When we talk about whether microglia are neuroprotective or neurotoxic, we only refer to the influence of microglia on neurons. However, many studies indicate that neurons are not merely passive targets of microglia but rather exert control over microglial activities [94] . There are considerable interactions between neurons and microglia. For example, Polazzi hypothesized that activation of microglia as a consequence of neuronal injury is primarily aimed at neuroprotection, with the loss of specific communications between neurons and microglia leading to the neurotoxic behavior of microglia [95] . Accumulating evidence demonstrates that there is significant information exchange between neurons and microglia. Depending on whether they are healthy or injured, neurons send "on" or "off" signals to influence microglial activation. On one hand, the activation of [81, 82] microglia by neuronal injury or degeneration has been widely reported [91, 96] . On the other hand, in the healthy brain, microglial activation is tightly restricted by signaling from neurons. CD200-CD200R has been identified as one of the critical pathways in attenuating microglial activation. CD200 is a member of the immunoglobulin superfamily and is expressed on the neuronal membrane surface, while the CD200 receptor (CD200R) is primarily present in the macrophage lineage, which includes microglia [97] . The disruption of CD200-CD200R interactions results in an accelerated microglial response, whereas intensified CD200-CD200R interactions contribute to an attenuation in neurodegeneration [98] . In mice that have had CD200 selectively removed from neurons, microglia exhibited an activated phenotype and were numerous upon facial nerve transaction; damaged CD200-deficient neurons elicited an accelerated microglial response, which demonstrated a loss of the neuronal inhibitory signal for microglial response [97] . Apart from direct interactions through receptor-ligand combinations, electrical activity and soluble factors released from intact neurons also maintain microglial quiescence. In a neuron-glia co-culture, the blockade of neuronal electrical activity by tetrodotoxin or a glutamate receptor antagonist facilitated microglial activation induced by IFN-γ [99] . Soluble molecules from neurons such as neurotrophins and anti-inflammatory agents downregulate antigen expression on cultured rat microglia [99, 100] . Additionally, released factors from neurons can also influence the survival of microglia. Fukui et al. demonstrated that treatment with conditioned media from mature neurons significantly induced the death of microglial cells independent of LPS, while heated neuron-conditioned media or low-calcium-ion media prevented the death of microglia [101] , indicating that specific factors released from neurons exert detrimental effects on microglia. It has been demonstrated that microglial cells undergo apoptosis following peripheral nerve injury [102] [103] [104] or in cases of experimental autoimmune encephalomyelitis(EAE) [105] Injured neurons induced either neuroprotective or neurotoxic behaviors in microglia depending on the manner of injury [91, [106] [107] [108] [109] , providing strong evidence to support the hypothesis of crosstalk between neurons and microglia. Thus, microglia are not merely surveyors of brain tissue but also receive and actively respond to signals from neurons.