INTEGRATIVE NEUROSCIENCE INITIATIVE ON ALCOHOLISM

Release Date:  January 22, 2001

RFA:  RFA-AA-01-002 (Notice of Limited Competition Request for Applications,
                     see NOT-AA-06-101)

National Institute on Alcohol Abuse and Alcoholism
 (http://www.niaaa.nih.gov/)

Letter of Intent Receipt Date:  March 16, 2001
Application Receipt Date:       April 27, 2001

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites 
applications for a Consortium for the “Integrative Neuroscience Initiative on 
Alcoholism “ (INIA).  This initiative will  support highly integrated 
multidisciplinary research across different research institutions to 
elucidate the neurobiological mechanisms underlying various aspects of 
neuroadaptation to alcohol (reinforcement, tolerance, sensitization, 
withdrawal and relapse).  This multidisciplinary initiative will integrate 
neurobiological, behavioral, and molecular genetic approaches to determine 
how these aspects of neuroadaptation ultimately contribute to excessive 
alcohol intake. Furthermore, the initiative will integrate existing resources 
within the  alcohol research community and will also create new resources 
that are crucial for the success of the research questions being addressed 
under this initiative.  INIA will also provide opportunities for 
collaboration between scientists in the alcohol field and prominent 
investigators from other research areas, resulting in the application of new 
ideas and technology to the study of neuroadaptation to alcohol. 

HEALTHY PEOPLE 2010 

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas. This RFA, Integrative 
Neuroscience Initiative on Alcoholism, is related to the priority area of 
alcohol abuse and alcoholism reduction. Potential applicants may obtain a 
copy of "Healthy People 2010" at: http://www.health.gov/healthypeople. 

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.   The Consortium Coordinator’s 
application  (lead application) and the core applications have to be from 
domestic organizations or institutions.  However, foreign institutions may be 
eligible as principal applicants of one or more of the participating sites 
for the research project components within the consortium. Racial/ethnic 
minority individuals, women, and persons with disabilities are encouraged to 
apply as principal investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be 
multiple  cooperative agreement  mechanisms (U01and U24).  These are 
assistance mechanisms (rather than an acquisition mechanism) in which 
substantial NIH scientific and/or programmatic involvement with the awardee 
is anticipated during performance of the activity.  Under the cooperative 
agreement, the NIH purpose is to support and/or stimulate the recipient"s 
activity by involvement in and otherwise working jointly with the award 
recipient in a partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity.  Details of the 
responsibilities, relationships and governance of the study to be funded 
under cooperative agreement(s) are discussed later in this document under the 
section "Terms and Conditions of Award."

FUNDS AVAILABLE  

The NIAAA intends to commit approximately $10,000,000 in FY 2001/ 2002 to 
fund one or more consortium or cluster of new cooperative agreements in 
response to this RFA.  An applicant may request a project period up to a 
maximum of 5 years support.  There is a cap of $5,000,000 in direct costs for 
each consortium or cluster of applications responding to this RFA for the 
first year budget period (with a maximum increase in cost in subsequent years 
of three percent).  Because the nature and scope of the research proposed in 
response to this RFA might vary, it is anticipated that the size of awards 
will vary also.  Although this program is provided for in the financial plans 
of the NIAAA, awards pursuant to this RFA are contingent upon the 
availability of funds for this purpose and the receipt of applications of 
outstanding scientific and technical merit.

Funds provided under this program may not be used for the purchase of land, 
nor for the purchase, construction, preservation, or repair of any building. 
However, costs of alteration and renovation of existing facilities necessary 
to accomplish the objectives of the grant may be allowed subject to NIH 
grants policy limitations and approval by NIAAA staff.

This RFA is a one-time solicitation. The total project period for an 
application submitted in response to this RFA may not exceed 5 years, with an 
anticipated award date of September 28, 2001.  In addition, meritorious 
Research Components from other Consortium applications not funded may be 
added to the funded consortium at the discretion of NIAAA and taking into 
account budget limitations and input from its National Advisory Council. 

RESEARCH OBJECTIVES, SCOPE AND ORGANIZATION

NIAAA recognizes the innovation, synergy, and conceptual advances that arise 
from interactions across scientific disciplines, methodologies, and levels of 
analysis.  It is anticipated that under this initiative knowledge will be 
generated and integrated from all levels of analysis using state-of-the-art 
techniques at each level.  Neuroscience expertise has become so sophisticated 
at any given level of analysis that integration at the level of individual 
investigators becomes very difficult to accomplish, particularly to a level 
of analysis outside of their domain.  The INIA initiative would induce such 
integration and significantly speed up the translation of such critical new 
information to the clinical condition. 

The incorporation of groups of scientists into a research consortium focused 
on the neuroscience of alcoholism will also offer additional advantages.  The 
rapid and detailed exchange of information among INIA members will provide 
immediate opportunities for applying the Consortium expertise to profitable 
research arenas.  The success of the proposed initiative will thus relate to 
the presence of research expertise that uses the full gamut of molecular, 
cellular, neurochemical techniques, neurocircuitry and neural network 
expertise, animal genetics, animal behavior and psychopharmacology to study 
the neuroscience of alcoholism.  Thus, information flowing both from the most 
basic molecular level to the behavioral level and back again can be melded 
into optimally productive research protocols at multiple levels of endeavor 
with the focus on the neurocircuitry of excessive alcohol intake. 

Organization

The following structure of INIA is envisioned.  The INIA Consortium will 
consist of a cluster of integrated cooperative agreement research 
applications (U01s) and a set of five distributed core facilities (U24s) and 
will be led by a Consortium  Coordinator (CC).  A highly integrated 
multidisciplinary research consortium will thus be formed from groups of 
investigators (within and across institutions) whose scientific and technical 
expertise will enable them to interactively study the neuroadaptive effects 
of ethanol from the molecular through the cellular and neural network levels 
to well characterized and validated behavioral models.  The approaches used 
will reflect the blend of experience and creativity of the INIA components 
and will be originated by these investigators.  Through formation of INIA, 
the integrated research project component groups will have access through the 
core facilities to resources, information, technologies, ideas, and expertise 
that are beyond the scope of any single research team. In addition, the 
consortium will recruit neuroscience expertise and approaches currently 
outside the realm of alcohol research and establish state-of-the-art research 
resources and information networks for alcohol research. 

The Consortium Coordinator is the scientist who assembles the integrated and 
collaborative research consortium and is responsible for submitting the 
cluster of applications in response to this RFA and for performance of the 
project. The consortium coordinator must be recognized in the area of alcohol 
research, especially in one of the three interactive research areas or 
domains of INIA described below.  Because a substantial level of effort will 
be necessary to manage a project of this magnitude, the Consortium 
Coordinator is expected to make a major commitment to directing, managing and 
executing the goals and collaborative nature of this project. 

The Consortium Coordinator application will be the lead application of the 
consortium and should include the Administrative Coordinating Core, together 
with the Administrative Management Plan, Plan for Data Sharing and 
Intellectual Property and the Pilot Project Component  (more details are 
given elsewhere in this announcement).  The lead application should discuss 
the theme and goals of the consortium and should include a scientific 
rationale for the various research project component and resource core 
applications that make up the consortium.  It should further describe the 
benefits of the proposed integration between projects and how the individual 
applications complement each other to enhance the scientific goals of the 
consortium.  Given that an important element of this initiative is the 
collaboration between leading scientists in the alcohol field and prominent 
investigators from other fields, the lead application should also discuss how 
the consortium has achieved that goal. It should describe how these 
investigators not previously active in alcohol research will participate in 
either the research project components or the resource core facilities 
applications of INIA. The lead application should also include a composite 
budget of the whole consortium in addition to its own individual budget. It 
is acceptable for the consortium coordinator to submit a research project 
component or a resource core application in addition to the lead application.  
While each application (U01 or U24) will originate from the principal 
investigator(s) research institution and awards will be made to individual 
institutions, it is the responsibility of the consortium coordinator to 
submit the cluster of applications of the consortium together with the 
appropriate cover letter as one package (See Application Procedures and 
Application Submission Section).

Research Project Components

Specific research project components to be undertaken under the consortium 
will take the form of U01 grant applications and are expected to be 
integrated with the other research projects of INIA.  These research project 
component applications are expected to address at least one of three research 
areas or domains, namely behavioral, neural circuitry or molecular research 
domains (discussed in more detail below).  It is anticipated that several of 
the U01 applications within the consortium will address the same research 
domain, but will differ in emphasis, approaches and research questions being 
addressed.  Research project component applications can request a maximum 
support period of five years.  Applications should include a detailed budget 
and must follow the traditional PHS 398 application instructions. 

The U01 research project component applications must utilize the resources 
and the new technologies developed of one or more resource cores (U24) at one 
or more sites and advance the scientific goals of INIA.  However, the 
research undertaken by a research project component can be performed at a 
research site other than the one housing the core site.  Exploratory and 
development projects will also use the U01 mechanism but will be limited to 
three years of support and with a maximum budget of up to $100,000 direct 
costs per year.

Behavioral Research Component.  This component will be responsible for the 
design and validation of  behavioral paradigms for use by INIA.  In addition 
to existing models for sensitization, tolerance, dependence, withdrawal, 
recovery, and relapse, additional behavioral/neurobiological models require 
development, validation, and refinement for specific, alcohol-related 
neuroadaptive phenomena.  These animal models may include models of inherent 
excessive drinking, excessive drinking driven by dependence and acute 
abstinence by protracted abstinence, by loss of satiety control, and models 
of vulnerability to relapse.  Separate models may be needed for mouse, rat, 
and non-human primates, depending on the specific phenomenon being studied 
and the appropriateness of the animal. The component will also choose 
environmental conditions influencing neuroadaptation, as well as genetically-
based strain differences.  Genetically-based models can use naturally 
occurring genetic variation (e.g., selective breeding, congenic strains 
generated from QTL mapping studies) or artificially induced mutations (e.g., 
targeted or random mutagenesis).  These models will provide the bases for 
interactive collaborations with other components of INIA.  Proper design of 
studies using genetically based models will require intimate collaboration 
between investigators with behavioral and genetic expertise, respectively.  
These investigators may reside either in this component, or in the Animal 
Models Core (see below).

Neural Circuit Research Component.  This component will identify and analyze 
neural circuits employing advanced electrophysiological, neurochemical, and 
anatomical techniques underlying the various neuroadaptive responses to 
alcohol. Research is required using multicellular/multiregional techniques in 
behaving animals to identify and map neural connections within circuits, to 
study changes in properties of cells, receptors and ion channels within the 
circuit that occur with ethanol-induced neuroadaptation, and to demonstrate 
how these responses contribute to excessive alcohol consumption. 

Because alcohol-induced neuroadaptation may result in changes in synaptic 
morphology in relevant neural circuits, anatomical techniques will be needed 
to assess synaptic density and size and number of dendrites.  In addition, 
once neurons have been identified whose activity correlates best with the 
behavioral state being studied, neuroanatomical pathway tracing protocols, 
such as those employing horseradish peroxidase and pseudorabies virus as 
tracers, will need to be used to identify intranuclear projections of those 
neurons or internuclear connections along the neural circuit.

Confocal fluorescence microscopy or other high-resolution optical imaging 
techniques to map neural circuits and pathways can be used in combination 
with neurophysiological recording techniques, to identify changes in 
excitability and neuronal communication within identified neurons during 
neuroadaptation.  The results found will be integrated with gene expression 
studies.  Lastly, approaches developed from computational neurobiology will 
be used to model neural networks, and in an iterative process, identify new 
avenues of research.

Molecular Research Component.  This component will identify the molecular 
changes induced by ethanol in the neural circuits identified by the Neural 
Circuits Component. Studies could include receptors and subunit changes and 
signal transduction pathways, looking for common elements that might 
stimulate neuroadaptive changes.  An important element of the research is to 
find specific proteins responsible for the induction and maintenance of 
alcohol dependence.  This may require developing innovative new molecular 
approaches to study neuroadaptation to alcohol exposure.

Resource Core Facilities

To support the Components of the Consortium, five distributed core resources 
(U24s), each of which can be located at multiple physical sites, will be 
needed by INIA.  The Animal Production, Gene Expression, Imaging and 
Informatics Cores will provide facilities for central processing of 
information generated at different levels of analysis.  This information will 
be shared by the Research Components through the Informatics Core.  The power 
of such an approach is immense, and it will require a strong integrative 
arrangement.  It is possible that some of the core facilities would have 
multiple sites.  For example, under the Animal Production Core one site could 
be devoted exclusively to mice, whereas another geographically different site 
could be devoted to rats.  In this case, an application (U24) should be 
submitted from each of the sites with a detailed scientific rationale and 
budget for that core site.  The consortium coordinator should clearly detail, 
as part of the Administrative Management Plan, the number, location and 
specialties of the sites comprising every core facility.  Each core component 
is expected to be directed by an investigator with established expertise 
relative to the support or service provided, usually a faculty-level 
individual.

Administrative Coordinating Core.  The Administrative Coordinating Core will 
provide the organizational framework for the management, direction, and 
overall coordination of the consortium.  It will coordinate use of core 
resources to the Research Project Components and will acquire and direct data 
from the Research Components to the Informatics Core.  The consortium 
coordinator will manage the administrative core.  The Administrative 
Coordinating Core will include an Administrative Management plan (See below) 
and this core will also be responsible for the collaborative responsibilities 
such as the functions of the Scientific Advisory Panel and the overseeing of 
a Steering Committee to help develop interactive protocols, evaluate results, 
and suggest future directions.  The core will also administer the Pilot 
Projects Component of INIA  (discussed below) as well as the sharing of data 
and information between the INIA components. This core is responsible for 
scientific enrichment activities such as workshops for the researchers and 
investigators of INIA. In addition, the core will be responsible for 
organizing an annual meeting of the INIA investigators. 

Animal Production Core: This core will provide genetically altered animals to 
the Research Project Components.  They can be acquired from outside INIA or 
developed within INIA by the use of techniques such as targeted mutation or 
random mutagenesis.  Whereas mutants created by random mutagenesis with 
altered alcohol-related behavior are not yet available, NIAAA has funded 
screens to generate such mutants, and encourages investigators to use these 
mutants as they become available for their studies of behavioral and neural 
adaptation to alcohol. 

The most recently developed knockout methods disrupt the gene only in a 
restricted set of tissues rather than in the whole animal (tissue-specific 
knockouts), or disrupt the gene by precisely timed delivery of a chemical 
inducer (inducible knockouts).  NIAAA encourages investigators to employ 
these more sophisticated technologies.  Although reliable methods for 
germline modification in the rat are not yet available, they are under active 
development.  INIA applicants should document (now) their readiness to apply 
these methods as they become available.

Gene Expression Core: This core will be responsible for the High-Throughput 
Gene Expression  Assays (cDNA and Oligonucleotide Microarrays) and high-
throughput protein arrays.  It will establish facilities which could utilize 
commercially available as well as custom-made microarrays for mRNA 
expression.  It will also have the capabilities of manufacturing and 
distribution of custom cDNA and oligonucleotide-based arrays on glass or 
plastic slides for use by the consortium researchers.  It will also be 
responsible for standardizing arrays for comparison of data among different 
research groups as well as maintain a repository of the alcohol-related 
expression data of INIA projects.  It will also develop and implement 
techniques for data retrieval, distribution storage and analysis in the 
Informatics Resource Core of INIA.  Lastly, it will begin developing the 
technology and the resources in the area of proteomics.

Imaging Core.  This core will provide imaging services to the components. It 
will develop small animal imaging techniques for in vivo studies.  The core 
will focus on multiple imaging technologies for small animals, emphasizing, 
but not limited to, those technologies which can provide biochemical, genetic 
or pharmacological information in vivo. Technology research and development 
of innovative new imaging technologies appropriate for small animals, as well 
as refinement and development of technologies already established will also 
be an additional focus of this core. The future of MR for animal and human 
studies will ultimately incorporate "molecular imaging" which could involve 
the tagging of gadolinium-coated liposomes or dextran-coated iron particles 
with molecules that bind to surface cell receptors.

Informatics Core.  This core collects and stores data generated by the 
Research Project Components and will provide an interactive user interface 
for all components.  It will devise methods for integrating data from 
different levels of analysis from the molecular to the behavioral levels.  In 
addition, it will be responsible for creating a database for alcohol-related 
proteomics research data as well as gene expression data generated from 
multiplex hybridization array assays.  With the establishment of these 
databases, there is also a need for additional refinement of bioinformatic 
tools (such as developing interoperable informatics software packages) to 
facilitate extraction and efficient dissemination of information from these 
databases.  Consistent with NIH policy 
(http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm and 
http://grants.nih.gov/grants/policy/policy.htm), it is expected that the 
databases developed will be available for use by non-INIA investigators.  
Applicants will need to develop a plan to be approved by the Institute 
indicating how they will comply with the policy.

OTHER ELEMENTS OF THE INTEGRATED AND COLLABORATIVE PROJECT – INIA

Administrative and Project Management Plans: The Consortium Coordinator must 
include an Administrative Management Plan that outlines the policies and 
procedures for access of participating investigators to the collaborative 
project resources.  The application should address the flow of information 
within the project, the integration among individual projects and plans for 
how the information will be integrated into the solution of the overall 
scientific theme or question being addressed.  The application must include a 
Project Management Plan, including an ongoing evaluation plan, to ensure 
consistent forward progress of the project.  The mechanism to add new 
participating investigators and dealing with members whose association with 
the project has not been productive should be documented in the proposal.  
The plan should also include proposed methods for information dissemination 
both within the collaborative project and to the scientific community.  
Furthermore, the application will include a mechanism to consider and respond 
to concerns of the scientific community directly affected by the operation 
and impact of the project.  A discussion of scientific community views will 
be part of the agenda for annual meetings of the Steering Committee with the 
Scientific Advisory Panel.

Plan for Data Sharing and Intellectual Property: NIH requires applicants who 
respond to this RFA to develop and propose specific plans for sharing the 
data and materials generated through the large-scale collaborative project.  
This requirement addresses the interests of the Government in the 
availability of, and access to, the results of publicly funded research.  The 
initial review group will comment on the proposed plans.  In addition, as one 
of the criteria for award, NIAAA staff will also consider the adequacy of the 
plans.  Because dissemination is a critical and important aspect of this RFA, 
the proposed sharing and data release plans, after negotiation with the 
applicant when necessary, will be made a condition of the award.  The members 
of the consortium should disclose to the Steering Committee their ties to 
profit-making organizations to aid the project in avoiding conflict of 
interest situations.  Applicants are also reminded that the grantee 
institution is required to disclose each subject invention to NIAAA within 
two months after the inventor discloses it in writing to grantee institution 
personnel responsible for patent matters. 

Pilot Project Component: Pilot projects provide the consortium with a 
flexible means to develop and explore quickly new research activities or 
directions, and unique scientific opportunities that could evolve into 
independently funded research projects.  These funds are not intended to 
supplement ongoing projects.  Pilot projects must be in a separate pilot 
project component that incorporates all of the pilot studies of the proposed 
consortium and should be included in the consortium coordinator’s 
application.  The total costs for the Pilot Project component should not 
exceed $400,000 per year.

The process for selecting pilot projects should be fully, though concisely 
described. For the first 2 years that funds are requested for pilot projects, 
the application must provide descriptions of the projects to be supported. It 
is recognized that for years 3-5, it may not be possible to provide 
comprehensive descriptions of the pilot projects to be supported, since some 
of these projects will develop on the basis of scientific breakthroughs or 
directions occurring at the time.  However, the application must provide the 
specific number of pilots planned in each year.  While the specific number of 
pilot projects to be proposed is at the discretion of the Principal 
Investigator, requested direct cost funding for each pilot study may not 
exceed $50,000 per year. All proposed pilot projects need not be ongoing at 
any one time, but may be phased in at different points during the course of 
the proposed consortium.  It is recognized that the relative priority or need 
for specific pilot projects may change over time.  While the consortium’s 
framework for management of pilot funds and the mechanism for operating the 
program are left to the discretion of the Program Coordinator, the 
application must provide specific information to enable adequate scientific 
evaluation by a peer review committee.  The application should include: a 
full description of the management of the pilot project component, including 
a description of the process to be followed by the consortium’s program 
coordinator in selecting new pilot projects and replacing projects should it 
become necessary.  A full description of each pilot study proposed in the 
first 2 years will include its rationale, objectives, approach, 
investigators, and significance for the consortium.  A description of the 
number and anticipated direction of pilot projects in the 3-5 years will be 
provided including their significance to the consortium.  The research 
description of any individual pilot project may not exceed five pages, the 
entire narrative for this Pilot Project Component may not exceed 25 pages 
irrespective of the number of pilot projects proposed. 

SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS

Terms and Conditions of Award 

The following Terms and Conditions will be incorporated into the award 
statement and will be provided to the consortium coordinator, to the 
principal investigators of the individual research components and core 
facilities, and to the appropriate institutional officials at the time of 
award.  The following special terms of award are in addition to, and not in 
lieu of, otherwise applicable OMB administrative guidelines, HHS grant 
administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable 
when State and local Governments are eligible to apply), and other HHS, PHS, 
and NIH grant administration policies.  The administrative and funding 
instrument used for this program will be the cooperative agreement, an 
"assistance" mechanism (rather than an "acquisition" mechanism), in which 
substantial NIAAA programmatic involvement with the awardees is anticipated 
during performance of the activities.  Under the cooperative agreement, the 
NIAAA supports and stimulates the recipients" activities by involvement in 
and otherwise working jointly with the award recipients in a partnership 
role, it is not to assume direction, prime responsibility, or a dominant role 
in the activities.  Consistent with this concept, the dominant role and prime 
responsibility resides with the awardees for the project as a whole. Awardees 
will retain custody of and have primary rights to the data developed under 
these awards, subject to Government rights of access consistent with current 
HHS, PHS, and NIH policies. Awardees should comply with their institutional 
intellectual property policies and practices as approved in the award. 
However, awardees will be expected to share (make available) these data 
openly with the scientific community. 

1.  Investigator Responsibilities

	A. Consortium Coordinator’s Responsibilities: 

The consortium coordinator will coordinate project activities scientifically 
and administratively at the awardee institution. The consortium coordinator 
will have the overall responsibility for the scientific and technical 
direction and the administration and overall operation of the consortium. To 
assist the consortium coordinator with the governing of the project, a 
steering committee will be established from among the participating 
investigators and NIAAA staff. The consortium coordinator will chair the 
steering committee.  As for all participating investigators, the consortium 
coordinator must abide by the operating rules and guidelines developed by the 
steering committee. The consortium coordinator will agree to accept 
participation of NIAAA staff in those aspects of management of the project 
described under "NIAAA Program Official’s Responsibilities." The consortium 
coordinator will also ensure the timely dissemination of information 
generated by the consortium component projects to both the consortium project 
members and the scientific public. 

B.  Participating Investigator Responsibilities:

In addition to the consortium coordinator, as well as principal investigators 
(PIs) of individual research project components and core facilities of the 
consortium, each research project component will include a team of 
investigators who will contribute to and benefit from participation in the 
consortium.  These members of the consortium will be referred to collectively 
as participating investigators.  They will receive separate awards and have 
control over their own operating budgets.  The PI of the individual research 
project award and the resource core award will be responsible for the 
scientific and technical direction of the project, as well as for following 
consortium policies and rules.  Participating investigators must also agree 
to abide by the policies and rules set up for the collaborative research 
consortium.   It is expected that over the period of the award, additional 
applications for participation in the consortium will be submitted to NIAAA 
for review and award consideration, as deemed appropriate by the consortium 
coordinator and steering committee and with the approval of the NIAAA program 
official, these additions will be reported in the annual progress report. 

2.   NIAAA Staff Responsibilities

The NIAAA Program Official and the two Staff Collaborators will have 
substantial scientific-programmatic involvement during conduct of this 
activity, through technical assistance, advice and coordination above and 
beyond normal program stewardship for grants, as described below. The 
dominant role and prime responsibility for the activity resides with the 
awardees for the project as a whole, although specific tasks and activities 
in carrying out the studies will be shared among the awardees, the NIAAA 
Program Official, and the Staff Collaborators.

The two NIAAA Staff Collaborators will have voting membership (one vote) on 
the Steering Committee and, as determined by that committee, its 
subcommittees.

The NIAAA Staff Collaborators will coordinate and facilitate the INIA 
Consortium programs, will attend and participate as a voting member in all 
meetings of the INIA Steering Committee, and will provide liaison between the 
Steering Committee, the INIA Consortium, and the NIAAA.

 The NIAAA  Staff Collaborators will assist the Steering Committee in 
developing and drafting operating policies and policies for dealing with 
recurring situations that require coordinated action.

The NIAAA Program Official will review the scientific progress of individual 
components, and review them for compliance with the operating policies 
developed by the Steering Committee, and may recommend withholding of 
support, suspension, or termination of an award for lack of scientific 
progress or failure to adhere to policies established by the Steering 
Committee.

3.  Collaborative Responsibilities

Scientific Advisory Panel 

The INIA project will include an external scientific advisory panel whose 
purpose is to meet annually with the consortium coordinator and the steering 
committee to assess progress and provide feedback to the INIA investigators 
and NIAAA on proposed goals for the next year of support.  The members will 
be designated by the NIAAA in consultation with the steering committee, after 
the award has been made, and will be drawn from research scientists not 
involved in the project. The NIAAA staff collaborators will attend the 
meeting of the scientific advisory panel as members of the steering 
committee, but will not be members of the scientific advisory panel. The 
scientific advisory panel will meet at least once a year immediately prior to 
the submission of the annual progress report. 

Steering Committee

The NIAAA staff collaborators and the awardees that comprise the INIA will be 
responsible for forming a Steering Committee as defined below. The Steering 
Committee will be the main governing board of the INIA. It will develop 
collaborative protocols, and function to set priorities for model derivation, 
define the parameters for model validation, identify technological 
impediments to success and strategies to overcome them, and decide when 
models should be made available to the research community for individual 
investigator-initiated projects.

The Steering Committee will be composed of the consortium coordinator, 
principal investigators of the research project components and core 
facilities, and the NIAAA staff collaborators.  The members of the Steering 
Committee will each have one vote.  The chairperson of the steering committee 
will be the consortium coordinator.  NIAAA reserves the right to appoint 
additional members of NIAAA staff as nonvoting members of the INIA Steering 
Committee and Subcommittees.

The Steering Committee may, when deemed necessary, invite additional, 
non-voting scientific advisors to the meetings at which research priorities 
and opportunities are discussed.  NIAAA reserves the right to augment the 
scientific or consumer expertise of the INIA Steering Committee when 
necessary.

There will be two Steering Committee meetings initially (during the first two 
years of support), one in the Washington, D.C. area, and the other at a time 
and site agreed upon by the Steering Committee and the NIAAA.  In years 3-5, 
the Steering Committee will meet once a year.  The first meeting of INIA will 
be a Planning Meeting, which will take place in the Washington, D.C. area 
very shortly after award of the grants.  At the Planning Meeting, the 
Committee will: a) determine the size of the Steering Committee and the 
representation of individual research project and resource core awardees on 
the Steering Committee, b) draft a charter, the purpose of which is to define 
the administrative policies and procedures for oversight of the project, the 
process for monitoring compliance with those policies and procedures, and the 
process for recommending that the NIAAA act on evidence of non-compliance of 
any consortium component with Steering Committee policies, c) agree upon the 
terms of the charter, d) discuss the models and approaches that were proposed 
in the individual component and core applications, any relevant new 
information, and set initial priorities for the models to be derived and for 
new technologies to be developed, and, e) discuss and set initial standards 
for validating the models for further biological studies. At their first 
meeting each year, the Steering Committee will formulate plans for any new 
pilot projects to be funded. They will discuss projects to be pursued jointly 
with funds set aside from the pilot projects budget. At subsequent meetings, 
the Steering Committee will refine the scientific objectives and 
characterization and validation strategies of INIA, as necessary, consistent 
with progress in the INIA consortium components and other laboratories, and 
with the goals of identifying available models with sufficient promise for 
further analysis.

At any time during the INIA project, the Steering Committee may examine the 
characterization and validation data for models derived by the INIA 
consortium components, and decide when a model is sufficiently validated that 
it may be distributed to the research community for further investigations or 
applications. The NIAAA will provide the means to disseminate the models 
themselves and the information related to them.

The Steering Committee will plan one or more workshops a year to which 
non-INIA participants will also be invited to enable the INIA consortium to 
explore scientific or technologic innovation that occurs during the course of 
the project.  For the second and subsequent years of operation of the INIA 
consortium, the Steering Committee will plan a symposium to inform the 
research community of the progress made toward derivation or refinement of 
models, their characterization and validated uses, and any technological 
advances related to design and derivation of these models.  The NIAAA Program 
Official and other NIAAA staff will provide the Steering Committee with 
advice on participants for the workshops and symposia, and manage the 
logistics for these meetings.

The Steering Committee may establish subcommittees as it deems appropriate.  
The NIAAA Program Official and the other NIAAA/NIH staff who are Steering 
Committee members may serve on subcommittees.

Awardees will be required to accept actions and recommendations approved by 
the Steering Committee.  

4. Arbitration

Any disagreement that may arise on scientific or programmatic matters (within 
the scope of the collaborative mechanism award) between U01 and U24 awardees 
and the NIAAA may be brought to arbitration.  An arbitration panel will be 
composed of three members: one selected by the Steering Committee (with the 
NIAAA Program Official not voting), or by the individual awardee in the event 
of an individual disagreement, a second member selected by the NIAAA, and, 
the third member selected by the two prior selected members.  This special 
arbitration procedure in no way affects the awardee"s right to appeal an 
adverse action that is otherwise appealable in accordance with the PHS 
regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 
16.

SCIENTIFIC BACKGROUND AND RATIONALE OF INIA

Background

Chronic exposure to alcohol results in several neuroadaptative phenomena, 
including tolerance, sensitization, dependence, withdrawal and relapse, that 
may contribute to the development of alcohol abuse and alcoholism. However, 
despite many years of study of the biochemistry, anatomy, and physiology of 
these neuroadaptive processes, the precise roles of these processes in 
mediating excessive alcohol intake is still unclear.  An integrative approach 
that combines the use of animal behavioral models with molecular, cellular, 
and systems level measures of brain function will clarify these roles.  
Research on neuroadaptation related to chronic alcohol exposure falls into 
three general areas: behavior, neurobiology, and genetics. 
 
Behavioral Neuroadaptive Phenomena

Tolerance.  Tolerance, a diminished physiological or behavioral response to a 
particular dose of ethanol, can develop over the course of a single exposure 
(acute tolerance) or following repeated exposures (rapid and chronic 
tolerance).  Most of the research on tolerance has focused on the physical 
measures (motor, hypothermic, sedative effects).  However, more recently, 
theorists have highlighted the motivational aspects of tolerance, linking 
tolerance and withdrawal as components of the same neuroadaptive process.  
The opponent-process theory posits that homeostatic adaptive processes 
counteract the initial acute effects of the drug.  Removal of the drug 
unmasks this counteractive process and can result in a withdrawal syndrome 
(negative affective state).  However, there is also sufficient evidence that 
alcohol tolerance depends on the learning process.  Classically conditioned 
environmental cues or operant conditioning paradigms may produce internal 
adaptive responses that attenuate the effects of alcohol.  On the other hand, 
tolerance can develop in novel environments where conditioning effects are 
minimal.  The neural circuitry and neurobiological mechanisms that 
distinguish the temporal, physiological, motivational, and learning 
components of tolerance are currently unknown. 

An important question is whether a causal link exists between tolerance and 
the development of alcohol dependence.  Some evidence suggests that tolerance 
to the aversive effects of alcohol unmasks ethanol"s hedonic effects and may 
increase drinking.  Another mechanism suggests increased intake results from 
tolerance to alcohol"s reinforcing effects.  Changes in the brain reward 
system have been implicated, but the exact mechanisms mediating tolerance to 
alcohol’s rewarding effects remain to be demonstrated.  

Using selectively bred animals, alcohol-preferring rats show more behavioral 
tolerance to alcohol than do alcohol-nonpreferring rats.  Tolerance to 
ethanol-induced ataxia and hypothermia correlate with initial sensitivity in 
C57BL/6J and DBA/2J mice and their recombinant inbred strains.  Although 
correlational studies can generate hypotheses about common genetic 
mechanisms, targeted mutagenesis may provide a more powerful tool for 
demonstrating a causal link between tolerance and dependence.

Sensitization.  Behavioral sensitization, a process by which the response to 
a drug increases with repeated exposures, suggests that repeated use of a 
drug increases its incentive value, leading to increased use.  Environmental 
cues and stressors can contribute to the development of drug sensitization.  
Much of the work on sensitization derives from studies on enhanced locomotor 
activity produced by psychomotor stimulants.  Although sensitization to the 
activating effects of low to moderate doses of ethanol has been demonstrated, 
as well as elevated sensitivity to ethanol"s effect on brain stimulation 
reward, ethanol sensitization has not been consistently reproduced in animals 
because of species and strain differences. 

Another type of ethanol sensitization is the increased withdrawal response 
following multiple intoxication and withdrawal episodes.  Progressive 
intensification of withdrawal seizures following repeated alcohol withdrawal 
episodes has been demonstrated in mice and rats, and is referred to as 
"kindling" because of its similarity to kindled brain seizures.  Research is 
needed to elucidate the neural mechanisms and circuits as well as genetic and 
environmental factors that contribute to ethanol sensitization and its 
relationship to alcohol dependence.

Dependence, Withdrawal, and Relapse.  Abrupt discontinuation of chronic 
alcohol consumption often results in a withdrawal syndrome.  These symptoms 
include autonomic hyperactivity, tremors, seizures, perceptual distortions, 
and affective changes.  Investigators have more recently concentrated on 
neural circuits related to the negative affective component of withdrawal 
(e.g., anxiety, stress, depression, and insomnia).  These studies suggest 
that alcoholism is maintained, in part, by a need to reduce the negative 
emotional states associated with abstinence and withdrawal.  Because brain 
stimulation reward techniques reveal a prolonged increase in reward 
thresholds following chronic alcohol administration, brain reward circuits 
(i.e., the median forebrain bundle) may be disrupted by chronic alcohol 
administration. 

A key area for research is to understand neuroadaptive factors that 
contribute to relapse.  Animal models are available to study the 
neurobiological mechanisms by which repeated cycles of excessive drinking and 
withdrawal increase the likelihood of relapse.  One model, which emphasizes 
enhanced reinforcing properties as a mechanism of relapse, is the alcohol 
deprivation effect, a transient increase in alcohol consumption following 
periods of forced abstinence.  In lines of alcohol-preferring rats, repeated 
deprivation cycles and extended deprivation periods (2-8 weeks) prolonged the 
deprivation effect and enhanced the reinforcing efficacy of ethanol. 

Another recent model, based on the concept of allostasis, focuses on negative 
emotional factors during withdrawal as the basis for drug relapse.  
Allostasis is a change in the internal set point of a physiological 
regulatory system outside the normal range. By decreasing brain reward 
function during withdrawal (due to negative symptoms), chronic alcohol use 
causes an allostatic elevation of the ethanol reward set point or threshold.  
These alterations could explain alcohol relapse and increased intake as a 
means to reinstate normal reward function and to achieve the same rewarding 
effects previously experienced with ethanol.  Recent studies in rats indicate 
that experience with alcohol can induce long lasting changes in the 
reinstatement of alcohol use after protracted abstinence.  These approaches 
can be used to study the underlying cellular, molecular, genetic and 
environmental mechanisms that lead to relapse.

Currently, the biological mechanisms underlying the behavioral manifestations 
of neuroadaptation are not well understood.  In addition, the relevance of 
these phenomena to excessive ethanol intake has not been elucidated.  More 
research is needed to clarify causal relationships between behavioral 
adaptive responses and neurobiological adaptive responses. 

Biological Neuroadaptive Phenomena

Molecular, Cellular & Anatomical Neuroadaptation.  The behavioral 
neuroadaptive phenomena discussed above are long lasting, are independent of 
the presence of ethanol, and are believed to result from neuroadaptive 
changes in the brain.  When perturbed, the brain attempts to maintain 
homeostasis in several ways.  The most immediate compensatory changes occur 
in the synthesis and release of neurotransmitters.  This is accomplished by 
feedback to enzymes that synthesize them or by altering the activity of 
presynaptic autoreceptors, thereby altering the rate of neurotransmitter 
release.  In most cases, this mechanism, initiated over minutes to hours, is 
sufficient to maintain neural activity within a physiological acceptable 
range.  If the perturbation is removed early, systems quickly revert to their 
basal levels. 
                                  
Over a period of hours to days, other changes with longer lasting effects 
occur.  These changes include up- and down-regulation of receptors or ion 
channels, alterations in signal transduction pathways, and changes in gene 
expression.  Post-synaptic up- and down-regulation of receptors and ion 
channels occurs in response to chronic changes in synaptic input.  This can 
involve changes in the synthesis of the receptor or one or more of its 
subunits to compensate for the altered synaptic input.  For example, if 
synaptic input is impaired, synthesis of postsynaptic receptors increases.

Studies of other acquired long-term changes in brain function can provide a 
paradigm for studies of the effects of chronic ethanol exposure.  For 
example, the downstream consequences of learning are both morphological and 
molecular.  Synaptogenesis as well as pruning of synapses and changes in 
shape and number of dendritic spines have been known for some time.  It is of 
interest that such morphological changes have been observed in cortex of rats 
sensitized to cocaine and it seems likely that alcohol dependence also 
produces such changes.  In addition, learning also remodels individual 
synapses at the molecular level with changes in receptor density, receptor 
types and activity of protein kinases and phosphatases as has been observed 
with chronic alcohol exposure and discussed previously.  Of particular note 
is the insertion of AMPA receptors into the postsynaptic membrane during LTP.  
Recent evidence suggests that the acquisition of a new behavior, such as 
increased alcohol consumption, may rely on some of the same changes in 
neurocircuitry as are found in learning and memory.  Thus, better 
understanding of mechanisms of neuroadaptation to alcohol may result from 
research on changes in molecular circuitry defined in models of learning such 
as LTP and LTD as well as more complex paradigms.

Post-translational modification of proteins can occur in response to abnormal 
neural activity in an attempt to maintain normal synaptic function. There are 
several mechanisms by which protein modification can occur in response to 
altered synaptic function. For example, protein kinases, which catalyze the 
phosphorylation of specific substrate proteins, are activated by a variety of 
intracellular messengers, including cyclic nucleotides, calcium, nitric oxide 
and the metabolites of phosphatidylinositol and arachidonic acid. There is 
the potential for an alcohol perturbation to differentially affect the many 
protein kinases. Because kinases have different protein substrates, different 
amounts of alcohol can lead to different degrees of altered synaptic 
function.  It is important to understand the differential effects of alcohol 
at the molecular level to understand the behavioral adaptation to alcohol 
intoxication.

Investigators have characterized a multitude of changes in gene expression 
induced by chronic ethanol exposure in brain and in cultured neurons, 
including transcription factors, signal transduction components, and 
neurotransmitter receptors.  The behavioral significance of the vast majority 
of these changes is still unclear.  For example, the catalytic subunit of PKA 
in NG108-15 cells exposed to ethanol translocates to the nucleus where it 
phosphorylates CREB.   It seems reasonable to presume that a similar 
translocation would occur in neurons in the brains of mice (or humans) 
exposed to ethanol.  Phosphorylation of CREB would be expected to lead to 
widespread changes in gene expression.  However, because of the many other 
molecular changes induced by ethanol (independently of its effects on PKA), 
it would be impossible to determine from measurements of gene expression 
alone which changes actually mediate ethanol-induced changes in behavior.  
The use of gene knockouts in mice has begun to clarify this confusing 
picture.  Mice lacking the gene encoding a regulatory subunit of PKA show 
increased consumption of ethanol, and reduced sensitivity to its sedating 
effects, thereby implicating PKA in the regulation of these behaviors.  NIAAA 
therefore strongly encourages Investigators to use mouse gene knockouts (and 
more sophisticated modifications of this methodology) to elucidate causal 
relationships between gene expression and behavior.

Identification & Characterization of Neural Circuits.  Identification and 
characterization of neural circuits in the brain that mediate the myriad of 
neuroadaptive behavioral effects of chronic ethanol exposure is another 
important objective of alcohol research.  As discussed previously, the 
actions of alcohol on the brain have been intensively studied at both the 
molecular and behavioral levels.  These studies have provided abundant 
information on the potential molecular targets of ethanol and on candidate 
neural pathways involved in its behavioral effects.  To bridge the gaps 
between these molecular and behavioral studies, further research at the 
neural circuit level is crucial and can now be pursued applying several 
recent technical advances, which should facilitate finding the neural 
circuits underlying neuroadaptative responses to alcohol exposure.  An 
important part of this initiative is the study of the circuit as a whole 
rather than focusing on a specific nucleus or brain area. 

Neural circuits have been studied for the acute reinforcing effects of 
ethanol. A loop that starts in the ventral tegmental area appears to mediate 
reward of a variety of substances and stimuli, including ethanol and most 
other addictive drugs. Neurons originating from this region project to the 
nucleus accumbens, and ultimately to the prefrontal cortex.  Completing the 
circuit, neurons from the nucleus accumbens and the cortex project back to 
the ventral tegmental area.  The actions of ethanol on parts of this circuit 
have been extensively studied such as on the ventral tegmental area and the 
nucleus accumbens, whereas the prefrontal cortex and its connections to the 
ventral tegmental area have received less attention.  In addition, the 
amygdala as well as the hippocampus may be part of the circuit or regulate it 
because of their role in associative learning, a process required to 
associate drinking alcohol and obtaining a positive response. However, it is 
not clear how this reinforcing circuitry contributes to excessive ethanol 
consumption.

Similarly, other circuits may mediate other actions of ethanol such as 
sedation and aggression, as well as the manifestations of ethanol dependence.  
Motor dysfunction has been shown to involve the cerebellum and basal ganglia.  
Various known neural circuits may be involved.  For example, in the 
cerebellum, cerebral input through the inferior olivary nucleus in the brain 
stem to Purkinje cells in the cerebellum back to the cerebral cortex is one 
possibility.  In the basal ganglia, a neural circuit involving a loop from 
the substantia nigra to the caudate nucleus and back, with input from the 
cerebral cortex, putamen and globus pallidus, is another option.  Again, how 
these circuits might contribute to behavioral neuroadaptive phenomena has not 
been addressed.

Molecular studies indicate that ethanol can interact with many major central 
neurotransmitter receptors, including those for GABA, glutamate, dopamine, 
serotonin, acetylcholine, and some peptide neurotransmitters.  Imaging, 
behavioral, and neuropharmacological studies have begun to reveal candidate 
brain regions that are involved in different ethanol-associated behaviors.  
These studies have helped identify possible circuits based on known 
anatomical connections. 

To understand the mode of operation of a given neural network, the different 
neurons that form the circuitry should be identified, their membrane 
properties should be defined in terms of their firing properties, and a 
description should be made of how these neurons interact synaptically in both 
spatial and temporal terms.  To accomplish this, newly developed techniques 
will allow simultaneous in vivo measurements of electrical and chemical 
responses to ethanol from groups of individual neurons in more than one brain 
region during ongoing behaviors.  Other approaches will permit in vitro 
recordings from up to hundreds of neurons connected by different neural 
pathways.

Extracellular, single-unit recordings in anesthetized animals have long been 
used in neurophysiological studies.  Recently, modified methods of single-
unit recordings in freely behaving animals have converted this classic 
technique to a powerful new tool to study ethanol-induced impairments in 
motor and cognitive behaviors.  Another newly developed technique, the multi-
electrode single-unit recording in freely behaving animals, is even more 
powerful in neural circuit studies, especially when applied to 
neuropharmacologically defined neurons.  With this sophisticated approach, 
patterns of electrical activity of individual neurons from different areas of 
a distinct neural circuit can be measured simultaneously during a specific 
behavioral event.  This method also will allow analysis of changes in 
spatiotemporal patterns of neuronal activity related to ethanol-associated 
behaviors.

Neurochemically, in vivo microdialysis, iontophoresis, or fast-scan cyclic 
voltammetry, when combined with electrophysiological and behavioral 
approaches, provide a means of simultaneously recording neurophysiological 
and neurochemical activities in real-time with ongoing behaviors.  Recent 
research has demonstrated that microdialysis probes can be used in more than 
one brain area at the same time.  Coupled with local delivery of ethanol and 
neurotransmitter receptor agonists or antagonists to individual neurons or 
brain regions, transmitter release can be related to ethanol-induced events 
from the same neurons or regions in freely behaving animals. 

At the cellular level, various sophisticated optical methods including 
confocal microscopy, semiconductor array imaging, two-photon laser scanning 
microscopy, nonlinear fluorescence imaging, and fluorescent indicators of ion 
concentration and transmembrane electrical potential have been developed in 
the past decade.  Unlike classical electrophysiological methods, optical 
recordings can assess the activities of a large number of neurons from 
different parts of a circuit simultaneously, as well as both structural and 
functional changes induced by ethanol.  Although most of the optical 
recording methods can be used only in vitro, some of them also can be used in 
living tissues such as the newly developed organotypic brain slice and 
transplant.  Some optical techniques can even be applied in vivo.  These 
cutting-edge approaches have shown great promise in studying neural circuits.  
Once they are introduced and incorporated into alcohol research, more 
mechanistic questions of neural circuits mediating ethanol-related brain 
dysfunction can be addressed from several different levels. 

Many if not most actions within the brain are under genetic control.  In the 
case of neural circuits, genes not only regulate the production of the 
structure of neural circuits, they also regulate the expression of behavior 
mediated by those circuits.  The proteins involved can include enzymes 
mediating the synthesis and degradation of neurotransmitters, their 
receptors, and various postsynaptic signal transduction pathways.  Examining 
changes in genetic expression underlying changes in alcohol-modified neural 
circuits that accompany and presumably cause, the acquisition of excessive 
alcohol consumption are important areas of research.  It should be noted that 
changes in gene expression must also be used to focus studies on changes in 
functional proteins as well as neuronal morphology.  Thus, examination of 
molecular, anatomical and electrical circuitry must proceed together and 
inform each other of the most pertinent targets for analysis.

Genetic Models of Neuroadaptation

Innovative Animal Models of Alcohol-Related Phenomena.  Development of 
appropriate and well-characterized animal models of alcohol-related phenomena 
is necessary for successful integration of neuroscience research.  Animal 
models already developed for specific alcohol-related phenomena include 
invertebrates, rodents, and non-human primates, with different models being 
selected on the basis of specific research questions being asked.  Given that 
each organism and each model has strengths and weaknesses, there is no single 
optimal model for any research question.  Therefore, a continued investment 
in the development of models of alcohol-related phenomena is required for 
successful integration of neuroscience information. 

Examples of some possible models are described to highlight particular 
strengths.  A readily manipulated and relatively inexpensive species for gene 
identification is the fruit fly (Drosophila melanogaster).  This species has 
already been used to link a specific gene with increased sensitivity to the 
acute effects of alcohol.  Studies with Drosophila, as well as C. elegans 
(whose genome has been recently published) have the potential of rapidly 
identifying genes underlying an alcohol-induced behavioral trait.  Because so 
many genes are conserved through evolution, the genes and proteins identified 
can give significant clues for future study in mammals.

Inbred mice and rats have been used successfully to identify chromosomal 
regions containing genes (Quantitative Trait Loci -- QTLs) influencing 
alcohol-related phenomena, and studies are underway to identify these genes.  
The completion of the mouse and rat genome sequences will accelerate the pace 
of these studies.  QTL mapping studies have led to the generation of numerous 
strains congenic for small genomic regions bearing alternate alleles of genes 
influencing various kinds of ethanol-related behavior. 

Congenic strains differing at a relatively small number of genes (compared to 
the number differing between two selectively bred lines) can be used to 
discover genetic correlations between physiological and behavioral traits.  
Thus, correlated physiological and behavioral traits observed in congenic 
strains have a correspondingly greater likelihood of being influenced by the 
same gene, and hence mechanistically related to each other.  Comparisons 
between the physiology and behavior of congenic strains thus provide a firmer 
basis for inference of physiological mechanisms of behavior than perhaps 
comparisons between selectively bred lines. 
	
The ability to create mice and rats with defined genetic alterations will be 
critical for establishing the role of specific proteins in mediating specific 
behavioral endpoints of neuroadaptation to alcohol.  Directed mutagenesis and 
overexpression will complement traditional pharmacological approaches to 
perturb protein function.  These methods are particularly useful in 
situations where ligands for a protein of interest are unavailable, or where 
available ligands are not sufficiently specific to differentiate the 
functions of closely related proteins.  Directed mutagenesis will also prove 
essential to identify QTL alleles responsible for natural inter-individual 
variation in neuroadaptive responses.  In addition, it will provide a 
critical means of demonstrating an obligatory role in neuroadaptation for the 
products of genes whose expression changes during this process. The 
capability of creating mice with defined genetic alterations serves an 
integrative function by permitting exploration of both the physiological and 
the behavioral consequences of altering the activity of a specific protein. 

High-Throughput Gene Expression Assays (cDNA and Oligonucleotide Microarrays)
Long-term changes in the physiological properties of neurons and the circuits 
in which they function are often mediated by changes in expression of genes 
encoding neuronal components (e.g., receptors, ion channels, intracellular 
signaling apparatus, cell adhesion molecules).  While alcohol researchers 
have begun to characterize alcohol-induced changes in expression of genes 
encoding some of the better characterized receptors  (e.g., GABA, NMDA), 
these studies are in their infancy.  The imminent identification of all the 
genes in the human and murine genomes suggests the possibility of much more 
comprehensive studies of changes in gene expression of neuroadaptation to 
alcohol, examining changes in the expression of tens of thousands, rather 
than merely tens, of genes.  Such studies promise to yield a clearer picture 
of which neurochemical pathways change their activity during adaptation to 
alcohol.  These studies serve an integrative function by virtue of their 
ability to examine changes in gene expression at levels of resolution ranging 
from brain-regional to cellular. 

Additional Technological Approaches

Development of Imaging Technolgy for Animal Models.  Most noninvasive 
functional imaging studies to date in humans and animals have investigated 
the acute and chronic effects of alcohol on local cerebral metabolism or 
regional cerebral blood flow to establish detailed neuroanatomical patterns 
of changes in functional activity throughout the brain.  To study the 
neuroadaptive changes associated with chronic alcohol use, longitudinal 
studies following chronic ingestion are needed to distinguish withdrawal-
related changes in brain metabolism from irreversible changes, and to 
determine the effects of abstinence on recovery of brain metabolic function. 
Integration of behavioral measures with these imaging studies could reveal 
neural circuits associated with alcohol-related neuroadaptive phenomena.  

Functional imaging technologies have the most promise for alcohol research in 
bridging the gap between brain chemistry and behavior. Magnetic Resonance 
(MR) imaging is also an important modality for noninvasive functional imaging 
animal studies of acute and chronic alcohol effects.  Structural MR can be 
used for highly detailed tracking of brain tissue loss and recovery over the 
course of alcohol exposure and withdrawal.  Furthermore, MR spectroscopy can 
provide information about the integrity of neuronal tissue with the 
determination of brain tissue concentrations of the neuronal marker, N-
acetyl-aspartate (NAA) and the presence of gliosis with determination of 
concentrations of myo-inositol (mI).

MR spectrocopy can also be used to determine the brain concentration of 
alcohol in vivo and MR spectroscopy can be employed in both single voxel and 
imaging modalities, the latter providing information about the spatial 
distribution of certain metabolites.  Although some amine and polypeptide 
receptor ligands have been labeled with radiotracers, only a few studies 
using positron emission tomography (PET) have measured alcohol"s effects on 
neurotransmission.  Furthermore, because alcohol affects many 
neurotransmitter systems, the development of new ligands targeting the 
glutamate, cholinergic and serotonin receptors are needed to combine 
functional imaging, neurochemistry, and behavior to eventually understand the 
underlying mechanisms of neuroadaptive changes, such as sensitization, 
tolerance, dependence, and withdrawal.  Thus, the development of imaging 
technologies for animals including rodents and primates could provide 
important information. Rodent animal models can be used for initial ligand 
development and testing and will be informative for determining responses 
that are specific to alcohol exposure.  So far, functional imaging studies 
utilizing glucose metabolism in rodents have not allowed repeated testing in 
the same animal.  Development of small animal imaging techniques would be 
more amenable to studying neuroadaptive changes in the same animal.  In 
addition, rodent imaging would allow integration of genetic and imaging 
techniques.  For example, genetically engineered rodent models have been used 
in alcohol research to study both pharmacological as well as behavioral 
processes.  Consequently, there are distinct advantages to studying alcohol-
related phenomena in the rodent where imaging and genetic techniques can be 
used in the same animal. 

Computational Neurobiology and Informatics.  Computational neurobiology 
integrates the disciplines of neurobiology, mathematics, and physics to study 
the functional organization and operation of the brain.  Neural networks 
mediating alcohol-related phenomena are hypothesized or empirically 
established and then modeled to determine, in an iterative process, the 
organizational principles and mechanisms underlying the targeted phenomena.  
It is anticipated that distributed neural networks are involved and are 
organized by coupled dynamic rules.  Computational neurobiology has been used 
successfully in systems-level models and in integrative approaches that 
incorporate data from the subcellular to behavioral levels.

Databases need to be developed to provide, in a user-friendly format, 
research information that is collected by individual investigators of INIA.  
Access by all investigators to genetic, molecular, cellular, anatomic, 
physiologic, neural network, and behavioral data is required to perform 
successful integrative neuroscience research.  Moreover, new methods are 
needed to facilitate the extraction of information from these large 
databases. 

STUDY POPULATIONS     

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 new 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable, and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

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 21) 
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://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations. Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites. Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

LETTER OF INTENT

The consortium coordinator should submit a letter of intent that includes the 
name, address, and telephone number of the principal investigator, the 
identities of other key personnel and participating institutions, and the 
number and title of the RFA in response to which the applications are being 
submitted. Although a letter of intent is not required, is not binding, and 
does not enter into the review of a subsequent application, the information 
that it contains allows IC staff to estimate the potential review workload 
and plan the review.  

The letter of intent is to be sent to:

Chief, Extramural Project Review Branch 
Office of Scientific Affairs, NIAAA
6000 Executive Boulevard, Suite 409
Bethesda, MD 20892-5452
(for express/courier service: Rockville, MD 20852)
Telephone:  (301) 443-4375
FAX:  (301) 443-6077

by the letter of intent receipt date listed.

APPLICATION PROCEDURES

All applications for an INIA Consortium will be compiled and submitted by the 
consortium coordinator.  It will include the Consortium Coordinator’s 
application as the lead application (described previously in more detail 
under Organization), the individual research project component applications 
as well as the resource core applications.  The research grant application 
form PHS 398 (rev. 4/98) is to be used in applying for these awards, with the 
modified format that is described below.  These forms are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of Health, 
6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-435-
0714, email: GrantsInfo@nih.gov.

For each research project or core component of the consortium, a signed, 
typewritten original application, five exact single-sided copies, and five 
sets of appendix material must be submitted as specified under APPLICATION 
SUBMISSION below.  Each application must be complete, with all approvals, 
budgets, and signatures from the appropriate officials of the applicant 
institution. All of the U01 and U24 applications constituting the proposed 
consortium must be submitted in a single package by the consortium 
coordinator.

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Failure to use 
this label could result in delayed processing of the application such that it 
may not reach the review committee in time for review.  In addition, the RFA 
title and number must be typed on line 2a of the face page of the application 
form and the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change. Please note this is in pdf format.

Cover Letter: A cover letter that identifies the total number of applications 
in the consortium and the principal investigator for each Research Project 
Component and Resource Core must be enclosed in the package of applications 
by the consortium coordinator.  For each component application in the 
consortium, the original, five copies, and the appendix material must be 
bundled together, clearly identified, and submitted as specified under 
APPLICATION SUBMISSION below.  Failure to follow the instructions regarding 
application receipt dates and packaging may lead to a delay in review. 

Each application must have its own descriptive title and a principal 
investigator.  The contributions from Resource Cores must be summarized in 
item (i) CONSULTANTS of the Research Plan. This must include an explicit 
description of the methods and procedures to be used, the services, tests, 
animals, or facilities to be provided, and a description of the involvement 
and protection of human subjects or vertebrate animals, if appropriate. This 
section should also describe the collaborative and integrative interactions 
of the project with other projects of the consortium. Item (i) must be 
complete, with enough detail for NIH staff and reviewers to understand the 
full scope of these interactions. 

Instructions for Preparing Applications on the PHS 398 (rev. 4/98)

The following instructions address ONLY the parts of the PHS 398 research 
grant application form for which information about the proposed interactive 
research consortium is requested. All other parts of the grant application 
should be prepared according to the instructions in the PHS 398 booklet (rev. 
4/98). 

FACE PAGE - AA: Item 2. Mark "Yes" and enter the RFA announcement number and 
title.  Items 7-8. Enter the direct costs and total costs - includes the 
costs of the specific research project. 

Form BB: Description. Provide a brief description (abstract) of the research 
proposed according to the instructions provided on page 10 of booklet for the 
PHS 398 (rev. 4/98). The description of the proposed interactions with the 
Consortium and the contribution of any of the Resource Cores to this 
application may be included. 

Performance Site(s). The performance site(s) of THIS project AND of any 
Resource Core in the consortium that will be used in this project (any 
involved institution should be named only once).

Key Personnel. List first the principal investigator and key personnel 
engaged on THIS project, followed by all key personnel engaged on any 
Resource Core that supports this project.  Then list, as collaborators, all 
principal investigators and professional personnel engaged in other research 
component projects of the consortium that interact specifically with this 
project application.

Form CC: 

TABLE OF CONTENTS. Add the page locations for item (i) of the Research Plan 
and for each of the shared resource cores proposed to be supported through 
this application. 

Forms DD and EE: Project Budget. Complete these pages as directed with the 
budget requests for this research project only.  Provide clear justification 
for all items requested in the first year and for any significant increases 
or decreases in any category in future years. 

Form FF: The biographical sketch for each key investigator involved and to be 
supported in this project should be included.

RESEARCH PLAN: 

The instructions in section C-9 (pages 14-19) of the PHS 398 must be followed 
to complete a. through d. (Page 16) of the Research Plan in detail. Attention 
may be given to the integration of the individual project into the overall 
consortium effort. The overall research plan (a-d) for the project may not 
exceed 25 pages. The following points may be addressed in the appropriate 
sections. 

a. SPECIFIC AIMS. Besides listing the specific objectives of the individual 
research project for the total period of requested support, briefly 
summarize how the overall objective or long-term goal of the research 
relates to the goals of the consortium.

b. BACKGROUND AND SIGNIFICANCE. Besides discussing the overall scientific 
significance of the proposed research, this section may briefly summarize 
the relevance of the project to the scientific goals of the consortium.

APPLICATION SUBMISSION
 
Submit a signed, typewritten original of the application, including the 
checklist, and three signed photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive Room 1040 MSC-7710
Bethesda, MD  20892-7710
Bethesda MD 20827 (for express/courier service)

At the time of submission, two additional copies of the application plus all 
five sets of the appendices must also be sent to:

Chief, Extramural Project Review Branch 
Office of Scientific Affairs, NIAAA
6000 Executive Boulevard, Suite 409
Bethesda, MD 20892-5452
(for express/courier service: Rockville, MD 20852)
Telephone:  (301) 443-4375
FAX:  (301) 443-6077

Applications must be received by April 27, 2001.  If an application is 
received after that date, it will be returned to the applicant without 
review.  

The Center for Scientific Review (CSR) will not accept any application in 
response to this announcement that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is essentially the 
same as one already reviewed.  This does not preclude the submission of a 
substantial revision of an application already reviewed, but such an 
application must follow the guidance in the PHS Form 398 application 
instructions for the preparation of revised applications, including an 
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, each cluster of applications will be reviewed for completeness 
by the Center for Scientific review (CSR) and for responsiveness by the 
NIAAA.  Incomplete and/or non-responsive applications will be returned to the 
applicant without further consideration.  Applications that are complete and 
responsive to the RFA will be evaluated for scientific and technical merit by 
an appropriate peer review group convened by the NIAAA in accordance with the 
review criteria stated below. As part of the initial scientific merit review, 
a process may be used by the initial review group in which applications 
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 National Advisory Council on 
Alcohol Abuse and Alcoholism. 

Review Criteria for the Consortium Coordinator Application (lead application 
and overall consortium)

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 comments, reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
multidisciplinary initiative will have a substantial impact on the pursuit of 
these goals. Each of these criteria will be addressed and considered in 
assigning the overall score, weighting them as appropriate for each 
application. 

1. Significance: Does this interactive multidisciplinary consortium project 
address a complex biological problem of overarching significance to 
biomedical science that would be difficult to address by separate grants?  
If the aims of the overall consortium are achieved, how will the 
scientific knowledge be advanced?  What will be the effect of these 
studies on the concepts or methods that drive this field?  Do the 
arrangements for data sharing maximize the impact of the interactive 
consortium project? 

2. Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the scientific 
aims of the collaborative project?  Does the applicant acknowledge 
potential problem areas and consider alternative tactics or designs?  Is 
the project management plan adequate? Is the administrative framework 
appropriate?  Do milestones articulate key indicators set for appropriate 
times that will demonstrate significant forward progress for the 
consortium project?  Are the plans to monitor and evaluate progress of the 
consortium project adequate?  Are the plans to share the data and findings 
within the consortium and the larger scientific community adequate? 

3. Innovation:   Does the project employ novel concepts, approaches, 
theories, or methods?  Are the aims original and innovative?  Will the 
multidisciplinary collaborative consortium challenge existing paradigms or 
develop new methodologies or technologies?  Will the multidisciplinary 
consortium attack a problem in a significantly new way? 

4.	Investigators:  Is the consortium coordinator’s major research activity 
within the research area of the multidisciplinary consortium?  Is the 
consortium coordinator well suited to the scientific and administrative 
leadership required to carry out this work?  Is the level of effort 
proposed for the consortium coordinator appropriate?  Is the work proposed 
appropriate to the experience level of the multidisciplinary consortium’s 
research and technical staff?  Are the research project component 
applications of the participating investigators within the area of the 
multidisciplinary consortium? Are the participating investigators well 
chosen for their roles in the collaborative project? 

5. Environment. Do the scientific environments in which the work will be done 
contribute to the probability of success?  Are support personnel and 
resources in place to advance the work?  Will the proposed 
multidisciplinary consortium take advantage of unique features of the 
scientific environments of the component projects?  Is there evidence of 
institutional support?  Are the requested core facilities critical to 
achieving the scientific goals of the multidisciplinary consortium, are 
they cost effective?  Is access to the core facilities appropriate?

6. Budget:  Is the requested budget and estimation of time to completion of 
the study appropriate for the proposed research?

In accordance with NIH policy, all applications will be reviewed with respect 
to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, and children, as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated. 

o The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application. 

Review Criteria for Core Resources

Consideration of the technical merit of the core units will include: 

(1) Facilities within the resource cores compared to the state-of-the-art. 
The contributions of the resource cores to fulfilling the goals of the 
consortium.

(2)  The adequacy of the approaches, methods and operational procedures for 
interacting with the consortium investigators.

(3) The extent to which resource core units promote greater collaboration 
and cohesiveness among the participating investigators. 

(4) Qualifications, experience, and commitment to the INIA mission of the 
investigators responsible for the core resources and their abilities to 
devote the required time and effort to the program.

(5) Appropriateness of the budgetary requests. 

Review Criteria for Research Project Components: 

 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 comments, reviewers will be asked to discuss the following 
aspects of each research project application in order to judge the likelihood 
that the proposed research will have a substantial impact on the pursuit of 
these goals. Each of the criteria listed below will be addressed and 
considered in assigning the score for a research project, weighting them as 
appropriate for each project. Note that the project does not need to be 
strong in all categories to be judged likely to have major scientific impact 
and thus deserve a high priority score. For example, an investigator may 
propose to carry out important work that by its nature is not innovative but 
is essential to move a field forward. In their evaluations, reviewers will 
comment on: 

(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 achieving the 
goals of the collaborative projects or consortium? Will the project tie or 
enhance the independent work of the participating investigator to the 
collaborative project, or will the project add an essential missing aspect 
to the collaborative project? 

(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? 

In addition to the above criteria, in accordance with NIH policy, all 
individual scientific projects will be reviewed with respect to the 
following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated. 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application. The scientific review group will also examine 
the provisions for the protection of human subjects and the safety of the 
research environment. 

Schedule

Letter of Intent Receipt Date:    March 16, 2001
Application Receipt Date:         April 27, 2001
Peer Review Date:                 July, 2001
Council Review:                   September 19, 2001
Earliest Anticipated Start Date:  September 28, 2001

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review).

o  availability of funds.

o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to: 

Antonio Noronha, Ph.D.
Chief, Neurosciences & Behavioral Research Branch
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD  20892-7003
301-443-7722 (office)
301-594-0673 (fax)
Email: anoronha@willco.niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Linda Hilley
Chief, Grants Management Office
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) 443-0915
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 authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all award 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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