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Synaptic Formation, Neural Circuits,
and Neurodevelopmental Disorders
Our long-term goal is to understand how neural circuits are established and maintained under normal and pathological conditions, and to discover how deficits in these processes lead to disease. Our research uses molecular tools, expansion microscopy, viral mapping, in vivo imaging using both two-photon microscopy and miniscopes, and acute brain slice electrophysiology to understand these biological mechanisms. To gain new perspectives, we collaborate regularly with colleagues from diverse disciplines. Dr. Cruz-Martín has joint appointments with the Department of Pharmacology & Experimental Therapeutics, Neurophotonics Center (NPC), and Psychological & Center for Systems Neuroscience at BU.
Our group is currently studying how genetic perturbations associated with neurodevelopmental disorders influence the function of the brain. Recent Genome-Wide Association Studies (GWAS) have shown that the major histocompatibility complex has the highest genetic association with schizophrenia (SCZ). In particular, the immune molecule complement component 4 (C4) is highly associated with SCZ such that specific structural variants increase expression of C4 and confer greater risk for this brain disorder. However, until recently it was not understood how C4 overexpression could be mechanistically linked to aberrant circuit wiring.
Using targeted genetic manipulation, my group has obtained important results that link increased expression of the neuroimmune molecule C4 to aberrant synaptic plasticity, microglia dysfunction, and deficits in social behavior.
Building on these new findings, my group is using new transgenic mouse lines developed in Cruz-Martín lab to test the effect of inflammation and microglia activation on brain development and behavior. These unique mouse models will open new windows of opportunity for studying the molecular mechanisms that link inflammation to circuit dysfunction in neuropsychiatric disorders. Overactive complement-mediated synapse elimination occurs in aging, Alzheimer’s disease models, and other disorders that exhibit cognitive or behavioral impairments. Therefore, our methods are applicable in general to the study of complement-associated neurological diseases, not just for SCZ.
The anterior cingulate cortex (ACC) is widely regarded as a nexus for decision-making, socially-driven interactions and affective states, including pain. Using 3D-printed miniscopes implanted in freely behaving mice to monitor neuronal activity, we recently identified distinct, non-overlapping subpopulations of VIP interneurons in the anterior cingulate cortex (VIPACC), that preferentially activated to either anxiogenic, anxiolytic, social, or non-social stimuli We also determined that stimulus-selective cells encode the animal’s behavioral states and VIP interneuron clusters may cooperate to improve this encoding. This work contributes to our understanding of how the cerebral cortex encodes information across diverse contexts, and provides insight into the complexity of neural processes involved in anxiety and social behavior in a brain area that has been associated with several disorders in human functional imaging studies.
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