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Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats.

Ferris CF, Yee JR, Kenkel WM, Dumais KM, Moore K, Veenema AH, Kulkarni P, Perkybile AM, Carter CS - Front Behav Neurosci (2015)

Bottom Line: These data were compared to OT (1 μg/5 μl) given directly to the brain via the lateral cerebroventricle.The change in BOLD signal to peripheral OT did not show any discernible dose-response.The results from this imaging study do not support a direct central action of peripheral OT on the brain.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational NeuroImaging, Northeastern University , Boston, MA , USA.

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.

No MeSH data available.


Intraperitoneal oxytocin and the olfactory bulb. The 3D images in the top left corner are magnifications of the olfactory bulbs shown in Figure 4. Below on the left are 2D activation maps from the rat brain atlas showing the precise location of the significantly altered positive (red) and negative (blue) voxels following IP OT (2.5 mg). The figures on the right show the localization of the voxels on the original neuroanatomical images. The vertical color strip indicates the percent change in BOLD signal. The lines (A, B, C) through the 3D top images show the approximate position of the axial 2D images below. The middle figure in the bottom panel shows the positive BOLD activation pattern on the original bulb neuroanatomy while the left figure shows the specific layers segmented and annotated as they appear in the rat atlas. The figure to right shows an autoradiogram of approximately the same section depicting OT binding in the granular layer (dark contrast). The tables show the median number of positive and negative for vehicle, 0.1, 0.5, and 2.5 IP OT at 10 and 20 min post IP injection. For the 0.1 mg dose positive BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; ^P < 0.05 compared to 2.5 mg; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose positive BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh; βP < 0.05 compared to 2.5 mg. For the 2.5 mg dose positive BOLD, 10 and 20 min: **P < 0.01 compared to Veh. For the 0.1 mg dose negative BOLD, 20 min: **P < 0.01 compared to Veh; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose negative BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh. For the 2.5 mg dose negative BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; §P < 0.05, +P < 0.01 compared to 0.1 mg.
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Figure 5: Intraperitoneal oxytocin and the olfactory bulb. The 3D images in the top left corner are magnifications of the olfactory bulbs shown in Figure 4. Below on the left are 2D activation maps from the rat brain atlas showing the precise location of the significantly altered positive (red) and negative (blue) voxels following IP OT (2.5 mg). The figures on the right show the localization of the voxels on the original neuroanatomical images. The vertical color strip indicates the percent change in BOLD signal. The lines (A, B, C) through the 3D top images show the approximate position of the axial 2D images below. The middle figure in the bottom panel shows the positive BOLD activation pattern on the original bulb neuroanatomy while the left figure shows the specific layers segmented and annotated as they appear in the rat atlas. The figure to right shows an autoradiogram of approximately the same section depicting OT binding in the granular layer (dark contrast). The tables show the median number of positive and negative for vehicle, 0.1, 0.5, and 2.5 IP OT at 10 and 20 min post IP injection. For the 0.1 mg dose positive BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; ^P < 0.05 compared to 2.5 mg; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose positive BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh; βP < 0.05 compared to 2.5 mg. For the 2.5 mg dose positive BOLD, 10 and 20 min: **P < 0.01 compared to Veh. For the 0.1 mg dose negative BOLD, 20 min: **P < 0.01 compared to Veh; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose negative BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh. For the 2.5 mg dose negative BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; §P < 0.05, +P < 0.01 compared to 0.1 mg.

Mentions: The changes in positive and negative BOLD in the different areas of the olfactory bulb are better viewed in the 2D activation maps shown in Figure 5. At top is an enlargement of the olfactory bulbs depicting the 3D activation maps for positive and negative BOLD. The volumes of activation for each area of the bulb and the other areas of the POS for both the 10 and 20 min time periods are shown in the tables to the right. The data used to generate the 3D and 2D activation maps were taken from the vehicle and 2.5 mg/kg dose of OT collected during the 10-min time period. The precise location of the positive and negative voxels is shown registered to the MRI rat atlas and the original anatomy. These composites are the average number of voxels showing a significant increase above baseline for vehicle (n = 12) and 2.5 mg OT (n = 12). The approximate locations of the 2D axial sections relative to the 3D activation maps are indicated by the lines A, B, and C. It is clear from the position of positive and negative BOLD voxels that they do not overlap. Time-course plots showing the change in positive and negative BOLD signals in the glomerular and granular layers are presented in Figure 6. The insert shows a higher magnification of the first 3 min post IP injection of OT. Within the first minute, there is a significant decrease in negative BOLD over baseline for both glomerular layer (t11 = 4.27, P = 0.001) and granular layer (t11 = 4.14, P = 0.002). However, it is not until 3 min post injection that the positive BOLD significantly exceed baseline (glomerular: t10 = 3.70, P = 0.004; granular: t10 = 3.09, P = 0.01) showing the negative BOLD activation pattern precedes the positive BOLD in the olfactory bulb (negative versus positive × time: F24,1056 = 42.06, P < 0.0001). As noted above, Tables S3 and S4 in Supplementary Material show a high level of significant activity in many brain areas within the first 10 min of OT administration that is greatly reduced by 20 min post peptide. The major exception to this trend at 10 and 20 min post OT is the POS, particularly the olfactory bulbs. As shown in the tables attached to Figure 5, all doses of OT show significant changes in negative and positive BOLD from vehicle (*<0.05, **<0.01). Given the significant increase in BOLD activation in the olfactory bulb after IP OT, we performed receptor autoradiography to determine the presence of OT receptor binding in olfactory bulb layers. OT receptor binding was highest in the granular cell layer of the olfactory bulb. By contrast, there was faint OT receptor binding in the external plexiform layer and glomerular layer of the olfactory bulb. The distribution of OT receptor binding in the olfactory bulb is illustrated in Figure 5.


Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats.

Ferris CF, Yee JR, Kenkel WM, Dumais KM, Moore K, Veenema AH, Kulkarni P, Perkybile AM, Carter CS - Front Behav Neurosci (2015)

Intraperitoneal oxytocin and the olfactory bulb. The 3D images in the top left corner are magnifications of the olfactory bulbs shown in Figure 4. Below on the left are 2D activation maps from the rat brain atlas showing the precise location of the significantly altered positive (red) and negative (blue) voxels following IP OT (2.5 mg). The figures on the right show the localization of the voxels on the original neuroanatomical images. The vertical color strip indicates the percent change in BOLD signal. The lines (A, B, C) through the 3D top images show the approximate position of the axial 2D images below. The middle figure in the bottom panel shows the positive BOLD activation pattern on the original bulb neuroanatomy while the left figure shows the specific layers segmented and annotated as they appear in the rat atlas. The figure to right shows an autoradiogram of approximately the same section depicting OT binding in the granular layer (dark contrast). The tables show the median number of positive and negative for vehicle, 0.1, 0.5, and 2.5 IP OT at 10 and 20 min post IP injection. For the 0.1 mg dose positive BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; ^P < 0.05 compared to 2.5 mg; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose positive BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh; βP < 0.05 compared to 2.5 mg. For the 2.5 mg dose positive BOLD, 10 and 20 min: **P < 0.01 compared to Veh. For the 0.1 mg dose negative BOLD, 20 min: **P < 0.01 compared to Veh; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose negative BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh. For the 2.5 mg dose negative BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; §P < 0.05, +P < 0.01 compared to 0.1 mg.
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Figure 5: Intraperitoneal oxytocin and the olfactory bulb. The 3D images in the top left corner are magnifications of the olfactory bulbs shown in Figure 4. Below on the left are 2D activation maps from the rat brain atlas showing the precise location of the significantly altered positive (red) and negative (blue) voxels following IP OT (2.5 mg). The figures on the right show the localization of the voxels on the original neuroanatomical images. The vertical color strip indicates the percent change in BOLD signal. The lines (A, B, C) through the 3D top images show the approximate position of the axial 2D images below. The middle figure in the bottom panel shows the positive BOLD activation pattern on the original bulb neuroanatomy while the left figure shows the specific layers segmented and annotated as they appear in the rat atlas. The figure to right shows an autoradiogram of approximately the same section depicting OT binding in the granular layer (dark contrast). The tables show the median number of positive and negative for vehicle, 0.1, 0.5, and 2.5 IP OT at 10 and 20 min post IP injection. For the 0.1 mg dose positive BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; ^P < 0.05 compared to 2.5 mg; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose positive BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh; βP < 0.05 compared to 2.5 mg. For the 2.5 mg dose positive BOLD, 10 and 20 min: **P < 0.01 compared to Veh. For the 0.1 mg dose negative BOLD, 20 min: **P < 0.01 compared to Veh; §P < 0.05 compared to 2.5 mg. For the 0.5 mg dose negative BOLD 10 and 20 min: * < 0.05 **P < 0.01 compared to Veh. For the 2.5 mg dose negative BOLD, 10 and 20 min: *P < 0.05 **P < 0.01 compared to Veh; §P < 0.05, +P < 0.01 compared to 0.1 mg.
Mentions: The changes in positive and negative BOLD in the different areas of the olfactory bulb are better viewed in the 2D activation maps shown in Figure 5. At top is an enlargement of the olfactory bulbs depicting the 3D activation maps for positive and negative BOLD. The volumes of activation for each area of the bulb and the other areas of the POS for both the 10 and 20 min time periods are shown in the tables to the right. The data used to generate the 3D and 2D activation maps were taken from the vehicle and 2.5 mg/kg dose of OT collected during the 10-min time period. The precise location of the positive and negative voxels is shown registered to the MRI rat atlas and the original anatomy. These composites are the average number of voxels showing a significant increase above baseline for vehicle (n = 12) and 2.5 mg OT (n = 12). The approximate locations of the 2D axial sections relative to the 3D activation maps are indicated by the lines A, B, and C. It is clear from the position of positive and negative BOLD voxels that they do not overlap. Time-course plots showing the change in positive and negative BOLD signals in the glomerular and granular layers are presented in Figure 6. The insert shows a higher magnification of the first 3 min post IP injection of OT. Within the first minute, there is a significant decrease in negative BOLD over baseline for both glomerular layer (t11 = 4.27, P = 0.001) and granular layer (t11 = 4.14, P = 0.002). However, it is not until 3 min post injection that the positive BOLD significantly exceed baseline (glomerular: t10 = 3.70, P = 0.004; granular: t10 = 3.09, P = 0.01) showing the negative BOLD activation pattern precedes the positive BOLD in the olfactory bulb (negative versus positive × time: F24,1056 = 42.06, P < 0.0001). As noted above, Tables S3 and S4 in Supplementary Material show a high level of significant activity in many brain areas within the first 10 min of OT administration that is greatly reduced by 20 min post peptide. The major exception to this trend at 10 and 20 min post OT is the POS, particularly the olfactory bulbs. As shown in the tables attached to Figure 5, all doses of OT show significant changes in negative and positive BOLD from vehicle (*<0.05, **<0.01). Given the significant increase in BOLD activation in the olfactory bulb after IP OT, we performed receptor autoradiography to determine the presence of OT receptor binding in olfactory bulb layers. OT receptor binding was highest in the granular cell layer of the olfactory bulb. By contrast, there was faint OT receptor binding in the external plexiform layer and glomerular layer of the olfactory bulb. The distribution of OT receptor binding in the olfactory bulb is illustrated in Figure 5.

Bottom Line: These data were compared to OT (1 μg/5 μl) given directly to the brain via the lateral cerebroventricle.The change in BOLD signal to peripheral OT did not show any discernible dose-response.The results from this imaging study do not support a direct central action of peripheral OT on the brain.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational NeuroImaging, Northeastern University , Boston, MA , USA.

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.

No MeSH data available.