Cortically projecting cells in the periaqueductal gray matter of the rat. A retrograde fluorescent tracer study

doi:10.1016/0006-8993(91)90029-U

Brain Research

Volume 543, Issue 2, 15 March 1991, Pages 201-212

https://doi.org/10.1016/0006-8993(91)90029-U Get rights and content

Abstract

The topographical organization of the afferent input from the periaqueductal gray matter (PAG) to the cerebral cortex has been assessed in rats by retrograde transport of the fluorescent tracers Fast blue (FB) and Diamidino yellow (DY). The olfactory, medial frontal (infralimbic, prelimbic and anterior cingulate cortices), lateral frontal (motor), parietal, temporal, occipital and insular cortices were explored by placing two fluorescent tracers into two different cortical regions. The PAG contained the largest number of labeled neurons in medial frontal cortex injections, followed by olfactory and lateral frontal cortices. Fewer retrogradely labeled cells were seen after injections in parietal, temporal occipital and insular cortices. All labeled cells were exclusively located in the medial and lateroventral divisions of the PAG (PAGm and PAGlv). The longitudinal extent of the labeling in PAGm was more extensive than in PAGlv. The labeled neurons in the medial frontal cortex group extended through most of the PAG, while in the remaining groups it was restricted to the caudal one-third of the PAG. Neurons with projections to two different cortical regions were only a small fraction of the total population of labeled cells. Our data indicate that the medial frontal cortex is the most important recipient of a direct PAG input, followed by the lateral frontal cortex. Parietal, temporal, occipital and insular cortices receive only a minor projection. It is concluded that the PAG sends direct projections over the majority of the cortical mantle. Therefore, the possibility arises that the cerebral cortex receives a direct influence from the brainstem without a thalamic relay.

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Previous studies examining the resting-state functional connectivity of the periaqueductal gray (PAG) in chronic visceral pain have localized PAG coordinates derived from BOLD responses to provoked acute pain. These coordinates appear to be several millimeters anterior of the anatomical location of the PAG. Therefore, we aimed to determine whether measures of PAG functional connectivity are sensitive to the localization technique, and if the localization approach has an impact on detecting disease-related differences in chronic visceral pain patients. We examined structural and resting-state functional MRI (rs-fMRI) images from 209 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We applied three different localization techniques to define a region-of-interest (ROI) for the PAG: 1) a ROI previously-published as a Montreal Neurological Institute (MNI) coordinate surrounded by a 3 mm radius sphere (MNI-sphere), 2) a ROI that was hand-traced over the PAG in a MNI template brain (MNI-trace), and 3) a ROI that was hand-drawn over the PAG in structural images from 30 individual participants (participant-trace). We compared the correlation among the rs-fMRI signals from these PAG ROIs, as well as the functional connectivity of these ROIs with the whole brain. First, we found important non-uniformities in brainstem rs-fMRI signals, as rs-fMRI signals from the MNI-trace ROI were significantly more similar to the participant-trace ROI than to the MNI-sphere ROI. We then found that choice of ROI also impacts whole-brain functional connectivity, as measures of PAG functional connectivity throughout the brain were more similar between MNI-trace and participant-trace compared to MNI-sphere and participant-trace. Finally, we found that ROI choice impacts detection of disease-related differences, as functional connectivity differences between pelvic pain patients and healthy controls were much more apparent using the MNI-trace ROI compared to the MNI-sphere ROI. These results indicate that the ROI used to localize the PAG is critical, especially when examining brain functional connectivity changes in chronic visceral pain patients.
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These social roles for IC may result from its extensive circuitry with SDMN structures, a feature that is not observed in other higher-order sensory processing sites in the cortex. IC is reciprocally connected with the VTA, BLA, VP, NAc, MeA and PAG (Faget et al., 2016; Reep and Winans, 1982; Dong and Swanson, 2006; Shi and Cassell, 1998; Reynolds and Zahm, 2005; Groenewegen et al., 1993; Wright and Groenewegen, 1996; Cádiz-Moretti et al., 2016; Pardo-Bellver et al., 2012; Neafsey et al., 1986; Herrero et al., 1991), projects to LS, BNST and mPOA (Dong and Swanson, 2004, 2006; Simerly and Swanson, 1986) and receives afferents from AH (Reep and Winans, 1982). The only SDMN structures with which IC lacks connectivity are Hipp and VMH (Fig. 1).
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Axons from the ventral regions, on the other hand, are directed to a larger variety of regions in the pons and on the floor of the 4th ventricle: descending fibers from the VLPAG and DR split into two bundles, one traveling more dorsally and connecting to locations on the 4th ventricle like the nucleus incertus, dorsal tegmental nucleus and locus coeruleus, and the second bundle diverting ventrally and innervating different points of the reticular formation and other pontine structures on its way toward the medulla. The ventral portions of the PAG, especially at the caudal extreme, project to the frontal cortices (Herrero et al., 1991). Sparse projections from the VLPAG reach the PrL and IL cortices, but most of the efferent connections to these areas depart from the DR (Conde et al., 1995; Hoover and Vertes, 2007; Meller and Dennis, 1991).
Many see the periaqueductal gray (PAG) as a region responsible for the downstream control of defensive reactions. Here we provide a detailed review of anatomical and functional data on the different parts of the PAG together with the dorsal raphe, which completes the circle of periaqueductal nuclei. Based on anatomical features, we propose a new subdivision of the periaqueductal gray that accounts for the distinct characteristics of the area. We provide a comprehensive functional view of the periaqueductal gray, going beyond simple panic and escape to integrate data on fear, anxiety, and depression. Importantly, we conclude that this periaqueductal cluster of nuclei is broadly involved in motivated behavior controlling not only aversive but also appetitive behavior and with some involvement in more complex motivational processes such as approach-avoidance conflict resolution. In sum, these highly conserved nuclei surrounding the aqueduct appear to be the simplest, foundational, elements of integrated motivated goal-directed control of all types.
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The lowest density of neurons was observed from the vlPAG and ventral mPAG after retrograde injection in the insular cortex (Herrero et al., 1991). Moreover, these PAG subdivisions also project to the olfactory cortex that includes the olfactory bulb (Herrero et al., 1991). This latter connection was also found in sheep in which the vPAG/dorsal raphe neurons send axons to the olfactory bulb (Levy et al., 1999).
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We propose that it is possible to reframe the dichotomy of ascending versus descending systems in terms of a recurrent system as it is required for a predictive coding framework (Friston, 2010; Mumford, 1992). First, in line with the principle of reciprocity of corticocortical connections (Felleman and Van Essen, 1991), the above-mentioned areas are not connected in a unidirectional fashion, as for example the term “descending system” suggests: for example, the rACC to PAG to RVM pathway also contains reciprocal connections (i.e., RVM to PAG to rACC; Beitz, 1982a; Herrero et al., 1991). Second, the involvement of the primary neuromodulators for pain—endogenous opioids—is not only evident in the classic PAG to RVM to spinal cord pathway but in nearly all regions of both the descending and ascending systems (with the notable exception of primary somatosensory cortex; Baumgärtner et al., 2006; Zubieta et al., 2001).
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Cortically projecting cells in the periaqueductal gray matter of the rat. A retrograde fluorescent tracer study

Abstract

Brain Research

J. Neurosci. Methods

Brain Research

Neuroscience

Neurosci. Lett.

Brain Research

Neurosci. Lett.

Brain Research

Neurosci. Lett.

Neurosci. Lett.

Brain Research

Brain Research

Neurosci. Lett.

Brain Research

Brain Res. Bull.

Endogenous pain control mechanisms: review and hypothesis

Ann. Neurol.

The midbrain periaqueductal grey in the rat. I. Nuclear volume, cell number, density, orientation and regional subdivisions

J. Comp. Neurol.

The midbrain periaqueductal grey matter in the rat. II. A Golgi analysis

J. Comp. Neurol.

Brainstem neurons projecting to neocortex: a HRP study in the cat

Exp. Brain Res.

An experimental silver study of the ascending projections of the central grey substance and adjacent tegmentum in the rat, with observation in the cat

J. Comp. Neurol.

An autoradiographic study of the projections ascending from the midbrain central grey, and from the region lateral to it in the rat

J. Comp. Neurol.

Cytoarchitecture of the periaqueductal grey matter in the cat: a quantitative Nissl study

Acta Anat.

Conexiones de la sustancia gris periacueductal (SGP) con la medula espinal. Estudio experimental en la rata

Efferent connections of the periaqueductal gray matter in the cat

J. Comp. Neurol.