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Abstract
Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.
Highlights
Neuropathic pain is caused by lesions and diseases of the somatosensory system and remains one of the most challenging problems in medicine [1]
To investigate changes of cortical microglia associated with neuropathic pain, we first performed in vivo two-photon imaging in the S1 of 2-month-old male mice expressing enhanced yellow fluorescent protein (EYFP) in microglia under the control of Cx3cr1 promotor [31]
Abnormal cortical plasticity is thought to be critical for chronic pain development after peripheral nerve injury, but the underlying mechanisms remain unclear
Summary
Neuropathic pain is caused by lesions and diseases of the somatosensory system and remains one of the most challenging problems in medicine [1]. The primary somatosensory cortex (S1) is critical for sensory processing, and its maladaptive plasticity has been implicated in mediating abnormal sensations associated with neuropathic pain, including the aversion to light touch (mechanical allodynia) [2,3,4]. Patients and animals under chronic pain states exhibit increased activation and somatotopic reorganization in the S1 [5,6,7], the extent of which are correlated with pain intensity levels [8,9]. Chronic pain states are associated with synapse remodeling [10,11], increased pyramidal neuron activity [12,13], and decreased GABAergic.
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