Sex differences in neural activation following different routes of oxytocin administration in awake adult rats
Introduction
Oxytocin (OT) is a neuropeptide synthesized mainly in the paraventricular and supraoptic nuclei of the hypothalamus (Buijs and Swaab, 1979). OT acts through the OT receptor (OTR) centrally as a neuromodulator and peripherally as a hormone via release from the posterior pituitary (Buijs and Swaab, 1979, Knobloch et al., 2012). Across species, OT regulates various social behaviors (Guastella and MacLeod, 2012, Veenema and Neumann, 2008) and often does so in sex-specific ways (Dumais and Veenema, 2016a, Dumais and Veenema, 2016b). For example, in humans, intranasal OT administration impaired social recognition memory and emotion perception in men, but not women (Herzmann et al., 2013, Lynn et al., 2014). In rats, intracerebroventricular (ICV) OT administration enhanced social recognition and reversed social defeat-induced social avoidance in males (Benelli et al., 1995, Lukas et al., 2011) but not females (Engelmann et al., 1998, Lukas and Neumann, 2014).
These sex-specific effects of OT on behavior suggest sex differences in neural activation in response to OT. Indeed, functional magnetic resonance imaging (fMRI) studies in humans have begun to uncover sex differences in neural activation following intranasal OT (Domes et al., 2007, Domes et al., 2010, Rilling et al., 2014). Surprisingly, fMRI studies examining neural activation in response to OT in awake rats have used males only (Ferris et al., 2015) or lactating females only (Febo et al., 2005). In male rats, ICV OT induced BOLD activation in brain regions such as the bed nucleus of the stria terminalis and lateral septum (Ferris et al., 2015). Interestingly, these brain regions show higher OTR binding density in male compared to female rats (Dumais et al., 2013) and are involved in sex-specific regulation of social behavior by OT (Bredewold et al., 2014, Dumais et al., 2016b). This suggests the potential for OT to modulate brain activation differently in male versus female rats.
Because OT does not readily pass the blood brain barrier, with only up to 1.3% of peripheral OT entering the brain (Mens et al., 1983, Ermisch et al., 1985) it is still debated whether OT administered via peripheral routes, including intranasal administration, directly affects brain activity (Leng and Ludwig, 2016). Therefore, it is important to understand how central versus peripheral routes of OT administration modulate neural activity, and whether these activation patterns are different in males compared to females. Rats can be a useful model to investigate potential sex differences in neural activation in response to OT because of the ability to compare different routes of administration including a direct route into the brain. To this end, we examined blood oxygen level dependent (BOLD) activation in awake male and female rats following central (ICV) or peripheral (intraperitoneal; IP) OT administration. The sex-specific effects of OT on social behavior (Dumais et al., 2016a, Dumais et al., 2016b) as well as the sex differences in OTR binding density (Dumais et al., 2013) in rats led us to hypothesize that ICV OT administration would elicit sex differences in neural activation Because peripheral OT has hampered access to the brain (Mens et al., 1983, Ermisch et al., 1985), and knowledge of sex differences in peripheral OTR is limited (except for on reproductive systems; Gimpl and Fahrenholz, 2001), we hypothesized that there would be fewer sex differences in neural activation following IP OT administration compared to ICV administration.
Section snippets
Animals
Adult male (300–325 g) and female (280–300 g) Sprague Dawley rats were obtained from Charles River Laboratories (Wilmington, MA), and were given at least one week to acclimate to the facilities at Northeastern University. Rats were maintained on a 12 h light/dark cycle (lights on at 0800 h) and food and water were available ad libitum. Rats were housed in standard Plexiglas cages (13 × 8.25 × 7 in) in same-sex pairs until 3–5 days before the first day of scanning at which they were housed individually.
ICV OT induced robust activation throughout the brain, including many regions dense in OTR
ICV OT induced positive BOLD activation in more brain regions in males than in females during the 20 min imaging period (Fig. 2). Specifically, compared to vehicle-treated rats, ICV OT-treated males showed a greater volume of positive BOLD activation in 41 regions, and ICV OT-treated females showed a greater volume of positive BOLD activation in 26 brain regions. Most notable were numerous cortical and subcortical regions that showed BOLD activation in ICV OT-treated males but not females.
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Discussion
This is the first rodent study to compare BOLD activation patterns between males and females in response to different routes of OT administration. ICV OT induced sex differences in more (26 versus 10) and in distinct (overlap in only 1) brain regions compared to IP OT. Interestingly, of the sex differences observed, males showed a greater volume of positive BOLD activation than females in nearly all brain regions following ICV OT (20 out of 26 regions) and in all brain regions following IP OT
Conclusions
The present work demonstrates that exogenous OT administration activated the rat brain in sex-specific ways, albeit more so after central than after peripheral OT administration. Importantly, irrespective of route, males showed a greater volume of BOLD activation in response to OT than females. Moreover, the notable similarities between rats and humans in the OT-induced sex-specific activation of the amygdala and insular cortex may provide an opportunity to use rats as a model system to further
Funding sources
This work was supported by NIMHF31MH100891 to KMD, NIMHR15MH102807 to AHV and NICHDP01HD075750 to CFF. These funding sources had no role in study design, in collection, analysis, or interpretation of data, in the writing of the report, or in the decision to submit the article for publication.
Contributions
Authors Kelly M. Dumais, Alexa H. Veenema, and Craig F. Ferris designed the study. Author Kelly M. Dumais performed all experiments and analyzed the data. Author Praveen P. Kulkarni assisted with data analysis. Authors Kelly M. Dumais and Alexa H. Veenema wrote the manuscript, and Craig F. Ferris and Praveen P. Kulkarni edited the manuscript. All authors have approved the final manuscript.
Acknowledgements
We would like to thank members of the Veenema Lab and Dr. Elizabeth Kensinger for critically reading the manuscript, and Dr. Jason Yee for technical assistance.
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