TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior

Abstract

Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), have important roles in neural plasticity and are required for antidepressant efficacy. Studies examining the role of BDNF-TrkB signaling in depression and antidepressant efficacy have largely focused on the limbic system, leaving it unclear whether this signaling is important in other brain regions. BDNF and TrkB are both highly expressed in the dorsal raphe nucleus (DRN), a brain region that has been suggested to have a role in depression and antidepressant action, although it is unknown whether BDNF and TrkB in the dorsal raphe nucleus are involved in these processes. We combined the adeno-associated virus (AAV) with the Cre-loxP site-specific recombination system to selectively knock down either Bdnf or TrkB in the DRN. These mice were then characterized in several behavioral paradigms including measures of depression-related behavior and antidepressant efficacy. We show that knockdown of TrkB, but not Bdnf, in the DRN results in loss of antidepressant efficacy and increased aggression-related behavior. We also show that knockdown of TrkB or Bdnf in this brain region does not have an impact on weight, activity levels, anxiety, or depression-related behaviors. These data reveal a critical role for TrkB signaling in the DRN in mediating antidepressant responses and normal aggression behavior. The results also suggest a non-cell autonomous role for BDNF in the DRN in mediating antidepressant efficacy.

Distinct Ventral Pallidal Neural Populations Mediate Separate Symptoms of Depression

“…Many studies have underscored serotonergic neurons in the DRN as a critical mediator of FLX actions (Adachi et al, 2016; Neumaier et al, 1996). Our tracing data reveals that VP PV neurons receive input from the DRN (Figure 2), which could alternatively explain how FLX treatment affects VP PV activity rather than direct effects on VP PV neurons themselves.…”

The Role of BDNF in the Neuroimmune Axis Regulation of Mood Disorders

“…BDNF-TrkB not only affects the survival, development, and functions of neurons but also promotes the formation of the dendritic spine, provides a structural basis for synapse formation and improves the transmission efficiency of synapses. BDNF/TrkB signaling has a major impact on the production of antidepressant effects (44). Knock-out of the BDNF gene or the reduction of the levels of BDNF in the forebrain blocks the behavioral effects of antidepressants (45).…”

Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond

“…Few studies have attempted to examine the concerted relative contributions of serotonin and dopamine towards discrete depressive-like behaviors. This is in spite of the fact that one of the main inputs to the VTA is the DRN (Beier et al, 2015; Faget et al, 2016; Watabe-Uchida et al, 2012) and alterations of this circuitry have been shown to mediate antidepressant efficacy (Adachi et al, 2017; Neumaier et al, 1996). Understanding how serotonergic inputs to the VTA can affect animals’ response to stress, especially in the context of depression, and how this input may modulate different downstream targets such as the LHb or dopaminergic signaling in the NAc or mPFC remain important questions to answer in the future.…”