Clin Auton Res DOI 10.1007/s10286-017-0478-7 REVIEW The “sacral parasympathetic”: ontogeny and anatomy of a myth Isabel Espinosa‑Medina1 · Orthis Saha1 · Franck Boismoreau1 · Jean‑François Brunet1 Received: 1 September 2017 / Accepted: 18 October 2017 © The Author(s) 2017. This article is an open access publication Abstract We recently defned genetic traits that distinguish neuronal aggregates of the brainstem and, as claimed for sympathetic from parasympathetic neurons, both pregan- more than a century, in the intermediolateral column of the glionic and ganglionic (Espinosa-Medina et al., Science sacral spinal cord, where they form the “sacral parasym- 354:893–897, 2016). By this set of criteria, we found that pathetic nucleus.” The assignation of the sacral outfow to the sacral autonomic outfow is sympathetic, not parasympa- the parasympathetic division of the autonomic nervous sys- thetic as has been thought for more than a century. Proposing tem was introduced at the turn of the twentieth century by such a belated shift in perspective begs the question why the Langley, in a remarkably cursory fashion, with a brief justi- new criterion (cell types defned by their genetic make-up fcation in 1899 [2], followed by reafrmation in footnotes and dependencies) should be favored over the anatomical, to two articles published in 1905 [3] (p. 403) (“I use the physiological and pharmacological considerations of long word para-sympathetic for the cranial and sacral autonomic ago that inspired the “parasympathetic” classifcation. After systems”) and 1911 [4] (p. 173) (a schematic, introduced a brief reminder of the former, we expound the weaknesses by “I divide the nervous system as follows:”). It was never of the latter and argue that the novel genetic defnition helps challenged since. Later, when the pelvic ganglion (improp- integrating neglected anatomical and physiological observa- erly called “plexus”—which better describes a mere rear- tions and clearing the path for future research. rangement of fbers—in species where it is more difuse) was recognized as receiving both thoracolumbar and sacral Keywords Anatomy · Parasympathetic neurons · Pelvic inputs (through, respectively, the hypogastric and pelvic ganglion · Sacral parasympathetic nucleus · Sympathetic nerves) [5, 6] (Fig. 1a), it was deemed to be of a mixed neurons sympathetic/parasympathetic nature, a unique case among autonomic ganglia. Possibly because of this complication, standard schematics of the autonomic nervous system omit Introduction either the pelvic ganglion altogether or its sympathetic input [7–9] (Fig. 1b–e). Nevertheless, the anatomical convergence Neurons in the sympathetic and parasympathetic ganglia in the pelvic ganglion—and projection from there to the vis- receive input from preganglionic neurons located in the cera—of a sympathetic outfow from the lumbar level and of central nervous system (CNS). Sympathetic preganglionics a supposedly parasympathetic one from the sacral level has are in the intermediate zone of the thoracolumbar spinal represented the framework for the study of pelvic physiology cord. Parasympathetic preganglionics are in nuclei or loose at least since the 1930s. * Jean‑François Brunet A genetic viewpoint [email protected] We recently defined developmental genetic signatures 1 Institut de Biologie de l’ENS (IBENS), INSERM, CNRS, École Normale Supérieure, PSL Research University, that distinguish sympathetic from parasympathetic neu- 75005 Paris, France rons and assessed their status in the sacral outfow of the Vol.:(0123456789)1 3 Clin Auton Res Fig. 1 Schematics of the autonomic innervation of the pelvis. a Schematic of the projection of the spinal cord (spinal nerves T12, L1, L2, S2 and S3) to the lumbar and sacral autonomic ganglia. The pelvic ganglion receives a dual input, thoraco-lumbar through the hypogastric nerve, and sacral from the pelvic nerves. The sacral paravertebral chain does not receive projections (rami communicantes) from the sacral cord. Abbreviations: HGN hypogastric nerve, IMG inferior mesenteric ganglion, PG pelvic ganglion, PN pelvic nerve, CPN common pelvic nerve, LSpl lumbar splanchnic nerves, RC ramus communicans, SC spinal cord, PV paravertebral chain. b Schematic of the cranio-sacral division by Gaskell [11]: no pelvic ganglion is shown, and the extra-mural neurons post- ganglionic to the pelvic nerves are represented exactly like the intramural ones postganglionic to the vagus nerve. c Kuntz [31] represents the pelvic ganglion as a purely parasympathetic relay, devoid of lumbar con- nection, 10 years after his own description of a dual input [5]. d The 24th edition of Gray’s anatomy (1948) omits the pelvic ganglion on the path of the pel- vic nerve. This is unchanged in recent editions [9]. e Testut and Latarjet [8] [Italian translation (1971) of the 9th French edition (1949)] omit the pelvic ganglion and represent (in blue) scat- tered distal relays of the sacral preganglionics. Contemporary printed or online schematics display variations on these features (e.g. [7]) mouse [1]. We found that sacral preganglionic neurons, like genuine sympathetic neurons. Likewise, all neurons in the thoracolumbar ones and unlike cranial ones, depend on the pelvic ganglion, as well as intramural ganglia of the blad- basic loop–helix–loop transcription factor Olig2 but not der, like sympathetic ones and unlike parasympathetic ones, on the homeodomain transcription factor Phox2b, and that express the transcription factors Islet1, Gata3 and Hand1 but they express Foxp1 but not Phox2a, Tbx2, Tbx3 or Tbx20. neither Hmx2 nor Hmx3, and they develop independently of Sacral preganglionic neurons thus have the hallmarks of their aferent nerves. Thus, by the criterion of cell type, the 1 3 Clin Auton Res Fig. 2 Connections between the spinal cord and the sympathetic ▸ chain, as originally described by Gaskell: Fig. 4 from [11] showing (in black) the white ramus comunicans from the spinal cord (which would be on the right of the fgure, not shown) through the ventral roots of the second thoracic (D2) to third lumbar (L3) nerves, but nei- ther rostrally nor caudally from there. Neither the superior cervical ganglion (S.C.G.) nor the sacral ones (S1 and below) receive input from their rostro-caudal level, but rather from the thoracolumbar cord below or above, respectively, via longitudinal projection through the paravertebral chain. The projections from sympathetic ganglia to the spinal nerves (grey rami communicans) are shown in red. A.V. annu- lus of Vieussens (or subclavian loop), R.V. ramus vertebralis, St.G. stellate ganglion neurons of the autonomic nervous system in the sacral spinal cord and in the pelvic ganglion are all sympathetic. This conclusion clashes with the traditional view, which is based on a variety of arguments that we critically review below. The anatomical arguments The lumbar gap, the white ramus communicantes and the nervi erigentes At a time when the autonomic nervous system was still considered to be entirely “sympathetic”, foreshadows of the “sacral parasympathetic” outfow can be spotted in the paral- lel drawn by Walter Gaskell between the cranial and sacral visceral nerves. He frst described [10] that the nerves from the CNS to autonomic ganglia form a continuous series at thoracic and upper lumbar levels, framed by two gaps at brachial and lower lumbar levels and then resuming below at sacral levels as projections to the pelvic ganglia and above at cranial levels as projections of the vagus nerve to “dis- tal” ganglia (that Gaskell changed his mind about: “ganglia of the trunci vagi and ganglion petrosum” in 1885 [10] (p. 11) give way to “excitor neurons of the main viscera” in 1920 [11]). Thus, the cranial and sacral outfows symmetri- cally bracket, at a distance, the thoracolumbar one. Gaskell acknowledges that the parallel between the brachial and lumbar gaps is “rough” [11] (p 27). This parallel is actu- ally false: the caudal gap coincides with the lumbar plexus (and might be explained by an ontogenetic depletion of preganglionic neurons in favor of somatic motor neurons for the hindlimb, both born from the same pool of progenitors [12]). In contrast, the rostral gap extends beyond the brachial plexus to include the entire cervical spinal cord. A second “cranio-sacral” parallel suggested by Gaskell was that, above the brachial and below the lumbar gaps, projections resume only to distal or “collateral” ganglia, ramus communicans there is trivial; in contrast, there are not to the paravertebral sympathetic chain; in other words, sacral paravertebral ganglia, however diminutive, so that there are no white rami communicantes [10] (Figs. 1a, 2). the absence of this connection at sacral levels is a genu- Again, the parallel is superfcial: there is no paravertebral ine oddity. The pelvic ganglion is connected to branches of chain at the cranial level, so that the absence of a white the spinal nerves that bypass the paravertebral chain, the 1 3 Clin Auton Res Fig. 3 Semi-schematic repre- sentation of the pelvic nerves from Testut and Latarjet, 9th edition [8]: the pelvic nerves (labeled 14, in red] emanating from the third and fourth sacral nerves (SIII and SIV) directly project to the pelvic ganglion (labeled 13, in blue) while completely bypassing the sacral paravertebral chain (labeled 10 and connected to the spinal nerves by one or two grey rami communicantes, unlabeled on the fgure). Other numbers refer to the coccygeal plexus (9), pre- sacral nerve (anterior hypogas- tric plexus) (11), hypogastric nerves (12), eferent branches of the pelvic ganglion (15), ganglion of Walther (ganglion impar) (16), branch of sacral sympathetic contributing to the meningeal nerve (18) nervi erigentes of Eckhard [13], which can appear to the as to have spawned the category of “short noradrenergic [i.e. anatomist as unrelated to anything at thoracolumbar levels sympathetic] neurons” [15] and so distant from external gen- (Fig. 3). (According to Langley [14] (p. 234), these nerves itals as to create the unusual danger of accidental or surgical had already been divorced from the “great sympathetic” by disruption of nerves between a supposedly parasympathetic J.-B.