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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 (fMRI) in awake rats imaged at 7.0 tesla. These data were compared to OT (1ug/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.

In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type versus knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain.

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, HETzQ175, and HOMzQ175 genotypes in response to the odor of almond. The study was designed to see how alterations in the huntingtin gene in a mouse model of Huntington's disease would affect the perception and processing of almond odor, an evolutionarily conserved stimulus with high emotional and motivational valence. Moreover, the mice in this study were "odor naive," i.e., never having smelled almond or any nuts. Using a segmented, annotated MRI atlas of the mouse and computational analysis, 17 out of 116 brain regions were identified as responding differently to almond odor across genotypes. These regions included the glomerulus of the olfactory bulb, forebrain cortex, anterior cingulate, subiculum, and dentate gyrus of the hippocampus, and several areas of the hypothalamus. In many cases, these regions showed a gene-dose effect with HETzQ175 mice showing a reduction in brain activity from wild-type that is further reduced in HOMzQ175 mice. Conspicuously absent were any differences in brain activity in the caudate/putamen, thalamus, CA3, and CA1 of the hippocampus and much of the cortex. The glomerulus of the olfactory bulb in HOMzQ175 mice showed a reduced change in BOLD signal intensity in response to almond odor as compared to the other phenotypes suggesting a deficit in olfactory sensitivity.