Hippocampal 5-HT1B Receptor mediates Impulsive Aggression through Neural Input from the Dorsal Raphe

Abstract

Background: Impulsive aggression is characterized by outbursts of rage and violence It is a core symptom of intermittent explosive disorder (IED) Currently the first-line medication for impulsive aggression is selective serotonin reuptake inhibitor (SSRI) suggesting changing in serotonin (5-HT) activity is involved in the regulation of impulsive aggression However the neural circuitry and underlying mechanism remain elusive Purpose: This study aims to investigate the role of 5-HT1B receptor (5-HT1BR) within ventral hippocampus (vHip) as well as neural circuitry underlying impulsive aggression Results: The post-weaning social isolation (SI) model in mice was established to mimic early-childhood maltreatment in human Mice experienced SI showed increased attack number after receiving footshocks compared to group housing (GH) mice The increased attack behavior was reversed after bilateral hippocampal microinjection of the 5-HT1BR agonists anpirtoline or CP-93129 Inversely pretreatment with a 5-HT1BR antagonist SB-224289 blocked the response of SI mice to CP-93129 Moreover application of PKA inhibitors H89 or Rp-8-Br-cAMPS reduced the attack behavior and importantly occluded the effect of 5-HT1BR agonist SI mice showed reduction in response to anti-aggressive effect of CP-93129 The serotonergic neurons are mostly innervated by raphe nucleus (RN) To investigate the functional role of neural circuitry from RN to vHip in impulsive aggression firstly we transduced AAV5-hSyn-hM3D(Gq)-mCherry into the median raphe (MR) of the SI mice mCherry expression was found in vHip by immunofluorescence assay (IF) suggesting a neural circuitry from the MR output to the vHip Surprisingly microinjection of Clozapine-N-Oxide (CNO) into the vHip failed to decrease attack behavior in SI mice Additionally c-Fos expression in the vHip showed no significant change in the CNO-injected mice In parallel we transduced AAVrg-hSyn-hM3D(Gq)-mCherry into the vHip and implanted cannulas into the MR Consistently infusion of CNO into the MR showed no influence in attack behavior nor c-Fos expression in the vHip indicating that MR-vHip neural circuit plays a relative non-significant role in aggressive modulation Accordingly AAV5-hSyn-hM3D(Gq)-mCherry was transduced into the dorsal raphe (DR) of the SI mice Interestingly CNO infusion into the vHip reduced the stress-induced attack behavior in hM4D(Gq)-expressing mice and the effect was abolished by SB-224289 pretreatment In addition c-Fos expression in the vHip was significantly decreased in the CNO-injected mice indicating that activation of DR neurons effectively inhibits neural activity of the vHip Correspondingly AAVrg-hSyn-hM3D(Gq)-mCherry was bilaterally transduced into the vHip and cannulas were implanted into the DR of the SI mice Infusion of CNO into the DR resulted in the inhibition of stress-provoked attack behavior and c-Fos expression in the vHip Remarkably the anti-aggressive effect of CNO was also abolished by SB-224289 pretreatment Conclusion: Our results suggest that the DR-vHip pathway is critical for the regulation of stress-provoked attack behavior in SI mice Targeting 5-HT1BR could be a new strategy for the treatment of impulsive aggression

Date of Award	2020
Original language	English
Supervisor	Po-Wu Gean (Supervisor)