Oxytocin-Responsive Neurons in Prefrontal Cortex as Key Regulators of Female Social and Sexual Behavior

Oxytocin-Responsive Neurons Prefrontal Cortex Key Regulators Sexual Behavior
Oxytocin-Responsive Neurons – Prefrontal Cortex – Sexual Behavior

A publication in the journal Cell reveals the discovery of a population of somatostatin positive, regular spiking interneurons that express the oxytocin receptor that are involved in the regulation of female social behavior in mice, highlighting the prefrontal cortex role in sexual behaviors.

The ‘love hormone’ oxytocin contributes to social and sex behaviors in humans. Previous research indicates that intranasal administration of the ‘prosocial’ hormone oxytocin activates the brain’s frontal cortex, but which cells are targeted by oxytocin, and how this hormone influences neural circuits is poorly understood.

It is also known that inhibition in the brain cortex is generated by a large variety of cortical interneurons that release the neurotransmitter γ-aminobutyric acid (GABA).

In the Cell article the authors report the discovery of a population of somatostatin (Sst)-positive, regular spiking interneurons that express the oxytocin receptor (OxtrINs).

The Cell study emphasizes the importance of the prefrontal cortex in social and sexual behavior, and particularly the subpopulation of somatostatin-positive interneurons expressing the receptor for oxytocin.

In the study, researchers at The Rockefeller University in New York City found that this subpopulation of oxytocin-responsive neurons is required for female mice to show sexual interest in the male mice.

According to eurekalert.org, the senior author Nathaniel Heintz stated that these findings may indicate that “this critical cell population may mediate other aspects of behavior in response to the elevated oxytocin levels that occur in a variety of different contexts”.

This may include social behaviors such as intimacy, love or mother-child bonding.

Taken together, the study identifies a novel subpopulation of oxytocin receptor-expressing cortical interneurons that play a gender- and state-specific role in oxytocin signaling in the medial prefrontal cortex.

Source: Cell, 2014, 159:295-305. doi: 10.1016/j.cell.2014.09.02

Cell Article’s Highlights

  • Oxtr Cre BAC transgenic mice target a subset of Sst-positive cortical interneurons
  • OxtrINs respond to Oxytocin by increasing their firing rate
  • OxtrINs in mPFC are required for female social interest in male mice during estrus
  • Oxytocin action in mPFC is required for female sociosexual behavior

Read more: cell.com


A 2019 study by Yalun Tan et al.  describes a distinct population of neurons in the prefrontal cortex (PFC) that are depolarized by oxytocin and send direct excitatory glutamatergic projections to forebrain nuclei that are known to mediate social behavior.

The investigators found that oxytocin receptors (OXTRs) are expressed on glutamatergic neurons in the PFC, optogenetic stimulation of which elicited activation of neurons residing in several mesolimbic brain structures.

These results suggest that an oxytocin-sensitive PFC to basolateral amygdala (BLA) circuit is required for social recognition. The implication is that impaired social memory may manifest from dysregulation of this circuit.

Of note, as discussed by the authors – subjects with autism spectrum disorders (ASDs) have difficulty identifying a person based on remembering facial features; however, ASDs and typical subjects perform similarly when remembering objects.

In subjects with ASD, viewing the same face increases neural activity in the PFC, which may be analogous to the optogenetic excitation of oxytocin receptor (OXTR) expressing neurons in the PFC that impairs social recognition in mice. The implication is that overactivation of OXTR-expressing neurons in the PFC may contribute to ASD symptomology.

A 2021 study by Walter Francesconi et al. reports that oxytocin regulates the intrinsic inhibitory network of the BNSTDL, where it increases intrinsic excitability and spontaneous firing of Type I, regular spiking interneurons, which leads to a potentiation of GABA-ergic inhibition and a reduction of spontaneous firing of Type II, burst firing neurons.

Of note, the dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear.

As discussed by the authors, their results suggest that OTR activation in the BNSTDL facilitates cued fear and reduces anxiety by inhibiting the Type II BNST→CeA output neurons (see also the Cover Image, right panel).

This may help to understand what might be the role of the BNST and its interactions with the CeA in the neurobiology of fear and anxiety and further highlight the unique potential of targeting oxytocin receptors for the treatment of anxiety disorders.

Cover Image Credit (Left panel): Graphical Abstract from the article in Cell, ‘Oxytocin Modulates Female Sociosexual Behavior through a Specific Class of Prefrontal Cortical Interneurons’, see more at Cell, Volume 159, ISSUE 2, P295-305, October 09, 2014; Right panel: Graphical Abstract from the article in ‘Oxytocin excites BNST interneurons and inhibits BNST output neurons to the central amygdala’ in Neuropharmacology. 2021 Jul 1; 192: 108601.  Highlights: a) Oxytocin directly excites and increases spontaneous firing of Type I BNST interneurons; b) Oxytocin indirectly inhibits Type II BNST neurons, c) Oxytocin inhibits Type II BNST output neurons to the central amygdala (BNST→CeA); d) Oxytocin reduces GABA-ergic transmission in Type III BNST neurons; e) Oxytocin might facilitate cued fear by inhibiting the Type II BNST→CeA neurons