Researchers identified gene variants influence size of brain stem

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Researchers have found a link between 48 common genetic variations and the size of the brainstem and other subcortical structures deep within the brain.

These structures control a wide array of functions ranging from learning and fear response to heart rate and voluntary movement.

Damage to the structures is involved in the development of several diseases, including cognitive, psychiatric and movement disorders.

Three-hundred researchers from three large consortiums, together with researchers from UT Health San Antonio, reported the findings Oct. 21 in the journal Nature Genetics. 

The meta-analysis includes almost 40,000 individuals from more than 50 studies around the world, said research lead author Claudia Satizabal, Ph.D., of UT Health San Antonio.

She is an assistant professor of population health sciences and investigator with the university’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.

“The participants are largely normal people who were enrolled in different research studies, and a part of each study involved an MRI brain scan and a blood draw,” Dr. Satizabal said.

“Each study team worked with its own data and compared genetic variants from the blood samples with volumes of the subcortical structures as derived from brain scans.

Then we gathered all the results and combined them into a meta-analysis to obtain a better picture at the population level of which variants determine volume of those structures.”

Forty of the 48 genetic variations were novel — they had not been seen before, Dr. Satizabal said.

The analysis also identified 199 genes related to the variants that may be implicated in determining the volume of subcortical structures.

These genes regulate many functions, including brain development and susceptibility to neurological disorders.

The meta-analysis is the result of a large collaboration between the CHARGE consortium (Cohorts of Heart and Aging Research in Genomic Epidemiology), the ENIGMA consortium (Enhancing Neuro-Imaging Genetics through Meta-Analysis), and the UK Biobank, which includes studies encompassing the United States, Canada, Europe, the United Kingdom, Southeast Asia and Australia.

“This type of study is the first step in understanding the biology of disease, in this case relating to disorders that involve subcortical structures,” said Sudha Seshadri, M.D., professor of neurology at UT Health San Antonio and director of the Glenn Biggs Institute.

Dr. Seshadri is a senior investigator of the CHARGE consortium and a senior author on the Nature Genetics paper. Jayindra Himali, Ph.D., who recently joined the Biggs Institute from Boston University, is also a study co-author.

The seven subcortical brain structures analyzed in the study are the accumbens, amygdala, brainstem, caudate, pallidum, putamen and thalamus. Their functions vary. For example:

  • The amydala is implicated in some psychiatric disorders and is active in anxiety and fear.
  • The brainstem coordinates involuntary functions such as heart rate and alertness.
  • The caudate is implicated in motor function and cognition.
  • The caudate, putamen and pallidum form a brain network involved in multiple functions.

The brainstem and other subcortical structures are involved in disorders such as Huntington’s disease and in essential activities such as sleep and appetite.

Many of the diseases that cause difficulties with memory and movement begin in the brainstem, Dr. Seshadri said.

This includes Alzheimer’s disease and dementia with Lewy bodies. Several other diseases affect the brainstem throughout their course, such as Parkinson’s disease and progressive supranuclear palsy.

“Understanding the biology of these structures is therefore very important,” Dr. Seshadri said.

“The new information that our study provides could help design new experiments to understand or even look for treatments in diseases involving malfunction or damage of subcortical structures,” Dr. Satizabal said.

The study is primarily based on white participants, although some samples in African Americans from the U.S. and Asians from Southeast Asia were included. No Hispanic populations are represented. “Hopefully we can include more diverse samples in future studies,” Dr. Satizabal said.

Forty of the 48 genetic variations were novel — they had not been seen before, Dr. Satizabal said.

The Glenn Biggs Institute seeks to increase representation of Hispanics in studies of Alzheimer’s disease and other neurodegenerative disorders, Dr. Seshadri said. Hispanics are at 1.5 times higher risk of developing Alzheimer’s than non-Hispanic whites.

The study also found that the genes related to subcortical structures in humans similarly affect the neuroanatomy of invertebrates such as fruit flies.

Funding: Funding for the study was provided by National Institutes of Health


For over a century, teachers and scientists have described the mammalian brain stem as having three parts—the midbrain, the pons, and the medulla oblongata—and the names of numerous structures inside the brain stem are consistent with this subdivision. This subdivision was based purely on the external appearance of the human brain stem and there is an urgent need to update the names of brain stem structures to be consistent with modern research findings relative to molecularly defined brain stem developmental units. Studies of developmental gene expression show that the current use of the term “pons” is in most cases very misleading (Puelles et al., 2013; Watson et al., 2017a). In addition, gross misinterpretations of brain stem organization have led to the mistaken inclusion of diencephalic structures in the midbrain, and the failure to recognize the isthmus as the first segment of the hindbrain. This essay will summarize the problems that have arisen from the conventional use of the traditional brain stem nomenclature, and will suggest alternatives based on developmental gene expression, progeny analysis, and fate mapping. In addition, we will comment on the names given to a number of internal brain stem structures and offer alternatives where we think it necessary.

The key to understanding the “natural” (i.e., gene-modulated) anatomy of the brain stem lies in an appreciation of its segmental rostrocaudal organization, without forgetting its parallel dorsoventral differentiation. A complete picture of the segmental organization has been revealed by a number of studies of gene expression during development, which have been summarized by Puelles et al. (2013) and Tomás-Roca et al. (2016).Go to:

Gene Expression Reveals the Segmental Organization of the Brain Stem

The segmental organization of the brain stem was first observed by embryologists in the late nineteenth century, who described a series of outpouchings in the developing vertebrate brain stem (von Baer, 1828; Orr, 1887). The significance of this finding was lost in the subsequent period dominated by the columnar organization theories of Herrick (19101948). But over about the past 25 years, the outpouchings have been recognized as evidence for the fundamental segmental organization of the brain stem. The change came about through the advent of studies on developmental gene expression (e.g., Gaunt et al., 1986; Murphy et al., 1989; Wilkinson et al., 1989a,b; Sundin and Eichele, 1990; Krumlauf et al., 1993), the creation of molecularly-defined regional progeny, and clonal restriction (Lumsden and Keynes, 1989; Fraser et al., 1990; Lumsden, 19901991). These gene-based progeny studies were enabled by the invention of gene targeting in mice (Capecchi, 1989). It is now clear that the brain stem of all vertebrates is made up of a rostro-caudal series of segments that arise in early development and impose an anatomical and functional organization that persists in the adult brain. An additional point of significance is that the midbrain has in recent years been ascribed to the forebrain, taking it out of the brain stem. The midbrain has been found to share a number of gene expression patterns with diencephalon and hypothalamus and lacks true continuity with the hindbrain (Puelles, 2013). The midbrain contains two segments, called mesomeres (Puelles et al., 2012a; Puelles, 2013), whereas the hindbrain is divided into 12 neuromeres—the isthmus and 11 rhombomeres (Puelles et al., 2013; Tomás-Roca et al., 2016; Watson et al., 2017a). Unfortunately, some authors (notably those led by Lumsden and Krumlauf) have consistently ignored the significance of the isthmus and have not accepted the existence of the four caudal rhombomeres (r8 to r11), based on the fact that they lack overt constrictions between them (e.g., Lumsden and Krumlauf, 1996; Tümpel et al., 2009). However, the gene expression evidence for the isthmic segment (Watson et al., 2017c) and the presence of four “hidden” rhombomeres, known as cryptorhombomeres, is now very strong (Marín et al., 2008; Puelles, 2013; Puelles et al., 2013; Tomás-Roca et al., 2016). One surprising finding in relation to the caudal rhombomeres is that the pyramidal decussation is located in the spinal cord, and not in the caudal hindbrain as has been traditionally assumed (Tomás-Roca et al., 2016). The pyramidal tract fibers decussate after they cross the medullo-spinal boundary and so the pyramidal decussation in no longer a component of the hindbrain.

The first comprehensive attempt to illustrate the boundaries and contents of the segmental elements of the brain stem (two mesomeres, isthmus, and 11 rhombomeres) in different planes of section was presented in the chick brain atlas of Puelles et al. (2007). Many of the segments in the brain stem in birds and mammals can be confidently identified by the presence of one or more signature nuclei; examples are the trochlear nucleus in the isthmus and the abducens nucleus in r5. A diagram summarizing mammalian segmental components can be found in Tomás-Roca et al. (2016), and a modified version of this figure is shown in our Figure 4Table 1 shows the segmental position of selected structures in the mammalian brain stem and adjacent diencephalon and spinal cord.

A relatively small set of genes is involved in establishing the rostrocaudal segmental plan of the central nervous system. Those vital to brain stem development include Pax family genes, Otx2, Wnt1, Gbx2, Fgf8, Shh genes, and Hox family genes. Their role in the segmentation of the brain stem is summarized in Figure 1, which shows that expression of Pax 6 in the alar diencephalon ends sharply at the junction between the pretectal area and the midbrain (Schwarz et al., 1999; see images in Puelles et al., 2012a; Duan et al., 2013), Otx2 is expressed in forebrain and midbrain (Puelles et al., 2012a,b); Gbx2 is expressed in the rostral hindbrain (isthmus and r1) but not in the midbrain (Puelles et al., 2012a); Fgf8 is selectively expressed in the isthmus (Watson et al., 2017c); and the Hox genes are expressed from r2 to the caudal end of the spinal cord (Puelles et al., 2013). The expression of the Hox-related gene Egr2 reveals the anatomy of rhombomeres 3, 4, and 5 in a convincing way (Figure 2).

There is a question as to whether the gene expression data acquired from mice can be confidently applied to other mammals, and perhaps to other vertebrates. We are confident such extrapolations can be made, because the anatomy and development of the brain stem is highly conserved (for a general discussion of this issue see Nieuwenhuys et al., 1998; Gilland and Baker, 2005). For example, the pattern of gene expression in the development of the brain stem in chicks mirrors that described in the mouse in almost every respect, even though the species are separated by around 300 million years of evolution. A few exceptions do exist (such as the translocation of the facial motor nucleus from r4 to r6 in mammals), but the point to point similarities are extraordinary (Cambronero and Puelles, 2000; Puelles et al., 2007; Tomás-Roca et al., 2016). However, the evolutionary history of brain stem development is a much bigger subject than we have attempted to address in the present paper.

Problems With Traditional Brain Stem Nomenclature

When the traditional nomenclature of the brain stem is tested against the new understanding of brain stem organization based on developmental gene expression, five major areas of misinterpretation become apparent. These are the true identity of the pons, the existence of the isthmus, the true definition of the midbrain without diencephalic and hindbrain additions, the location of the substantia nigra and VTA (though this is rather a diencephalon problem), and the segmental origin of the cerebellum.

The True Identity of the Pons

The primary problem with the use of the word “pons” is that its historical meaning attaches to the voluminous formation seen on the ventral surface of the human brain. The basilar pontine formation is exceptionally large in humans (correlative with expansion of the cerebral cortex), and this has led to misinterpretation over its true topological position. In many mammals, the basilar pontine nuclei (Pn) and the reticulotegmental nucleus (RtTg) aggregate at the ventral part of rhombomeres 3 and 4, and the pontine bulge is restricted to the ventral surface of these two rhombomeres. An interesting developmental feature of the basilar pons is that the neurons that form the pontine nuclei develop in the rhombic lip of rhombomeres 6 and 7 and then migrate tangentially under the pia to their final location in rhombomeres 3 and 4 (Figure 2).

On the other hand, human anatomy textbooks uniformly state that the pons extends from the caudal end of the midbrain to the beginning of the medulla oblongata just rostral to the exit of the vestibulocochlear and abducens nerves. The differential growth of the basilar pons in humans hides much of the rostral prepontine hindbrain (from isthmus to part of rhombomere 2), on one side, and the part of the retropontine hindbrain containing the abducens nucleus, superior olive, and facial nucleus, on the other (Figures 3​,44).

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Figure 3
A comparison of the external view of the human brain stem (left) and generic mammalian brain stem (right). In the midbrain the emerging oculomotor nerve (3n) is shown. Note the interpeduncular fossa extends into the prepontine hindbrain (ipf), where the interpeduncular nuclear complex is found (not shown). The surfaces of the cerebral peduncles (cp) and the interpeduncular fossa (ipf) visible in the human brain stem are reduced by the rostral expansion of the cerebellopetal pontine fibers coursing through r2 into the cerebellum in r1(middle cerebellar peduncle—mcp). The trapezoid body (tz) and superior olive (SOl) identify rhombomere 5 (r5), but these structures are not visible on the ventral surface of the human brain stem as they are covered by the overhanging caudal pons. The migrated facial nucleus (7N) is found in rhombomere 6 (r6) (Di Bonito et al., 2013; Puelles et al., 2018), but it is also covered by the overhanging caudal expansion of pontine nuclei in the human brain stem. The inferior olive extends from rhombomere 8 (r8) to rhombomere 11 (r11). The spinal cord begins at the start of the pyramidal decussation (pyx).
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Figure 4
Nuclear and fiber landmarks that identify the segments of the hindbrain, midbrain and diencephalon. In this Figure, the cerebellum, fourth ventricle and hypothalamus are labeled for orientation. Note that fate-mapping data have shown that the cerebellum is a tectal structure restricted to the isthmus and r1, irrespective that in the adult it overhangs far backwards over the dorsal choroidal surface of the pontine, retropontine and medullary regions. The diencephalic prosomere 1 (dp1), which contains the pretectal posterior commissure (pc), Darkschewitsch nucleus (Dk) and the interstitial nucleus of Cajal (InC), is delimited anteroposteriorly by the extent of the posterior commissure (pc). The midbrain contains the oculomotor nucleus (3N) and emerging oculomotor nerve (3n) in mesomere 1 and the retrorubral field (RRF) in mesomere 2. Mesomere 2 is a thin wedge of the midbrain, caudal to 3N, the red nucleus and the inferior colliculus. The hindbrain is comprised of twelve segments—the isthmus (r0) and rhombomeres 1–11 (r1 to r11). The isthmus contains the trochlear nucleus (4N), the emerging trochlear nerve (4n) and the prodromal part of the interpeduncular nucleus (IP*). Rhombomere 1 (r1) contains the rostral and caudal parts of the interpeduncular nucleus (IP*), the dorsal and ventral tegmental nuclei, and the locus coeruleus (LC). Rhombomere 2 (r2) contains the rostral part of the motor trigeminal nucleus (5N) and the emerging motor trigeminal nerve. Rhombomere 3 (r3) contains the caudal part of the motor trigeminal nucleus (5N) and the rostral pontine nuclei (Pn). Rhombomere 4 (r4) contains the caudal pontine nuclei (Pn) and the emerging facial nerve (7n). Rhombomere 5 (r5) contains the abducens nucleus (6N), the emerging abducens nerve (6n), and the decussation of the trapezoid body (tz), along with the superior olivary complex. Rhombomere 6 (r6) contains the migrated facial nucleus (7N) and the emerging glossopharyngeal nerve (9n). Rhombomere 7 (r7) and 8 (r8) contain the compact ambiguus nucleus (AmbC) and the rostral end of the solitary nucleus (gustatory nucleus—SolR). Rhombomere 8 also contains the rostral tip of the inferior olive (IO). Rhombomere 9 (r9) contains the semicompact ambiguus nucleus (AmbSC) and the middle region of the inferior olive (IO). Rhombomere 10 (r10) contains the loose ambiguus nucleus (AmbL), the area postrema (AP), and the caudal region of the inferior olive (IO). Rhombomere 11 (r11) contains the retroambiguus nucleus (RAmb) and the caudal tip of the inferior olive. The spinal cord begins at the start of the pyramidal decussation (pyx).

One result of the superimposition of the human version of pontine topography and nomenclature to those mammals with a small basilar pons is that many structures far away from the basilar pons are called “pontine” because in the human brain they are overlaid by the enlarged “pontine” region. The solution to this problem is relatively simple: discontinue the use of the word “pons” as a topographical descriptor in all mammals, and restrict the use of the term pons to the basilar pontine formation in r3-r4. Note the variable pontine “expansion” into r1 and r2 in primate brains lacks any basilar pontine nuclei (Pn) in its interior, and contains exclusively crossed fibers of the middle cerebellar peduncle (mcp) that surround the trigeminal root in alar r2 (see Figure 6). The modern segmented hindbrain model emphasizes the need to distinguish prepontine, pontine, retropontine and medullary territories, each of which appears subdivided into transversal rhombomeric domains. This provides a new level of precision to support modern anatomical and functional analysis.


Source:
UT Health Science Center San Antonio
Media Contacts:
Will Sansom – UT Health Science Center San Antonio
Image Source:
The image is in the public domain.

Original Research: Closed access
“Genetic architecture of subcortical brain structures in 38,851 individuals”. Claudia Satizabal et al.
Nature Genetics doi:10.1038/s41588-019-0511-y.

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