Download Лекция 15

Лекция 15
Развитие головного
мозга
Спецификация клеток зародышевых листков
у млекопитающих
Гаструляция зародыша
млекопитающего (Gilbert, 2003).
Эмбриональное развитие
головного мозга
Образование мозговых пузырей
In the chick embryo brain volume expands 30-fold between days 3 and 5 development.
It appears, as the neurula folds close in the region between presumptive brain and
presumptive spinal cord, the surrounding dorsal tissues push in to constrict the neural
tube at the base of the brain and cause its swelling (Gilbert, 2000)
Ранний морфогенез головного мозга
(замыкание нервной трубки) (Gilbert,
2003)
Сравнение структур головного мозга
позвоночных
Embryonic
Forebrain
Midbrain
Hindbrain
Shark
Goose
Human
Эмбрион человека
Similar across species is due to phyletic constraints on the evolution on
new structures.
Similarity is expanding on basic nervous developmental modules.
Regional specification of anteror (rostral) part of neural
tube (Gilbert, 2003)
Gilbert, 2003
Рост нервной трубки (птицы)
(Gilbert, 2003)
«Дни рождения» нейронов и их последующая миграция
определяют слои коры головного мозга (Gilbert, 2003)
Миграция нефронов вдоль отростков радиальной глии в
развитии мозжечка, гиппокампа и коры (Gilbert, 2003)
Migrating neurons are apposed to glia
cells, which guide them from the ventricular zone to their final destination.
In vitro migration of hippocampal neurons
along the process of astroglia cells from
the cerebellum. Neurons can migrate along
a variety of radial glia fibers.
(Gilbert, 2003)
Коммитирование нейронов при образовании слоев в
мозжечке (Gilbert, 2003)
Кора головного мозга
The lobes of the cerebral cortex include the frontal (blue),
temporal (green), occipital (red), and parietal lobes (yellow).
The cerebellum (unlabeled) is not part of the telencephalon.
Гиппокамп
• The hippocampus is a part of the forebrain,
located in the medial temporal lobe. It belongs to
the limbic system and plays major roles in short
term memory and spatial navigation. Humans
and other mammals have two hippocampi, one
in each side of the brain. In rodents, where it has
been studied most extensively, the hippocampus
is shaped something like a banana. In humans it
has a curved and convoluted shape that
reminded early anatomists of a seahorse. The
name, in fact, derives from the Greek word for
deahorde (Greek: ιππος, hippos = horse,
καμπος, kampos = sea monster).
Локализация гиппокампа в коре
головного мозга
Гиппокампы локализованы в пересечении осей (зелёным)
Гиппокампы локализованы в срединной
части височной доли коры (красным)
Функции
• Hyppocampal olfactory
responses
• Role in General Memory
• Role in spatial memory and
navigation
The limbic system (or Paleomammalian brain) is a set of brain structures
including the hippocampus, amygdala, anterior thalamic nuclei, and limbic cortex, which
support a variety of functions including emotion, behavior, long term memory, and
jlfaction. The term "limbic" comes from Latin limbus, meaning "border" or "belt".
The limbic system includes many structures in the cerebral cortex and subcortex of the brain. The term has been used within psychiatry and neurology,
although its exact role and definition has been revised considerably since the
term was introduced.
• The limbic system is embryologically older than
other parts of the brain. It developed to manage
'fight' or 'flight' chemicals and is an evolutionary
necessity for reptilies as well as humans.
• Recent studies of the limbic system of tetrapods
have challenged some long-held tenets of
forebrain evolution. The common ancestors of
reptiles and mammals had a well-developed
limbic system in which the basic subdivisions
and connections of the amygdalar nuclei were
established.
Промежуточный мозг
(Diencephalon)
• The diencephalon is the part of the
forebrain that contains such important
structures as the thalamus,hypothalamus
and the posterior portion of the pituitary
gland. The hypothalamus performs
numerous vital functions, most of which
relate directly or indirectly to the regulation
of visceral activities by way of other brain
regions and the autonomic nervous
system.
Diencephalon
• The diencephalon (or interbrain) is the region of
the brain that includes the thalamus,
hypothalamus, epithalamus, prethalamus or
subthalamus and pretectum. The diencephalon
is located at the midline of the brain, above the
mesencephalon of the brain stem. The
diencephalon contains the zona limitans
intrathalamica as morphological boundary and
signalling center between the prethalamus and
the thalamus.
Средний мозг -Mesencephalon
(Midbrain)
• In biological anatomy, the mesencephalon (or
midbrain) comprises the tectum (or corpora
quadrigemini), tegmentum, the ventricular mesocoelia
(or "iter"), and the cerebral peduncles, as well as several
nuclei and fasciculi. Caudally the mesencephalon
adjoins the pons (metencephalon) and rostrally it adjoins
the diencephalon (Thalamus, hypothalamus, et al).
• The human mesencephalon is archipallian in origin,
meaning its general architecture is shared with the most
ancient of vertebrates. Dopamine produced in the
substantia nigra plays a role in motivation and
habituation of species from humans to the most
elementary animals such as insects.
Mesencephalon
• During development, the mesencephalon forms
from the middle of three vesicles that arise from
the neural tube to generate the brain. In mature
human brains, the mesencephalon becomes the
least differentiated, from both its developmental
form and within its own structure, among the
three vesicles. The mesencephalon is
considered part of the brain stem. Its substantia
nigra is closely associated with motor system
pathways of the basal ganglia.
Средний мозг
• The optic tectum or simply tectum is a paired
structure that forms a major component of the
vertebrate midbrain. In mammals this structure is
more commonly called the superior colliculus
(Latin, higher hill), but even in mammals, the
adjective tectal is commonly used. The tectum is
a layered structure, with a number of layers that
varies by species. The superficial layers are
sensory-related, and receive input from the eyes
as well as other sensory systems.The deep
layers are motor-related, capable of activating
eye movements as well as other responses.
There are also intermediate layers, with mixed
sensory and motor properties
Tectum
Section through superior colliculus (unlabeled) showing path of oculomotor nerve
Средний мозг
• In some non-mammal species, including
fish and birds, the tectum is one of the
largest components of the brain. In
mammals, and especially primates, the
massive expansion of the cerebral cortex
reduces the tectum ("superior colliculus")
to a much smaller fraction of the whole
brain. Even there, though, it remains
functionally very important as the primary
integrating center for eye movements.
Задний мозг
• The rhombencephalon (or hindbrain) is a
developmental categorization of portions of the central
nervous system in vertebrates.
• The rhombencephalon can be subdivided in a variable
number of transversal swellings called rhombomeres. In
the human embryo we can distinguish eight
rhombomeres, from caudal to rostral: Rh7-Rh1 and the
isthmus (the most rostral rhombomere).
• A rare disease of the rhombencephalon,
"rhombencephalosynapsis" is characterized by a missing
vermis resulting in a fused cerebellum. Patients
generally present with cerebellar ataxia.
• The caudal rhombencephalon has been generally
considered as the initiation site for neural tube closure
В заднем мозге (rhombencephalon) первые нейроны
появляются в чётных ромбомерах (Gilbert, 2003).
Задний мозг (Metencephalon)
• Rhombomeres Rh3-Rh1 form the
metencephalon.
• The metencephalon is composed of the pons
and the cerebellum; it contains:
• a portion of the fourth ventricle,
• the trigeminal nerve (CN V),
• abducens nerve (CN VI),
• facial nerve (CN VII),
• and a portion of the vestibulocochlear nerve (CN
VIII).
Мозжечок
• The cerebellum (Latin for little brain) is a region
of the brain that plays an important role in the
integration of sensory perception, coordination
and motor control. In order to coordinate motor
control, there are many neural pathways linking
the cerebellum with the cerebral motor cortex
(which sends information to the muscles causing
them to move) and the spinocerebellar tract
(which provides proprioceptive feedback on the
position of the body in space). The cerebellum
integrates these pathways, like a train conductor,
using the constant feedback on body position to
fine-tune motor movements.
Мозжечок
Human brain, with the cerebellum in purple
Мозжечок
• The cerebellum is of archipalliar
phylogenetic origin. The pallium is a term
for gray matter that forms the cortex. The
archipallium is one of the most
evolutionarily primitive brain regions. The
circuits in the cerebellar cortex look similar
across all classes of vertebrates, including
fish, reptiles, birds, and mammals. This
has been taken as evidence that the
cerebellum performs functions important to
all vertebrate species.
Мозжечок
• During the early stages of embryonic
development, the brain starts to form in three
distinct segments: the prosoencephalon,
mesencephalon, and rhomboencephalon. The
rhombencephalon is the most caudal (toward
the tail) segment of the embryonic brain; it is
from this segment that the cerebellum develops.
Along the embryonic rhombencephalic segment
develop eight swellings, called rhombomeres.
The cerebellum arises from two rhombomeres
located in the alar plate of the neural tube, a
structure that eventually forms the brain and
spinal cord. The specific rhombomeres from
which the cerebellum forms are rhombomere 1
(Rh.1) caudally (near the tail) and the "isthmus"
rostrally (near the front).
Мозжечок
• Two primary regions are thought to give rise to the
neurons that make up the cerebellum. The first region is
the ventricular zone in the roof of the fourth ventricle.
This area produces Purkinje cells and deep cerebellar
nuclear neurons. These cells are the primary output
neurons of the cerebellar cortex and cerebellum. The
second germinal zone (cellular birthplace) is known as
the Rhombic lip, neurons then move by embryonic
week 27 to the external granular layer. This layer of
cells—found on the exterior the cerebellum—produces
the granule neurons. The granule neurons migrate from
this exterior layer to form an inner layer known as the
internal granule layer. The external granular layer ceases
to exist in the mature cerebellum, leaving only granule
cells in the internal granule layer. The cerebellar white
matter may be a third germinal zone in the cerebellum;
however, its function as a germinal zone is controversial.
Изменения паттернов экспрессии Hox-генов изменяют
спецификацию клеток нервного гребня (Gilbert, 2003)
Gilbert, 2000
Дефекты мозга зародышей с разрушенным геном
Sonic hedgehog (Gilbert, 2000)
Индукция передних районов мозга прехордальной
пластинкой
• The forebrain and midbrain regions are
defined by the underlying prechordal
mesoderm and anterior notochord. Two
genes that are expressed in these anterior
mesodermal tissues are Lim1 and Otx2. If
either one is missing, the embryo does not
form a forebrain or midbrain
Schematic representation of the alterations in the Pax2/5 compound mutant mouse. In
the wild-type neural plate, expression of Pax6 (red) and Pax2 and 5 (blue) delimit three
domains - the prosencephalon (PROS), mesencephalon/myelencephalon (MSE/MET)
and hindbrain (MY). In the Pax2/5 double mutant, the middle subdivison is absent, its
only remnant being a small ventral region (light blue) that expresses engrailed-2 and
corresponds to the basal region of the metencephalon. (After Schwarz et al; 1999.)
• Rubenstein and Puelles (1994) have proposed that the
forebrain is composed of six neuromeric regions called
prosomeres.
• Prosomeres p1-p3 comprise the diencephalon, whereas
prosomeres p4-p6 comprise the hypothalamus
(ventrally) and the telencephalon (dorsally). The
prosomeric boundaries coincide with the expression
boundaries of several genes that are thought to be
important in neural specification. They are also seen to
be the boundaries that limit the responses to certain
external stimuli. The p2/p3 boundary may be critical in
patterning the forebrain region. This boundary
corresponds to the zona limitans. It is also a source of
Sonic hedgehog, a diffusible protein known to induce
patterning during gastrulation and limb formation
Neuromeric structure of the brain with the hypothetical inductive events superpositioned on them. (A) The
mesencephalon/metencephalon boundary is positive for both Fgf8 and Wnt1 gene expression. The p2/p3 border
is thought to be the source of sonic hedgehog protein. (B) In situ hybridization of a 3-day chick embryo for Fgf8
expression. One of the major areas of expression can be seen at what will become the boundary between the
midbrain and hindbrain. (A- After Bally-Cuif and Wassef, 1995; B - After E. Laufer, C-Y. Yeo, and C. Tabin.
У человека
• 1. Сохранение скорости роста нейронов
плода после рождения.
• 2. Миграция клеток из переднего мозга в
промежуточный.
• 3. Активность транскрипции.
• 4. Специфическая форма гена FOXP2.
• 5. Продолжение процесса созревания
мозга во взрослом состоянии
Сохранение нейронами младенца человека скорости
роста, характерной для плода (до 12 месяцев) (Gilbert,
2003)
У человека миграция клеток конечного мозга в
промежуточный мозг (Gilbert, 2003)
Нейральные стволовые клетки у взрослого
человека (Gilbert, 2003)
Особенности развития среднего
мозга
• One of the critical regions for midbrain development is
the metencephalon/mesencephalon border that will
normally give rise to the tissues of the isthmus. No
morphological boundary can be seen here, but it is
marked by the most posterior portion of Otx2 gene
expression. When mid-to-anterior mesencephalon tissue
is transplanted to the diencephalon or
rhombencephalon, it induces the cells surrounding it to
develop mesencephalonic fates (in the diencephalon) or
cerebellar fates (in the rhombencephalon) (Bally-Cuif
and Wassef, 1994; Marin and Puelles, 1994). When
rotated, a "triplication" can ensue, since tissues on both
sides of the graft are induced
Присутствие клеток среднего мозга в мозжечке. The presence of mesencephalon cells in the
cerebellum was shown by replacing chick mesencephalon with the corresponding region from the quail. (A)
Summary drawing of the distribution of quail (red triangle) and chick (green triangle) Purkinje cells and quail
(red circles) and chick (green circles) ventricular epithelial cells. The Purkinje cells overlie a ventricular
epithelium of the same species type. III and IV indicate the third and fourth ventricles, respectively. Is is the
isthmus. (B) Derivatives of the brain vesicles, seen schematically from the dorsal surface (A from Hallonet et al.,
1990; B after Hallonet and Le Douarin, 1993)
The mesencephalon/metencephalon ("mes/met") junction region can act as an inducer of midbrain development and
engrailed expression when rotated or transplanted to other regions of the brain. (A) Transplantation of the mes/met junction
results in the induction of engrailed gene expression and midbrain and cerebellar structures in ectopic positions. (B) Rotation of
the mes/met junction causes "triplications" of certain structures, such as the optic tectum. Abbreviations: gt, griseum tectale; TS,
torus semicircularis; P1, pretectal segment; P2, dorsal thalamic segment; cb, cerebellum; ot, optic tectum; ist, isthmus; III, third
cranial, or oculomotor, nerve; IV, fourth cranial, or trochlear, nerve. The postulated polarity is represented by arrows. (B after
Rubenstein and Puelles, 1994.
Индуцирующие свойства пограничных отделов
головного мозга
• This mes/met-inducing region appears to be controlled by
fibroblast growth factor 8 (FGF8). Crossley and colleagues
(1996) found that this isthmus-forming tissue secreted FGF8.
Moreover, when they transplanted FGF8-containing beads into
the diencephalon or rhombencephalon, they obtained the
same duplicated midbrain structures. Control beads soaked in
saline did not show any such duplications. The FGF8 beads
also induced the expression of three genes in the surrounding
tissues–Wnt1, Engrailed-2, and Fgf8 itself. These three genes
are normally expressed in the isthmus region. Wnt1 and
Engrailed are known to be important in the formation of the
cerebellum. Even though the cerebellum does not express
Wnt1 genes, mice deficient in Wnt1 lack their midbrain regions
as well as the cerebellum (McMahon and Bradley, 1990;
Thomas and Cappecchi, 1990). Wnt1 appears to maintain
Engrailed gene expression in the cerebellar precursor cells,
enabling the cells to proliferate (Dickinson et al., 1994;
Danielian and McMahon, 1996).
Гематоэнцефалический барьер
• В представлениях о гематоэнцефалическом барьере
в качестве основных положений подчеркивается
следующее: 1) проникновение веществ в мозг
осуществляется главным образом не через
ликворные пути, а через кровеносную систему на
уровне капилляр — нервная клетка; 2)
гематоэнцефалический барьер является в большей
степени не анатомическим образованием, а
функциональным понятием, характеризующим
определенный физиологический механизм. Как любой существующий в организме физиологический
механизм, гематоэнцефалический барьер находится
под регулирующим влиянием нервной и гуморальной
систем; 3) среди управляющих
гематоэнцефалическим барьером факторов ведущим
является уровень деятельности и метаболизма
нервной ткани
Гематоэнцефалический барьер
Нейроны, глия, внеклеточное
пространство и кровь
•
•
•
•
ЦНС защищена от резких изменений внешней среды гематоэнцефалическим
барьером. Гематоэнцефалический барьер - полупроницаемый барьер между
кровью и нервной тканью, препятствующий проникновению в мозг крупных или
полярных молекул, а также клеток крови, в том числе иммунной системы.
Плотные контакты между клетками эндотелия капилляров ЦНС препятствуют
выходу лейкоцитов, микроорганизмов и даже макромолекул в
субарахноидальное пространство.
У некоторых микробов выработались высокоспециализированные механизмы
(пока малоизученные) преодоления этого барьера. Известно, что вирусы
бешенства и ыирцсы простого герпеса (у человека) и реовирус (у
экспериментальных животных) попадают в ЦНС, передвигаясь по нервам, а
инкапсулированные бактерии и грибы обладают поверхностными
компонентами, позволяющими им проходить через гематоэнцефалический
барьер.
Таким образом, механизмы преодоления гематоэнцефалического барьера
высокоспециализированы. Так, они имеются лишь у определенных серотипов
возбудителей, способных вызывать менингит. Менингит новорожденных,
например, вызывают только те Streptococcus agalactiae, которые относятся к
серотипу III. Другие серотипы тоже патогенны, но вызывают инфекционные
процессы вне ЦНС. Такая избирательность, видимо, определяется
пространственной структурой капсульного полисахарида серотипа III, так как
капсульные полисахариды других серотипов содержат те же компоненты, но
имеют иную пространственную структуру.
Астроциты - единственные клетки, располагающиеся между капиллярами и
телами нейронов и участвующие в транспорте веществ из крови к нейронам и
транспорте продуктов метаболизма нейронов обратно в кровь, - формируют
гематоэнцефалический барьер. Он обеспечивает избирательное прохождение
из крови в ткань мозга различных веществ. Благодаря гематоэнцефалическому
барьеру в экспериментах многие продукты обмена, токсины, вирусы, яды при
введении в кровь почти не обнаруживаются в спинномозговой жидкости.
Гематоэнцефалический барьер
• Ведущим компонентом морфологического субстрата
гематоэнцефалического барьера, обеспечивающим
его функции, является стенка капилляра мозга.
Существуют два механизма проникновения вещества
в клетки мозга: через цереброспинальную жидкость,
которая служит промежуточным звеном между
кровью и нервной или глиальной клеткой, которая
выполняет питательную функцию (так называемый
ликворный путь), и через стенку капилляра. У
взрослого организма основным путем
движения вещества в нервные клетки является
гематогенный (через стенки капилляров); ликворный
путь становится вспомогательным, дополнительным.
Глиальные клетки ЦНС позвоночных можно разделить на
несколько групп
•
Astrоcytes make contacts with cappilaries and neurons (fibrous astrocytes,
which contain filamenta and are prevalent among bundles of myelinated
nerve fibers in the white matter of the brain; protoplasmic astrocytes, which
contain less fibrous material and are abundant in the gray matter around
nerve cell bodies, dendrites and synapses
•
Oligodednrocytes are predominant in the white matter, where they form
myelin around large axones
•
Radial glial cells play essential role in the developing mammalian central
nervous system. In adult CNS resembling radial glia are the Bergman cells
in the Cerebellum and Müller cells in the retina.
•
Ependymal cells that line the inner surfaces of the brain , in the ventricles,
are usially classified as glial cells
•
Microglial cells are distinct from neuroglial cells in structure , properties, and
lineage. They resemble marophages in the blood and probably arise from
them.
Глиальные клетки мозга млекопитающих:
олигодендроциты и астроциты