The BDNF-TrkB Pathway Acts Through Nucleus Accumbens D2 Expressing Neurons to Mediate Stress Susceptible Outcomes

Abstract

Brain-derived neurotrophic factor (BDNF) has a critical role in stress response including neuropsychiatric disorders that are precipitated by stress, such as major depressive disorder (MDD). BDNF acts through its full-length BDNF receptor tyrosine kinase B (TrkB) to trigger a pro-plasticity effect. In contrast, the truncated isoform of the BDNF receptor (TrkB.t1) triggers an anti-plasticity effect. In stress outcomes, BDNF acting in the hippocampus has a stress resilience effect, and, inversely, in the nucleus accumbens (NAc), BDNF acts as a stress susceptible molecule. It is unknown if BDNF-TrkB acts on a specific NAc projection neuron, i.e., medium spiny neuron (MSN or spiny projection neuron), a subtype in stress outcomes. To determine this, we performed chronic social or vicarious witness defeat stress (CSDS or CWDS) in mice expressing TrkB.t1 in dopamine receptor 1 or 2 containing MSNs (D1- or D2-MSNs). Our results showed that TrkB.t1 overexpression in NAc D2-MSNs prevented the CSDS-induced social avoidance or other stress susceptible behaviors in male and female mice. We further showed that this overexpression in D2-MSNs blocked stress susceptible behavior induced by intra-NAc BDNF infusion. In contrast, our results demonstrate that overexpression of TrkB.t1 on NAc D1-MSNs facilitates the SDS susceptible behaviors. Our study provides enhanced details into the NAc cell subtype role of BDNF-TrkB signaling in stress outcomes.

Chronic social defeat stress induces a depression-relevant outcome in male prairie voles

“…2 ), future work is needed to delineate a formal way to categorize susceptible versus resilience-related behavior within the SDS-vole population, as has been done with mice (Krishnan et al, 2007; Vialou et al, 2010). This may be important because resilience underlies active neurobiological processes that are different from non-stressed animals (Feder et al, 2009; Pagliusi et al, 2022). Also, future pharmacological approaches evaluating whether the administration of traditional and/or fast-acting antidepressant medications rescue the SDS-induced maladaptive social behavior observed in prairie voles are needed.…”

“…To examine the effects of SDS on sociability, all animals were tested in a 2-step social interaction procedure, as described in mice (Iñiguez et al, 2010; Pagliusi et al, 2022). In the first session (2.5 min), the experimental prairie vole was allowed to freely explore an open-field arena (40 cm height x 40 cm length x 40 cm width) that contained an empty circular wire holding-cage (7 cm diameter; Stoelting #60450).…”

An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer’s Disease

“…On the other hand, stress exposure caused significant downregulation of both TrkB.T1 and TrkB.FL in the NAc of males only, and it was associated with upregulation of TrkB.T1 in the PFC [43]. Recently, NAc cell subtype contributions of the BDNF/TrkB system in the stress outcomes have been demonstrated [44]. TrkB.T1 overexpression in the NAc dopamine receptor 2 (D2)-containing medium spiny neurons (MSNs) prevents chronic social stress outcomes in mice, although this overexpression in NAc D1-MSNs potentiated stress-susceptible outcomes after the social defeat stress paradigm [44].…”

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

“…Many of the systemic and local factors that regulate the interactions of the tumor microenvironment and tumor survival-proliferation-metastasis may be intimately linked to the mitochondrial melatonergic pathway and mitochondrial function. Tumor regulating receptors, such as the alpha 7 nicotinic acetylcholine receptor (α7nAChR), which melatonin induces [ 33 ], and the AhR, which significantly determines the NAS/melatonin ratio [ 34 ], as well as the TrkB-FL and TrkB-T1, upon which NAS induces proliferative effects via TrkB-FL [ 30 ] and mixed effects via TrkB-T1 [ 35 ], are all expressed on mitochondria and, as indicated, intimately interact with the melatonergic pathway. Consequently, the mitochondrial melatonergic pathway is closely associated with mitochondrial function and factors acting to regulate mitochondrial function, such as pineal melatonin and gut microbiome-derived butyrate.…”