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. 2022 Feb:348:113924.
doi: 10.1016/j.expneurol.2021.113924. Epub 2021 Nov 12.

Minocycline fails to treat chronic traumatic brain injury-induced impulsivity and attention deficits

K M Pechacek  1 , A M Reck  2 , M A Frankot  2 , C Vonder Haar  3
Affiliations

Minocycline fails to treat chronic traumatic brain injury-induced impulsivity and attention deficits

K M Pechacek et al. Exp Neurol. 2022 Feb.

Abstract

Traumatic brain injury (TBI) impacts millions worldwide and can cause lasting psychiatric symptoms. Chronic neuroinflammation is a characteristic of post-injury pathology and is also associated with psychiatric conditions such as ADHD and bipolar disorder. Therefore, the current study sought to determine whether TBI-induced impulsivity and inattention could be treated using minocycline, an antibiotic with anti-inflammatory properties. Rats were trained on the five-choice serial reaction time task (5CSRT), a measure of motor impulsivity and attention. After behavior was stable on the 5CSRT, rats received either a bilateral frontal TBI or sham procedure. Minocycline was given at either an early (1 h post-injury) or chronic (9 weeks post-injury) timepoint. Minocycline was delivered every 12 h for 5 days (45 mg/kg, i.p.). Behavioral testing on the 5CSRT began again after one week of recovery and continued for 12 more weeks, then rats were transcardially perfused. Impulsivity and inattention were both substantially increased following TBI. Minocycline had no therapeutic effects at either the early or late time points. TBI rats had increased lesion volume, but minocycline did not attenuate lesion size. Additionally, microglia count measured by IBA-1+ cells was only increased acutely after TBI, and minocycline did not differentially change the number of microglia in TBI rats. Despite this, minocycline had clear effects on the gut microbiome. Based on the results of this study, minocycline may have limited efficacy for post-injury psychiatric-like symptoms.

Keywords: Controlled cortical impact; Executive function; Five choice serial reaction time task; Microglia.

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Conflict of interest statement

The authors have no competing financial interests.

Figures

Fig 1.
Fig 1.
A) Diagram of the five-choice serial reaction time task (Adapted with permission from Vonder Haar et al., 2016; Copyright American Chemical Society). B) Timeline of study.
Fig 2.
Fig 2.
Microglia represented by Iba-1+ cells. A-C) Number of Iba-1+ cells in PL, OFC, and HPC. In the PL and OFC, TBI increased number of microglia (p = 0.003; p = 0.020). D-F) Microglia circularity analysis in the PL, OFC, and HPC. In the PL there were differences at all indices for TBI rats (p = 0.005; p = 0.005; p = 0.010; p = 0.016). Within the OFC, TBI rats had changes at indexes 0 and 0.1 (p = 0.003, p = 0.033). G) Images representing microglia and outlines of circularity at each index.
Fig 3.
Fig 3.
Effects of TBI and minocycline on cytokine levels. A-C) IL-1β levels in the perilesion (A), OFC (B), HPC (C). Minocycline or TBI did not impact levels of IL-1β (p’s > 0.05). D-E) TNF-α levels in the frontal cortex (D) and HPC (E). Levels of TNF-α were not affected by TBI or Minocycline in either region (p’s > 0.05).
Fig 4.
Fig 4.
Effects of TBI and minocycline on gut microbiome. A) Minocycline decreased the Shannon index (p = 0.004), a measure of alpha diversity. B) Minocycline also caused clear changes in beta diversity as represented by a PCoA plot of weighted unifrac distances (p = 0.001). C) These changes were reflected by shifts in phyla abundance due to minocycline: reduced Firmicutes (p < 0.001), increased Bacteroidetes (p = 0.002), and increased Proteobacteria (p < 0.001).
Fig 5.
Fig 5.
Behavioral data in the early and late treatment groups. A-D) TBI induced impairments in premature responses, accuracy, omissions, and task efficacy index (p’s < 0.001). A-H) Minocycline failed to recover deficits at both the early and late time points (p’s > 0.075).
Fig 6.
Fig 6.
Lesion analysis. A) TBI decreased brain volume but minocycline did not have an effect from early or late treatment (early: p = 0.259; late: p = 0.388). B) Minocycline did not decrease the lesion size in TBI animals (early: p = 0.909; late: p = 0.280). C) Representative pictures of bilateral frontal TBI in each group.
Fig 7.
Fig 7.
Microglia represented by IBA-1+ cells. A-C) IBA-1+ cell count in each group. In the HPC, minocycline decreased IBA-1+ cells in the early treatment (p < 0.027). D-F) Microglia circularity analysis in the PL, OFC, and HPC. In the HPC for the early treatment, there was a circularity by minocycline effect driven by decreased IBA-1+ cells at indices 0.0 and 0.1 (p = 0.006; p = 0.032). C) Images representing microglia and outlines of circularity at each index.
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