Abstract
A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood–brain barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level-dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5, or 2.5 mg/kg) during functional magnetic resonance imaging (fMRI) in awake rats imaged at 7.0 T. These data were compared to OT (1 μg/5 μl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis, we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors, e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose–response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity.
Highlights
Oxytocin (OT) and OT-like peptides are evolutionarily conserved molecules found in all vertebrates [for review, see Gimpl and Fahrenholz (2001)]
Central versus Peripheral Oxytocin The 3D color model at the top of Figure 2 depicts the location of 14 brain areas in the rat reported to have a high density of OT receptor binding (De Kloet et al, 1985; van Leeuwen et al, 1985; Freund-Mercier et al, 1987; Tribollet et al, 1988; Dumais et al, 2013)
There was no significant change in negative blood oxygen level-dependent (BOLD) for ICV OT; while IP OT reduced activity in the anterior olfactory nucleus and ventral medial hypothalamus shown highlighted in blue
Summary
Oxytocin (OT) and OT-like peptides are evolutionarily conserved molecules found in all vertebrates [for review, see Gimpl and Fahrenholz (2001)]. Made in neurons localized to the paraventricular, supraoptic nuclei and accessory nuclei of the hypothalamus, OT can be released into the systemic circulation through axons terminating in the neurohypophysis of the pituitary gland. OT neurons in the hypothalamus make efferent connections to multiple areas of the brain, e.g., olfactory bulbs, basal ganglia, thalamus, and amygdala. OT functions in a variety of species-specific social behaviors associated with sexual behavior, social recognition, pair bonding, and maternal care [see reviews Pedersen (1997), Insel and Young (2001), Carter and Keverne (2002), Numan and Insel (2003), and Veenema and Neumann (2008)]. As a chemical signaling system, the OT released peripherally into the blood stream and that released centrally in the brain can act independently of one another or in concert (Landgraf and Neumann, 2004)
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