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Page 2 of 24 Neuroimmunol Neuroinflammation 2019;6:15 I http://dx.doi.org/10.20517/2347-8659.2019.019

2. The segmented brain - why the hypothalamus is not part of the diencephalon and other
surprises

Charles Watson 1,2

1 University of Western Australia, Perth, WA, Australia
2 Neuroscience Research Australia Sydney, NSW, Australia

The traditional approach to classifying parts of the brain has been challenged by new findings on
developmental gene expression. The columnar model espoused by Herrick in the early 20th century has
been replaced by the prosomeric model of Puelles and Rubenstein (Puelles et al. TINS 2013;36:570). The
prosomeric model shows that the brain is made up of a series of distinct segments - the hypothalamus
(two segments), diencephalon (three segments), and midbrain (two segments), and the hindbrain (twelve
segments).

The hypothalamus forms the rostral end of the neural tube and is divided into terminal and peduncular
segments. The “new” diencephalon is divided into three rostro-caudal segments - the prethalamus, the
thalamus, and the pretectal area. The midbrain, which is now included in the forebrain on gene expression
grounds, can be divided into a large rostral segment (mesomere 1) and a much smaller pre-isthmic segment
(mesomere 2). The hindbrain is also segmented, consisting of the isthmus and 11 rhombomeres (r1 to r11).
In all areas of the brain, each segment contains all the dorsoventral elements of the neural tube: roof plate,
alar plate, basal plate, and floor plate.

The most striking new features of the prosomeric model are seen in the hypothalamus. Firstly, it is now
evident that the hypothalamus is not a part of the diencephalon (as was previously assumed), but a separate
region which sits rostral to the diencephalon developmentally. The terminal segment of the hypothalamus
forms the rostral end of the neural tube. The apparent ventral position of the hypothalamus (its name
means “under the thalamus”) in the adult brain is simply due to the sharp bend in the neural axis created
by the cephalic flexure. This 180° bend even gives the illusion that the hypothalamus is continuous with the
midbrain. Secondly, it is now evident that the subpallial and pallial components of the telencephalon are
derived from the alar plate of the peduncular hypothalamus. The alar plate of the terminal hypothalamus
gives rise into the preoptic area and the eye vesicle.

In the newly defined diencephalon, gene expression evidence now shows that the posterior commissure
and related pretectal nuclei belong to the caudal diencephalon and not to the midbrain, as is popularly
supposed. Within the hindbrain, the cerebellum arises from the alar plate of the isthmus and r1, and the
pontine nuclei migrate from the alar plate of r6 to a ventral position in r3 and r4.

The traditional picture of brain anatomy has been based on a superficial interpretation of topography as
seen in the adult human brain, without regard to the underlying ontological realities. The new discoveries
concerning the underlying segmental nature of the brain give us a new understanding of the real
interrelationships of brain structures. It will probably take years before the old formulations are abandoned;
in the meantime it is important that medical students are presented with this new evidence, instead of
being fed outdated ideas based on simplistic interpretations of brain topography.