Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates

Abstract

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXTderivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systemslevel mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…While we cannot exclude the presence of such effects, we do not believe they are an important confounder of our results for two reasons: first, if the effects we observed after synthetic OT solely reflected drug effects on vasculature, then we should expect to see the same effects when administering OT intranasally and intravenously as both routes increase the concentration of the peptide in the systemic circulation to supraphysiologic levels-this is not what we found; second, vascular effects are likely to be reflected on changes in global brain perfusion, but our results did not show any significant effects of any treatment on global CBF-in fact, we included global CBF as a nuisance variable in all of our analyses, therefore accounting for unspecific global vascular effects on CBF. The idea that the reported effects of OT on rCBF do not reflect unspecific vascular effects on global perfusion is further supported by preclinical data showing that the modulation of rCBV by intranasal OT in rodents is likely to result from neural activity 71 . Finally, the univariate analyses we present in this paper should not be used to define the temporal dynamics of the effects of synthetic OT on rCBF (as has been previously explored using pattern recognition analyses) 16 because of the risk of false negatives in specific time-intervals.…”

Sex differences in neural activation following different routes of oxytocin administration in awake adult rats

“…Despite numerous human studies, it is still unknown whether intranasal OT administration modulates brain activation through central (via the nasal epithelium) or peripheral routes, or both (Churchland and Winkielman, 2012; Evans et al, 2014; Leng and Ludwig, 2016). Importantly, a recent study using fMRI in mice shows that activation patterns elicited by intranasal OT administration is distinct from activation elicited by peripheral OT administration (Galbusera et al, 2017), suggesting, at least partly, a central mechanism of action of intranasal OT. Future studies using intranasal OT in rats and humans and blocking peripheral effects of OT will be valuable in gaining a better understanding of how intranasal OT modulates brain activation and whether this occurs in sex-specific ways.…”

Brainwide mapping of endogenous serotonergic transmission via chemogenetic-fMRI

“…Twenty-five minutes later each subject received an intravenous administration of vehicle or drug. fMRI responses were mapped and quantified as previously described (Galbusera et al, 2017). Briefly, fMRI time series were spatially normalized to a common reference space and signal intensity changes were converted into fractional rCBV changes.…”

“…When combined with non invasive neuroimaging methods, cell-type specific manipulations can be used to map the functional substrates of endogenous modulatory transmission, without the confounding contribution of peripherallyelicited vasoactive or pharmacological effects (Ferenczi et al, 2016). Towards this goal, here we describe the combined use of mouse cerebral-blood volume based fMRI (Galbusera et al, 2017) and cell-type specific DREADD (Designed Receptors Exclusively Activated by Designed Drugs (DREADDs) (Armbruster et al, 2007)) chemogenetics, an approach we term 'chemo-fMRI', to map the brainwide functional targets of phasic 5-HT stimulation.…”