NIH PA IDENTIFYING FUNCTIONAL LINKS BETWEEN IMMUNE, BRAIN FUNCTION INCL. BEHAVI

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IDENTIFYING FUNCTIONAL LINKS BETWEEN THE IMMUNE SYSTEM AND BRAIN FUNCTION

INCLUDING BEHAVIOR

Release Date: January 16, 2002

PA NUMBER: PA-02-045

EXPIRATION DATE: February 2005

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Institute of Mental Health

(http://www.nimh.nih.gov/)

National Institute of Neurological Disorders and Stroke

(http://www.ninds.nih.gov/)

National Institute on Drug Abuse

(http://www.nida.nih.gov/)

National Institute of Arthritis and Musculoskeletal and Skin Diseases

(http://www.niams.nih.gov/)

SNIP..

PURPOSE OF THIS PA

The Program Announcement replaces PA-93-009.

The National Institute of Mental Health (NIMH), National Institute on

Neurological Disorders and Stroke (NINDS), National Institute on Drug Abuse

(NIDA), and National Institute of Arthritis and Musculoskeletal and Skin

Diseases (NIAMS) request research grant applications to study neuroimmune

molecules and mechanisms involved in regulating normal and pathological

central nervous system (CNS) function. Areas of research interest include

those raised in discussions at the recent workshop " Strategies for

Identifying

Functional Links Between the Immune System, Brain Function, and Behavior "

http://www.nimh.nih.gov/research/linkssummary.cfm. This program

announcement

(PA) also incorporates topics explored at the " Research Roundtable on

Pediatric Autoimmune Neuropsychiatric Disorders Associated with

Streptococcus

(PANDAS) " http://www.nimh.nih.gov/research/pandassummary.cfm.

RESEARCH OBJECTIVES

Background

Immune molecules such as cytokines, chemokines, and growth factors and

immune

cells can modulate brain function through multiple signaling pathways

originating from peripheral and CNS cells. Immunological, physiological and

psychological stressors can engage cytokines and other immune molecules in

bi-

directional interactions with brain neuroendocrine, peptide, and

neurotransmitter systems. For example, brain cytokine levels increase

following stress exposure, and treatments that decrease the impact of stress

on behavior also reverse stress-mediated effects on cytokines.

Cytokines and chemokines can also modulate CNS function in the absence of

overt immunological, physiological, or psychological challenges. For

example,

cytokines and cytokine receptor inhibitors affect cognitive and emotional

processes. Recent evidence suggests that immune molecules modulate brain

systems differently across the lifespan. Cytokines and chemokines regulate

neurotrophins and other molecules critical to neurodevelopmental processes,

and exposure to certain neuroimmune challenges early in life affects brain

development. In adults, cytokines and chemokines affect synaptic plasticity

and other ongoing neural processes. Finally, interactions of immune

molecules

with the hypothalamic-pituitary-gonadal system indicate that sex differences

are a significant factor determining the impact of neuroimmune influences on

brain function and behavior.

Research Scope

The potent effects of cytokine molecules in the brain are mediated through

multiple signaling pathways. However, details regarding the extent, routes,

or mechanisms whereby immune signaling molecules affect the brain in either

normal conditions or during immune challenge are largely unexplored. The

purpose of this PA is to identify research themes that may help to bridge

the

gap in understanding how immune mediators affect brain function and

behaviors

related to cognition and mood. This includes studies of the effects of

immune

molecules and cells on molecular and cellular neural processes, neuronal

signaling, glial-neural interactions, neural activation, and objective

behavioral endpoints of relevance to mood, cognition, and motivation.

Studies

examining immune molecule effects on neurodevelopment and across the

lifespan

as well as studies comparing effects in males and females are also

encouraged.

It should be noted that studies aimed at examining how the brain or

stressors

affect peripheral immune function are not appropriate for this solicitation.

Similarly, studies of immune cell entry and fate in brain are appropriate

only

if they examine how these cells affect ongoing brain processes and/or

behavior.

Areas of interest

Development and extension of research tools to examine how immune molecules

affect CNS function and behavior:

o Develop and characterize cytokine receptor selective ligands.

o Develop genetic tools to alter selective components of the immune system

and brain signaling pathways within limited developmental periods.

o Identify sensitive markers for determining the effects of pre- and post-

natal infection on normal brain development.

o Develop neuroimaging tools for studying cytokine effects within specific

brain regions.

o Develop non-invasive tools for examining blood/brain barrier permeability

to immune molecules and cells and antibodies.

o Develop long-term markers of immune response activation in brain.

Development and extension of animal models of immune signaling in brain:

o Model chronic therapeutic administration of cytokines as used in

chemotherapy to examine the mechanisms responsible for effects on mood

and cognition.

o Develop and refine models to examine the potential effects of pre- and

post-natal infection on brain development and adult brain function and

behavior.

o Model effects of acute and chronic immune challenge on neuroendocrine

systems, neurochemistry, electrophysiology, molecular signaling, and gene

expression in neurons.

o Model neural effects of autoantibodies and other immune molecules

implicated

in autoimmune disorders affecting mental health.

o Examine the potential role of abnormalities of the blood/brain barrier in

determining neuroimmune responses.

Identification of pathways mediating effects of peripheral and central

immune

activation on brain:

o Identify and characterize receptors and signal transduction mechanisms

responsible for cytokine and chemokines actions in brain.

o Identify factors regulating brain cytokine and chemokine expression,

release, and degradation.

o Determine the role of neurotransmitters, neuropeptides, and neurohormones

as potential mediators and/or modulators of cytokine and chemokines

expression

and signaling.

o Examine effects of cytokines and chemokines on gene expression and

activation of neurotransmitters, neurohormones, and other signaling

molecules

in brain.

o Elucidate the role of cytokines and chemokines as modulators of

neural-glial communication.

o Examine interactions of cytokines and chemokines with acute and chronic

psychoactive drugs at molecular, cellular, and behavioral levels.

Examination of genetic determinants of immune responses in brain:

o Model genetic variations of immune molecule expression as potential

susceptibility factors for developing neuropsychiatric symptoms.

o Examine combined effects of stress and/or adverse early environmental

experience with genetic alterations in immune signaling in predisposing

patterns of brain development and behavior.

o Examine the impact of gene deletion of cytokines/chemokines and their

receptors, neurotransmitters, peptides, receptors, hormones, or other

signaling molecules on cytokine actions in brain.

Identification of effects of cytokines/chemokines on brain function across

the lifespan:

o Examine the developmental expression of cytokines, chemokines, receptors,

and related signaling molecules in brain.

o Examine the development of blood brain barrier function and the

neurobiological impact of developmentally mediated changes in immune

molecule

infiltration of brain.

o Determine the effects of cytokines and chemokines on stem cell production

and fate.

o Examine the long-term consequences of acute and chronic infection

throughout the lifespan on susceptibility to adverse physiological and

psychological effects of stress.

Delineation of the physiological/behavioral actions of cytokines/chemokines:

o Examine the impact of immune molecules in well-characterized cellular and

behavioral model systems. Examples of areas of study might include neural

plasticity, circadian activity, sleep, learning, conditioned fear, eating,

memory, maternal behavior, or sexual behavior.

o Identify peripheral to brain and/or central pathways mediating specific

behavioral effects of cytokines and chemokines.

o Identify brain regions, cell types, receptors and signaling pathways

mediating specific behavioral effects of cytokines and chemokines.

CONTINUED AT

http://grants.nih.gov/grants/guide/pa-files/PA-02-045.html

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