Key Dates

Related Announcements

PAR-21-208 -  Cutting-Edge Basic Research Awards (CEBRA) (R21 Clinical Trial Optional)

PA-20-185 – NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-184 – NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-195 – NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-196 – NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

PAR-18-714 – Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 - Clinical Trial Not Allowed)

PAR-19-134 – Research Enhancement Award Program (REAP) for Health Professional Schools and Graduate Schools (R15 Clinical Trial Not Allowed)

Issued by

National Institute on Drug Abuse (NIDA)

Purpose

National Institute on Drug Abuse (NIDA) is issuing this Notice of Special Interest (NOSI) to inform potential applicants of its interest in research project grant submissions that examine the effects of drug use on the structural and functional diversity and plasticity of glia and non-neuronal cells on nervous system process in the context of drug misuse and substance use disorders (SUD). Glial and other non-neuronal cells include astrocytes, microglia, oligodendrocytes and ependymal cells.

Background

Glia cells, including astrocytes, microglia, oligodendrocytes and ependymal cells, exhibit brain region differences in their phenotypes, morphology, plasticity and functions within the central nervous system (CNS). These non-neuronal cells reserve domain-specific functions by acting as stable repositories of spatial information essential for local regulation of neuronal activity, with consequent modulation of neural circuit function. For example, microglia and astrocytes mediate immune responses, regulate metabolic processes and are critical modulators of gliotransmission. These are activities that serve to protect, inform and modulate neuronal function and neurocircuit activity. Oligodendrocytes are the myelinating cells within the CNS to optimize conduction speed of excitatory (glutamatergic) neurons. Oligodendrocyte differentiation, maturation and myelination are vital processes during the critical stages of brain development and maturation. Throughout brain development, oligodendrocytes express various proteins (i.e., ion channel protein receptors, neurotransmitter receptors, and opioid receptors) that tightly regulate the brain’s reward system. Drug use can impact the function and mechanism of myelin regulation that give rise to altered structural plasticity and neural circuits. Interference with endogenous opioid system is implicated with disrupted myelin formation and brain maturation. Studies also suggest that alcohol can affect microglia to indirectly impact oligodendrocyte myelination. How glial-neuron interactions affect myelination in the shaping of addictive behavior remains an underexplored research field. Ependymal cells are ciliated epithelial cells of glial origin. They form physical surface barriers between the entire ventricular surface of the CNS and the central canal of the spinal cord. Ependymal cells play key roles in propagating intercellular communication using the cerebrospinal fluid (CSF) to conduct long-distance volume transmission involving neuropeptide release. Evidence suggests that ependymal cells actively express immune mediators and are sensitive to inflammation upon CNS infection. As ependymal cells are involved in CSF circulation in clearance of toxic metabolites and myelin debris, as well as they can respond to CNS injury by providing an environment that protects against axonal degeneration and repairs synaptic connections, mechanisms that drive ependyma-CNS resident cell communication in the context of SUD remain to be discovered.
Glia display mosaic patterns in the brain via various behaviors. Glia can differentiate into different subtypes and phenotypes to exert different structural and/or functional roles depending on their spatial and temporal arrangements. For example, acute and chronic exposure of substances in the CNS can affect the progression of neuroimmune responses and change inflammatory profile, result in changes in glial representation, activation of astrocyte and impaired glutamate homeostasis, alterations in microglia M1/M2 polarization and associated metabolic states as well as oligodendrocyte maturation and myelination processes. Glia within the reward circuity have become increasingly promising cellular intervention targets for drug seeking behaviors. For example, knockdown of the astrocyte-enriched cytoskeletal protein ezrin reduces astrocyte association with synapses and increases heroin reinstatement. Microglia are also implicated as adaptive regulators of striatal function. Augmented nucleus accumbens microglia response through TLR4 mitigates the adverse changes to neural circuitry brought on by the chronic use of cocaine. These findings suggest altered activities of glial cells induced by drugs of abuse may disrupt neuronal activity to contribute to drug addiction behaviors. However, the impact of regional glia functional heterogeneity on SUD remains unclear. This initiative aims to understand how glia cells are allocated to different brain regions to support regionally diversified neurons. Specifically, research is encouraged to further understand how SUD disturbs glial subtype/phenotype distributions and functions that consequently shape neuronal function underlying addiction-related behaviors.

Research Objectives

NIDA seeks to stimulate basic and preclinical research to identify SUD-induced changes in glial cell phenotypes and function that contribute to the expression of SUD . The focus of research applications should be on understanding the roles of glial cells, including astrocytes, microglia, oligodendrocytes and ependymal cells, on neuronal processes and neurocircuit activity. The focus of this NOSI is to examine the effects of SUD on the neurobiology of glial cells. This NOSI encourages applications that integrate BRAIN technologies into glial biology in the context of SUD. Investigators are encouraged to leverage non-neuronal cell-type mapping/phenotyping data obtained through the BRAIN Initiative in their applications. Investigators are also encouraged to adopt techniques and tools developed from the BRAIN Initiative. For a list of BRAIN Initiative technologies and tools that could potentially be applied, see https://braininitiative.nih.gov/funding/funded-awards. Applications proposing to develop tools to study glial cell biology as pertains to SUD should be submitted through NIDA’s CEBRA program (PAR-18-437).

Examples of research areas that are encouraged include, but are not limited to:  

• Compare regionally encoded functional heterogeneity of glial cells in drug-naïve and drug-exposed environments
• Identify different subtypes and phenotypes of glial cells and changes in spatial and temporal arrangements caused by SUD
• Study the structural connectivity of glia networks, the generation, processing and spatiotemporal control of glia activity within these networks, and the consequential effects of changes in glia activity on neuronal structure and function in the context of SUD
• Delineate drug impacted glia-glia and glia-neuron interactions and crosstalk, and their roles in guiding the formation of aberrant neural circuitry linked to addictive behaviors
• Understand how regional glia allocation regulates synaptic plasticity and repair in response to SUD
• Understand the critical roles of reciprocal interactions between neurons and glia during neurodevelopment in the context of SUD
• Uncover the underlying molecular basis of glial cell involved cellular homeostasis program and how that affect drug seeking and reward processes
• Understand the biology of Glial functions involved in complement-mediated synaptic pruning in the SUD and/or HIV environment
• Unravel regional heterogeneity of glial cells and mechanism of glial cell interaction in the context of SUD
• Identify the key role of glial cellular metabolic mechanisms that are altered by chronic drug exposures
• Examine the dynamic interplay between glia populations and inflammatory cells in the context of SUD-associated neural immune activation
• Explore the roles of glia in SUD and/or HIV interactions and how they might be influenced by SARS-CoV2, sex differences, and/or sleep disturbance

This notice applies to due dates on or after June 5, 2021 and subsequent receipt dates through September 9, 2024.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PA-20-185– NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-184– NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-20-195– NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
• PA-20-196– NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)
• PAR-18-714– Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 - Clinical Trial Not Allowed)
• PAR-19-134– Research Enhancement Award Program (REAP) for Health Professional Schools and Graduate Schools (R15 Clinical Trial Not Allowed)
• PAR-21-208 - Cutting-Edge Basic Research Awards (CEBRA) (R21 Clinical Trial Optional)

All instructions in theSF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-DA-21-001” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Shang-Yi Anne Tsai, Ph.D
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5842
Email: stsai@nih.gov

Financial/Grants Management Contact(s)

Cheryl Nathaniel
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-6703
Email: nathanic@nida.nih.gov