Our results indicate that microglia in the hindbrain and nodose ganglia are activated for up to six weeks following subdiaphragmatic vagotomy. Fourteen days after vagotomy, microglial activation is shown by significantly increased Iba1 immunoreactivity and altered morphology in both the hindbrain and NG. Our observations confirm a prior report indicating that unilateral nodose ganglion removal activated microglia and increased other inflammatory markers in the ipsilateral NTS and DMV at 3 and 14 days after ganglionectomy [41
]. Our study extends these observations by demonstrating that increased microglial activation occurs in response to more distal vagal damage. In addition, we found that increased microglial activation was detectable in the NG and DVM up to 42 days after injury. To our knowledge, this represents the longest reported microglial activation following peripheral nerve damage.
This prolonged activation of microglia may have a significant effect on vagal structures through cytokine release. The cytokine IL-1β has been shown to activate vagal afferents in the NG [16
]. Blocking vagal afferent signaling with subdiaphragmatic vagotomy prevents the development of fever due to circulating IL-1β [14
]. Furthermore, cytokines that may be released from microglia, such as IL-1β and TNF-α, have been connected with decreased food intake, decreased gastric motility, and increased lipid metabolism, all combining to produce anorexia [6
]. Should microglial activation seen following vagotomy be accompanied by similar physiological effects, this may be a factor in the reduction of food intake and body weight following surgeries that involve intentional or accidental vagal damage [4
We found that minocycline treatment attenuated vagotomy-induced microglial activation in the NTS, DMV and NG. Minocycline is a tetracycline antibiotic that inhibits activation and proliferation of microglia and subsequent cytokine production [15
]. Minocycline was also reported to attenuate, but not abolish, microglial activation following unilateral nodose ganglionectomy [42
]. Minocycline treatment has been shown to prevent microglia-induced hyperalgesia and to be neuroprotective following damage [19
]. Therefore, preventive minocycline treatment may reduce the side effects of bariatric surgeries that are possibly a result of microglial activation in vagal structures, including severe nausea and light-headedness [5
Damage to a single nerve branch leads to microglial activation in terminal fields of spared branches [2
]. We postulated that the abdominal spinal innervation might behave as a “spared branch” following vagotomy. However, SC sections collected 14 days after vagotomy had significantly decreased Iba1 intensities. This unexpected reduction of microglial activity may be explained by vagal inhibition of spinal sensory signaling. It has been previously demonstrated that vagal activity influences a pathway of descending inhibition from the hindbrain—presumably the NTS—to the spinal afferent terminals in the dorsal horns of the SC [30
]. The subdiaphragmatic vagotomy performed in our study would disrupt the same descending pathway. This disruption may reduce microglial activation in the SC through a lack of descending input or the release of inhibition. Alternatively, the vagotomy may be causing the migration of microglia from the spinal cord toward the damaged nodose ganglia or hindbrain [7
In all studied regions, there was at least a trend towards decreased Iba1 intensity with minocycline treatment alone. The decrease in Iba1 intensity with minocycline was significant in the SC. Minocycline treatment on the order of days is not sufficient to reduce basal microglial activation [19
]. However, chronic treatment on the order of weeks or relatively large doses will reduce activation below basal levels [18
]. In our study, the apparent increase in minocycline effectiveness within the SC is likely due to lower basal density of microglia in comparison to the other studied regions rather than increased basal activity. This reduction may be the result of the anti-proliferative effect of minocycline or a reduction of Iba1 expression within still present microglia.