Cell sub-journal: Developmental adversity causes abnormal synaptic pruning, and adults are unresponsive to threats

Click on the blue word to focus on how our brain development is regulated by genes and early life experiences
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Early adverse life stress is a risk factor for anxiety, depression and other neuropsychiatric diseases
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Studies have shown that early stress can reshape neural connections in the cerebral cortex and cause behavioral disorders in adulthood
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Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus are the classical control unit of the endocrine response to stress
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March 29, 2022 University of California Tallie Z.
Baram's research team published an article in Cell Reports, revealing that adverse stress events during development cause microglial phagocytosis dysfunction, enhanced CRH neuron excitatory input in the PVN region, and adulthood A behavioral disorder that exhibits a blunted response to threatening behavior
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Figure 1: Adverse stress during development promotes excitatory input of CRH neurons in the PVN region.
Mice experience an increase in the number of excitatory synapses in CRH neurons in the PVN region after an early stress event on postnatal days 2 and 10, electrophysiological The experiment further confirmed that the spontaneous excitatory postsynaptic current in this region was enhanced, and the inhibitory postsynaptic current was changed, indicating that the early stress induced the enhanced excitatory input of CRH neurons in the PVN region
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Normal synaptic pruning of microglia during development is essential for correct neural circuit formation
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Using scanning transmission electron microscopy, the researchers found that microglia phagocytosis of CRH neurons in the PVN region decreased excitatory synapses after early stress
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The number and morphology of microglia in the PVN region were not altered after early stress
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However, two-photon microscopy revealed that microglial branching dynamic contact neuronal structure was attenuated after early stress, and ex vivo experiments showed that chemogenetic activation of microglia can enhance the activity of microglial branching
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Figure 2: MerTK expression in the PVN region Microglia pruning synapses involves multiple cellular and molecular signaling events, including activation of the phagocytic receptor MerTK
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Immunofluorescence experiments showed that MerTK in the PVN region was mainly expressed on microglia, and was hardly expressed on astrocytes and neurons
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Although early stress did not cause MerTk expression in the PVN region, its expression on microglia was reduced
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In vitro cell culture found that the excitatory synapse density of CRH neurons in normal state on postnatal day 8 increased after incubation with MerTk inhibitor, which indicated that early stress inhibited MerTk activity and weakened the phagocytic ability of microglia
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Figure 3: Flowchart of shadow experiment simulation It has been shown that inhibiting CRH neurons in the PVN region can attenuate the defense behavior of mice in the looming-shadow experiment
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By placing virtual shadows above the experimental area that could be cast to the ground to simulate the approaching mice of sky predators in their natural environment, this increased threat elicited defensive behaviors: a targeted flight or a freezing behavior
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This behavioral finding that early-experienced stress-induced mice have a delayed response to threat manifestations in adulthood suggests that early stress-induced microglial dysfunction causes behavioral impairments in adulthood: the researchers used CX3CR1-Cre mice and Gq-DREADD mice were crossed, and about half of the pup's brain microglia expressed Gq-DREADD, which could activate microglia by CNO administration during development
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They found no increase in excitatory synapses in the PVN region following activation of microglia during early stress, and no blunted responses to threatening behaviors in adulthood
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Collectively, we reveal that stress-sensitive PVN region CRH neurons suffer from reduced microglia phagocytosis of excitatory synapses after receiving early stress, causing persistent behavioral changes
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This phagocytic dysfunction of microglia is dependent on MerTk
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[References] 1.
https://doi.
org/10.
1016/j.
celrep.
2022.
110600 The pictures in the text are from references