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Principal Investigator: ARIE KAFFMAN
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $419,367
Funding agency: National Institute of Mental Health
Project Abstract
Exposure to unpredictable and complex stress early in life increases the risk for developing anxiety disorder
and abnormal connectivity between the amygdala, the prefrontal cortex (PFC), and the hippocampus (HPC).
Exactly how early life stress (ELS) modifies fronto-limbic connectivity and how these changes contribute to
increased anxiety are questions that are difficult to investigate in humans. Specifically, the question of how
ELS interacts with sex to alter fronto-limbic connections and anxiety are not addressable with current human
studies. To clarify these issues we developed a mouse model of ELS that we have named Unpredictable
Postnatal Stress (UPS), in which mice are exposed to unpredictable and complex stress early in life. We found
that UPS caused robust increase in anxiety that was not seen in mice exposed to simple and predictable form
of ELS, known as limited bedding (LB). Moreover, we found that UPS and LB preferentially increased anxiety
in male mice. Using resting state fMRI (rsfMRI), high resolution diffusion MRI (dMRI), and retrograde tracing
we found increased connectivity in male UPS mice that was present during the juvenile period and adulthood
and was highly correlated with anxiety. Preliminary data with dMRI indicate that fronto-limbic connectivity is not
altered in females and that these sex specific effects are associated with abnormal synaptic pruning and
reduced levels of the transcription factor IRF8 in male microglial, but not female microglia. We hypothesize
that amygdala connectivity with the PFC and the HPC undergoes microglial-mediated pruning during the
postnatal period. This process requires high levels of the transcription factor IRF8 in postnatal microglia and is
critical for programming levels of anxiety during the juvenile period and adulthood. UPS reduces expression of
IRF8 in males, but not female mice. This in turn leads to increase fronto-limbic connectivity and anxiety in UPS
males, but not UPS females. Work in aim 1 will use rsfMRI, dMRI, and dual retrograde tracing to characterize
the effects of UPS, sex and age on fronto-limbic connectivity. Studies in aim 2 will test whether reducing IRF8
in postnatal microglia is sufficient to phenocopy the effects of UPS on anxiety, fronto-limbic connectivity,
microglial gene expression, and phagocytic activity. In aim 3 we ask whether overexpressing IRF8 in postnatal
microglia can normalize anxiety and fronto-limbic connectivity in UPS mice. Successful completion of this
application will define a novel role for microglial IRF8 in refining fronto-limbic connections and programming
anxiety in the mouse; an important finding given the conserved role that IRF8 plays in guiding immune
responses in humans and mice. In addition, this work will provide a new paradigm to explain how ELS
differentially affects microglial function, amygdala connectivity, and anxiety in mice.
Terms: <21+ years old><Address><Adolescent><Adolescent Youth><Adult><Adult Human><Affect><Age><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anxiety><Anxiety Disorders><Basal Transcription Factor><Basal transcription factor genes><Beds><Brain><Brain Nervous System><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Complex><Cornu Ammonis><DWI (diffusion weighted imaging)><DWI-MRI><Data><Development><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Encephalon><Exposure to><Female><Functional MRI><Functional Magnetic Resonance Imaging><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genetic><Hippocampus><Hortega cell><Human><Immune response><Immunological response><Impairment><Individual><Life><Mediating><Mice><Mice Mammals><Microglia><Modern Man><Molecular><Murine><Mus><Names><Phagocytes><Phagocytic Cell><Phenocopy><Play><Prefrontal Cortex><Process><Psychopathology><Resolution><Rest><Risk><Rodent><Rodentia><Rodents Mammals><Role><Stress><Testing><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Animals><Work><abnormal psychology><adulthood><ages><amebocyte><amygdaloid nuclear complex><anxiety reduction><anxiety-like behavior><cell motility><dMRI><developmental><diffusion tensor imaging><early adversity><early childhood adversity><early life adversity><early life stress><fMRI><gitter cell><hippocampal><host response><immune system response><immunoresponse><insight><juvenile><juvenile human><male><mesoglia><microglial cell><microgliocyte><mouse model><murine model><name><named><naming><novel><novel imaging technique><overexpress><overexpression><perivascular glial cell><post-natal period><postnatal><postnatal period><programs><protein expression><resolutions><sex><social role><stress reduction><synaptic pruning><tool><transcription factor>