Sustained TNF signaling is required for the synaptic and anxiety-like behavioral response to acute stress

Abstract

Acute stress triggers plasticity of forebrain synapses as well as behavioral changes. Here we reveal that Tumor Necrosis Factor α (TNF) is a required downstream mediator of the stress response in mice, necessary for stress-induced synaptic potentiation in the ventral hippocampus and for an increase in anxiety-like behaviour. Acute stress is sufficient to activate microglia, triggering the long-term release of TNF. Critically, on-going TNF signaling specifically in the ventral hippocampus is necessary to sustain both the stress-induced synaptic and behavioral changes, as these could be reversed hours after induction by antagonizing TNF signaling. This demonstrates that TNF maintains the synaptic and behavioral stress response in vivo, making TNF a potential novel therapeutic target for stress disorders.

Network pharmacology analysis of a patented Chinese herbal medicine for alleviating anxiety disorder in in vitro fertilization-embryo transfer

“… 46 TNF levels change significantly in the cells, plasma, and serum of severely depressed patients, 47 , 48 while TNF signalling also plays an important role in the state of anxiety. 49 This is partly in line with the results of molecular docking analysis and MD simulations. It has been shown that the excessive production of cytokines is a key factor leading to inflammation in the nervous system, and the pathological state of anxiety and depression is crucial.…”

Chronically stressed male and female mice show a similar peripheral and central pro-inflammatory profile after an immune challenge

“…Male mice exposed to an acute stressor showed elevated levels of TNF-α in the ventral hippocampus, concurrent with anxiety-like behavior. Abolishing TNF-α production in these animals mitigated the stress-induced anxiety changes [ 61 ]. Previous behavioral findings from our laboratory indicated that exposure to the present CVS protocol also induced anxiety-like changes in both male and female mice [ 32 ].…”

Microglia: Activity‐dependent regulators of neural circuits

“…81 It is now appreciated that microglia contribute to this form of plasticity called synaptic or homeostatic scaling by releasing TNFα that leads to scaling up and down of synaptic AMPA and GABA A receptors. [82][83][84][85] It was further shown that seizures could be exacerbated by microglia-derived TNFα, and that blocking brain-derived TNFα reduced seizure severity. 86,87 These data raise the possibility that microglia are responding to large changes in neural network activity by releasing TNFα to modulate synaptic plasticity and function.…”

“…During times of prolonged heightened neural activity or prolonged quieting of neuronal firing, neuron numbers increase or decrease, respectively, the amount of neurotransmitter receptors expressed in the postsynaptic membrane (Figure 1D). 81 It is now appreciated that microglia contribute to this form of plasticity called synaptic or homeostatic scaling by releasing TNFα that leads to scaling up and down of synaptic AMPA and GABA A receptors 82‐85 . It was further shown that seizures could be exacerbated by microglia‐derived TNFα, and that blocking brain‐derived TNFα reduced seizure severity 86,87 .…”