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Fundamental Mechanisms and Functions of Co-transmission in the Brain
First available due date: February 5, 2025 (link to view opportunity.)
Overview
This Notice of Special Interest (NOSI) encourages basic neuroscience research in animals to investigate the fundamental mechanisms and functions of co-transmission (i.e., release of multiple neurotransmitters by one neuron) that support brain activity and behavior.
Background
It is well-known that different classes of neurons can release various combinations of neurotransmitters (i.e., co-transmission), fine-tuning the flow of information and enhancing the functional flexibility of brain circuits. Co-transmission is dynamically regulated by afferent inputs, intracellular calcium levels, pre-synaptic receptor signaling, and the presence of protein machinery involved in transmitter synthesis, transport, packaging, release, and recycling. Co-transmitters can be released from the same vesicle pool (i.e., co-release), different vesicle pools within a single synapse, or via spatially compartmentalized release from axonal collaterals or extra-synaptic sites. The effects of co-transmission are influenced by the fast vs. slow temporal patterns of release as well as the types of receptors (ionotropic, metabotropic) present in the pre-, post-, or extra-synaptic targets. As a result, the functional consequences may be synergistic, counteractive, or compartmentalized in time and space to enable temporal and spatial integration of neural signals for context- and circuit-specific information processing.
Human studies have implicated dysfunctional neurotransmission and receptor signaling in the pathophysiology of brain disorders. Basic research in animals has demonstrated that co-transmission provides another degree of functional flexibility for neural circuits. For example, co-transmission of fast-acting transmitters and neuromodulators can exert diverse spatiotemporal effects on target cells due to differential firing rate-dependent release, extracellular diffusion properties, and receptor/channel kinetics. The discovery of glutamate and GABA co-release indicates that this form of co-transmission may play a privileged role in regulating excitatory-inhibitory balance across a subset of neural circuits. Additionally, this line of research has provided fundamental insights into basic neurobiology by revealing non-canonical mechanisms by which neurons can import neurotransmitters from the extracellular space instead of synthesizing them, and switch the type of co-transmitters they release by altering expression of neurotransmitter synthesizing enzymes. Combined, this growing evidence demonstrates that co-transmission is a key regulator of neural processing which could be leveraged to fine-tune neural circuit function. Yet, we currently lack a comprehensive understanding of how co-transmission dynamically regulates brain function and behavior.
While modern tools have accelerated basic neuroscience research by enabling precision access to molecularly defined neuronal populations, few studies consider the role of co-transmitters when manipulating circuits of interest, leaving an incomplete understanding of how co-transmission sculpts circuit function. Evidence from transcriptomic and anatomical studies suggests co-transmission is possible in many brain regions based on colocalization of vesicular and membrane transporters and/or biosynthetic enzymes. However, additional studies are needed to determine whether co-transmission actually occurs, whether it has functional effects under physiological conditions, and whether alternative molecular mechanisms of neurotransmitter production support co-transmission.
Research Objectives
This NOSI encourages research studies in animals that systematically characterize forms of co-transmission, identify neurobiological and environmental factors influencing co-transmission, and examine the functional consequences of co-transmission within circuits supporting complex behaviors. The study of co-transmission will further our understanding of the heterogeneity of neuronal cell types, their neuromodulatory actions, and reveal novel mechanisms that could be leveraged to fine-tune neural circuits. Understanding how therapeutic candidates influence co-transmitter release may provide novel insight into their mechanisms of action, off-target effects, and lead to the development of new treatment targets.
Research supported by the Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative has developed comprehensive atlases of cell types in the mammalian brain. The BRAIN Initiative Cell Census Network (BICCN) has identified multiple classes of neurons that may be capable of co-transmission based on co-expression of genes encoding transporters and biosynthetic enzymes specific to certain neurotransmitters. Applicants may utilize reference maps and data generated from BICCN to propose studies investigating the functional consequences of co-transmission, prioritizing evolutionarily conserved cell types and circuits.
This NOSI supports both ex vivo molecular and cellular studies as well as in vivo examination of the effects of co-transmission. Applications proposing research on co-release (i.e., release of two or more neurotransmitters from the same vesicle pool) are also supported under this NOSI.
Specific Areas of Research Interest under this NOSI include:
- Systematic characterization of co-transmission by defining the presence of protein machinery enabling co-transmitter synthesis, transport, packaging, release, and recycling using proteomic approaches at cellular and sub-cellular resolution. Applications testing hypotheses and utilizing data generated from BICCN are also of interest.
- Elucidation of mechanisms regulating release of co-transmitted molecules including but not limited to 1) how cellular activity differentially impacts co-transmitter release; 2) post-transcriptional and post-translational modifications influencing the function of protein machinery enabling co-transmission; 3) mechanisms influencing co-transmitter release from axon collaterals emanating from the same neuron; 4) synaptic plasticity and other processes regulating transmitter switching in co-transmitting neurons.
- Assessment of the molecular and cellular functions of co-transmission and/or functional consequences of co-transmission at circuit and behavioral levels of analysis.
- Identification of pre-, post-, and extra-synaptic receptor and signal transduction pathways that mediate the effects of co-transmission (e.g., synaptic integration in target cells and circuits, postsynaptic effects on gene expression in target cells).
- Mechanistic studies investigating how co-transmission is impacted by environmental interventions such as stress, naturalistic conditions, enrichment, or novelty.
- Neurodevelopmental trajectories of co-transmission mechanisms and how changes in co-transmission across the lifespan affect cellular and circuit function and behavior.
- Computational models generating hypotheses about mechanisms and effects of co-transmission and experimental studies testing the predictions. A specific area of interest is biophysical modeling to generate predictions about the effects of pharmacological agents on co-transmission.
- Application of novel imaging, recording, and/or protein engineering tools for detection and manipulation of co-transmitted molecules. Applications adopting technologies and tools developed through the BRAIN Initiative are of interest.
- Manipulation of co-transmission toward the goal of identifying novel treatment targets and elucidating the mechanisms of action of therapeutic candidates for brain disorders.
Link to funding opportunity.
