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

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

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

What do we already know? I. Columbo, E. and Farina, C. 2016. Trends Immunol. 37: 608-20 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., 2015. Nature Neuroscience. 18, 1539; Cytokines Chemokines Neurotrophic factors neurotransmitters

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., 2015. 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

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. 2016. Nature Reviews Immunology 16, 22–34 Falinano AN et al. 2016. Nature 535, 425–429 Ménard C. et al. 2016. Neuropsychopharmacology, 1–19 Neurogenesis Glutamatergic system Monoamine system Social behavior GABAergic system Inflammatory cytokines (IFNs, IL-1b, IL-6 and TNF)

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

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

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.

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

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