1. Dynamic Neuroimmune Interactions in the Transition from Brain Function to Dysfunction
NIH Blueprint Initiative, FY2018
Changhai Cui, Ph.D.
NIAAA, NIH

2. Neuroimmune Signaling
Neurological disorders
Psychiatric disorders
Neuro- and retinal degeneration
Social behavioral deficit
Other disorders
Brain dysfunction
Neural development
Neurogenesis
Synaptic function
Aging process
Normal brain function

3. Goal of the Initiative
To understand the dynamic interactions of multiple neuroimmune components in the transition from normal brain function to dysfunction at the molecular, cellular, and circuitry levels

4. What do we already know? I.
Columbo, E. and Farina, C Trends Immunol. 37:
Multiple CNS-cell types in neuroimmune interaction and neuroinflammation
Cytokines
Altered neuroimmune signaling in microglia and astrocytes have been associated with a variety of CNS disorders.
Kettenmann et al., 2013, Neuron  77, 10 I.
Microglia
Astrocyte
presynaptic
spine
See also: Chung et al., Nature Neuroscience. 18, 1539;
Cytokines
Chemokines
Neurotrophic factors
neurotransmitters

5. What do we already know?
II. Microglia and astrocytes in the normal brain function
Neural development
Adult neurogenesis
Synaptic interaction
Chung, WS et al. (2015) Nature Neuroscience. 18, 1539–1545
Wu et al., Trends in Immunology. 36, 605
(epilepsy & schizophrenia)
(AD, ASD, schizophrenia)
(ASD, schizophrenia)
Astrocytes
Microglia
Neurotransmission & plasticity
Synapse formation
Synapse elimination
Epilepsy, schizophrenia, Alzheimer’s disease, Autism spectrum disorders, and other disorders
Do glia drive synaptic and cognitive impairment in disease?
Nature Neuroscience 18, 1539–1545 (2015) 
Figure 2 Astrocyte and microglia regulation of synaptic formation, function and elimination, and potential implications for disease. (a) Astrocytes (blue) and microglia (green) release soluble factors that regulate excitatory synapse formation and function. Aberrations in these processes may be relevant for epilepsy and schizophrenia. (b) Glia refine synaptic circuits by engulfing synapses. MEGF10 and MERTK are astrocytic receptors required for synapse phagocytosis. MEGF10 and MERTK may detect synapses for elimination through bridging molecules such as Gas6 and Pros1 for Mertk that bind ‘eat me signals’ on less active synapses. The identities of synaptic eat me signals for both receptors and bridging molecules for Megf10 are unknown. Microglia synapse pruning is dependent on the receptors CX3CR1 and CR3. The ligand of CX3CR1 is the neuronal CX3CL1 (fractalkine), which can either be membrane targeted or secreted. CR3 binds to C3, which may tag less active synapses and target them for elimination. Glial synapse elimination may be dysregulated in AD, ASD, schizophrenia or other neuropsychiatric diseases. (c) Astrocyes and microglia regulate synaptic transmission and plasticity. Astrocytes buffer K+ mostly through Na+/K+ ATPase and uptake glutamate through GLT1 and GLAST. Astrocytes also secrete d-serine and mediate synaptic plasticity. Microglia can affect synaptic plasticity through release of ROS, IL-1β, IL-6 and TNF. Microglia receptors required for proper synaptic function include CX3CR1 (with its ligand CX3CL1, also known as fractalkine), TREM2 and its downstream effector DAP12. These mechanisms may be important for ASD and schizophrenia.
Wake H. et al., Trends in Neurosciences 2013, (36) 209

6. What do we already know? III.
Immune regulation of neurocircuit function and dysfunction
Dysphoria-Anhedonia
Anxiety-Stress
Depression
Adapted from: Miller, AH and Raison, CL Nature Reviews Immunology 16, 22–34
Falinano AN et al Nature 535, 425–429
Ménard C. et al Neuropsychopharmacology, 1–19
Neurogenesis
Glutamatergic system
Monoamine system
Social behavior
GABAergic system
Inflammatory cytokines (IFNs, IL-1b, IL-6 and TNF)

7. Neuroimmune signaling / activity
Challenges
How does the transition from normal brain function to dysfunction occur?
Neuroimmune factors
Cell types
Neurocircuits
Neuroimmune signaling / activity
Normal function
Disease conditions
Transition

8. What do we want to achieve?
To understand the dynamic interactions of multiple neuroimmune components in the transition from normal brain function to dysfunction at the molecular, cellular, and circuitry levels

9. What do we want to achieve?
Concurrent measurements of dynamic activity changes in multiple neuroimmune components to define the role of each cell type in the transition from normal brain function to disease onset and progression.
Understand how inflammatory signals alter the cross-talk among neuroimmune components, and what their roles are in the dysregulation of specific neurocircuit function.
Determine how the functions of specific types of neurons or synapses are impacted by changes of neuroimmune signals or genetic alterations of neuroimmune components.
Understand how alterations of neuronal activity disrupt the homeostatic interactions of multiple neuroimmune components.
Understand how cell-type specific interference impacts the interaction of neuroimmune components and regulates transition to disease conditions.
Identify molecular signatures of the critical time points at which alterations in neuroimmune interactions may promote or suppress disease onset or progression.

10. How do we achieve the goal?
Combining neuroscience, neuroimmunology, novel techniques and methods
Leveraging technological advances to track changes of multiple neuroimmune components
Integrative approach
Collaborative R01s
Grant mechanism:
4.3 million total costs (FY2018)
Budget:
7 - 9 projects
Expectation:
Outcomes
Integrative view of dynamic interactions of multiple neuroimmune components in the transition from the normal brain function to disease conditions

11. Thank You BP Neuroimmune Project Team George Koob (NIAAA)
Antonio Noronha (NIAAA)
Troy Zarcone (NIAAA)
Soundar Regunathan (NIAAA)
Sangeeta Bhargava (NEI) Francesca Bosetti (NINDS)
Richard Conroy (OD)
Nancy Desmond (NIMH)
Emmeline Edward (NCCIH)
Greg Farber (NIMH)
Woody Lin (NIDA)
Miroslaw Mackiewicz (NIA)
Jill Morris (NINDS)
Carol Pontzer (NCCIH)
Vasudev Rao (NIMH)
Denise Russo (NICHD)
Yolanda Vallejo-Estrada (NIDCR) Andrew Weltz (NIBIB)
Yong Yao (NIMH)
Ursula Utz (NINDS)
Greg Farber (NIMH)
Alan Willard (NINDS)
Blueprint Coordinating Committee
Blueprint IC Directors