BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior

Abstract

Brain-derived neurotrophic factor (Bdnf) transcription is controlled by several promoters, which drive expression of multiple transcripts encoding an identical protein. We previously reported that BDNF derived from promoters I and II is highly expressed in hypothalamus and is critical for regulating aggression in male mice. Here we report that BDNF loss from these promoters causes reduced sexual receptivity and impaired maternal care in female mice, which is concomitant with decreased oxytocin (Oxt) expression during development. We identify a novel link between BDNF signaling, oxytocin, and maternal behavior by demonstrating that ablation of TrkB selectively in OXT neurons partially recapitulates maternal care impairments observed in BDNF-deficient females. Using translating ribosome affinity purification and RNA-sequencing we define a molecular profile for OXT neurons and delineate how BDNF signaling impacts gene pathways critical for structural and functional plasticity. Our findings highlight BDNF as a modulator of sexually-dimorphic hypothalamic circuits that govern female-typical behaviors.

Intronic enhancer region governs transcript-specific Bdnf expression in rodent neurons

“…Remarkably, the Bdnf transcripts from the first cluster of exons have been shown to regulate important aspects of behavior. In female mice, Bdnf exon I-containing transcripts are important for proper sexual and maternal behavior ( Maynard et al, 2018 ), whereas in male mice the Bdnf exon I- and exon II-containing transcripts regulate serotonin signaling and control aggressive behavior ( Maynard et al, 2016 ). Furthermore, it has been shown that Bdnf exon I-containing transcripts in the hypothalamus participate in energy metabolism and thermoregulation ( You et al, 2020 ).…”

“…Similar expression patterns for different BDNF transcripts are also observed in humans ( Pruunsild et al, 2007 ). Notably, different Bdnf transcripts have distinct contribution to various aspects of neural circuit functions and behavior ( Hallock et al, 2019 ; Hill et al, 2016 ; Maynard et al, 2016 ; Maynard et al, 2018 ; McAllan et al, 2018 ; Sakata et al, 2009 ).…”

Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function

“…This review will explore recent advances in understanding how such context-dependent signaling is achieved, focusing on two of the most extensively studied functions of neurotrophins: regulation of neuronal survival and axon and dendritic growth in the developing peripheral nervous system and regulation of synaptic function in the context of learning and memory in the adult central nervous system (CNS). However, the principles and mechanisms discussed will be relevant for understanding other neurotrophin functions as diverse as mediation of the effects of anti-depressant drugs 1, 2 , regulation of cardiac development 3 , hypothalamic control of energy balance 4 and oxytocin-dependent maternal behavior 5 , control of pancreatic glucose-induced insulin secretion 6 , and control of insulin-dependent glucose uptake 7 .…”

Intronic enhancer region governs transcript-specific BDNF expression in neurons

“…Remarkably, the BDNF transcripts from the first cluster of exons have been shown to regulate important aspects of behavior. In female mice, BDNF exon I-containing transcripts are important for proper sexual and maternal behavior (Maynard et al, 2018b), whereas in male mice the BDNF exon I and exon II-containing transcripts regulate serotonin signaling and control aggressive behavior (Maynard et al, 2016b). Furthermore, it has been shown that BDNF exon I-containing transcripts in the hypothalamus participate in energy metabolism and thermoregulation (You et al, 2020).…”