301) 594-6043
Email:  jp183r@nih.gov

Dr. Sarah H. Broman
Division of Fundamental Neuroscience and Developmental Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 8C06
Bethesda, MD  20892-9170
Telephone:  (301) 496-5821
FAX:  (301) 402-1501
Email:  sb73f@nih.gov

Dr. Irene Anne Eckstrand
National Institute of General Medical Sciences
45 Center Drive, Room 2AS.25K
Bethesda, MD  20892-6200
Telephone:  (301) 594-0943
FAX:  (301) 480-2228
Email:  irene_eckstrand@nih.gov

Dr. G. Reid Lyon
Child Development and Behavior Branch
National Institute of Child Health and Human Development
6100 Building, Room 4B05
Bethesda, MD  20852
Telephone:  (301) 496-9849
FAX:  (301) 480-7773
Email:  lyonr@exchange.nih.gov

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email:  diana_trunnell@nih.gov

Ms. Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4703
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov

Ms. Bonnie J. Smith
Grants Management Branch
Division of Extramural Research
National Institute of Dental Research
45 Center Drive, Room 4AN-32A, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  bonnie.smith@nih.gov

Dr. Gary Fleming
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  gf6s@nih.gov

Ms. Gladys Bohler
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 1004
Bethesda, MD  20892-9091
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  gb13y@nih.gov

Ms. Marcia Cohn
National Institute of General Medical Sciences
45 Center Drive, Room 2AN.44E
Bethesda, MD 20892-6200
Telephone:  (301) 594-3918
FAX:  (301) 480-1852
Email:  cohnm@nigms.nih.gov

Mr. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Building, Room 8A17E
Rockville, MD  20852
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  shawverd@hd01.nichd.nih.gov

Although the National Institute on Aging (NIA) is not a co-sponsor of the PA,
Applicants interested in studies concerning these issues as they pertain to
adult development and aging should refer to PA-98-076 or contact:

Dr. Jared B. Jobe
Behavioral and Social Research
National Institute on Aging
7201 Wisconsin Avenue, Suite 533, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-3137
FAX:  (301) 402-0051
Email:  jared_jobe@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.242 (NIMH), 93.862 (NIGMS), 93.854 (NINDS), 93.279 (NIDA),  93.273 (NIAAA),
93.121 (NIDR), 93.865 (NICHD).  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by
Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 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.  Awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy Statement
(April 1, 1994).

PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the nonuse 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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