Oxytocin signaling is necessary for synaptic maturation of adult-born neurons

Abstract

Neural circuit plasticity and sensory response dynamics depend on forming new synaptic connections. Despite recent advances toward understanding the consequences of circuit plasticity, the mechanisms driving circuit plasticity are unknown. Adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and circuit integration. We and others have shown that efficient adult-born neuron circuit integration hinges on presynaptic activity in the form of diverse signaling peptides. Here, we demonstrate a novel oxytocin-dependent mechanism of adult-born neuron synaptic maturation and circuit integration. We reveal spatial and temporal enrichment of oxytocin receptor expression within adult-born neurons in the murine olfactory bulb, with oxytocin receptor expression peaking during activity-dependent integration. Using viral labeling, confocal microscopy, and cell type-specific RNA-seq, we demonstrate that oxytocin receptor signaling promotes synaptic maturation of newly integrating adult-born neurons by regulating their morphological development and expression of mature synaptic AMPARs and other structural proteins.

Signaling mechanisms underlying activity‐dependent integration of adult‐born neurons in the mouse olfactory bulb

“…Furthermore, whole cell electrophysiological recordings show decreased AMPA/NMDA current ratios in Oxtr KO abGCs. Taken together, these loss‐of‐function studies demonstrate that oxytocinergic signaling regulates abGC morphogenesis and promotes maturation of MTC inputs onto abGCs (Pekarek et al, 2022).…”

“…The origin of oxytocinergic input is not definitively known, but current evidence suggests the paraventricular hypothalamic nucleus as a prominent source. This is because paraventricular oxytocinergic fibers innervate the RMS, and released OT may diffuse throughout the migratory pathway and into the OB (Pekarek et al, 2022). KO of OT receptor (Oxtr) from abGCs causes morphologic abnormalities, characterized by neurite overgrowth and higher dendritic spine density.…”

“…Notably, abGCs also receive various non-synaptic neuromodulatory inputs, such as acetylcholine from the horizontal limb of the diagonal band of Broca (HDB), serotonin (5-HT) from the dorsal raphe, noradrenaline from the locus coeruleus (Lepousez et al, 2015), and oxytocin (OT) from the paraventricular nucleus of the hypothalamus (Pekarek et al, 2022). GABAergic input initially predominates abGC input at early stages.…”

“…Once reaching the GCL, abGCs receive functional GABAergic and glutamatergic synapses on their soma and proximal dendrites (Belluzzi et al, 2003; Katagiri et al, 2011; Kelsch et al, 2008; Panzanelli et al, 2009), which arise from local MTCs, deep short‐axon cells (dSACs), top‐down projections from the OC (including the anterior olfactory nucleus and anterior piriform cortex), and other cortical, limbic, and subcortical projections (Arenkiel et al, 2011; Balu et al, 2007; Deshpande et al, 2013; Hanson et al, 2020; Komano‐Inoue et al, 2014; Lepousez et al, 2014; Padmanabhan et al, 2018). Notably, abGCs also receive various non‐synaptic neuromodulatory inputs, such as acetylcholine from the horizontal limb of the diagonal band of Broca (HDB), serotonin (5‐HT) from the dorsal raphe, noradrenaline from the locus coeruleus (Lepousez et al, 2015), and oxytocin (OT) from the paraventricular nucleus of the hypothalamus (Pekarek et al, 2022). GABAergic input initially predominates abGC input at early stages.…”

“…However, it has been increasingly appreciated that oxytocinergic neurons project to a diverse set of brain areas (Liao et al, 2020; Sharma et al, 2019; Warfvinge et al, 2020). Interestingly, developing abGCs dynamically express OT receptors (Oxtr) throughout the activity‐dependent critical period and respond to oxytocinergic input (Pekarek et al, 2022). The origin of oxytocinergic input is not definitively known, but current evidence suggests the paraventricular hypothalamic nucleus as a prominent source.…”