Principles of Neuroscience: Neural Development – Where It All Began
Neural Development
Our understanding of neuroscience is limited. Limitations in research have made it difficult to fully understand the true function of all parts of the nervous system. Our current understanding of neuroscience is based on the current knowledge and the strength of scientific arguments. Old conclusions may be reinterpreted as new methods and new analyses emerge (Brodal, 2004). The brain is possibly the most complex structure in nature, and while the full understanding of each part of this organ remains out of reach, great strides have been taken in the study of the other components and functions of the nervous system (Sanes et al., 2012). The further an animal is on the evolutionary scale the more complex their nervous system will be (Brodal, 2004). Mammals have developed the ‘neocortex’, so named as it is the most recently evolved part of the brain. Humans have the largest and most developed neocortices. The large surface area, distinct migratory pathways, and cell types of the neocortex account for the higher cognitive abilities of humans compared to other animals and primates (Clowry et al., 2010; Geschwind & Rakic, 2013; Karten, 2015; Rakic, 2009).
The nervous system develops in three phases. The first phase occurs during the first four months of gestation. New neurons are created throughout this phase and migrate throughout the CNS to become the highly specialised brain and neuronal cells. The high rate of neuronal cells allows the cortex to grow. In the second phase, which begins mid-gestation and continues to two years postnatal, increased cortical stress induces cortical folding. The cortex becomes highly organised and specialised. Neuronal plasticity and connectivity account for the high learning ability of human children this age. The third phase continues into adulthood and consists of some synaptogenesis, but mostly synaptic pruning, where unused synaptic connections are removed (Budday et al., 2015).
The Nervous System
The human nervous system is comprised of billions of neurons (nerve cells), specialised cells that carry electrical signals over great distances very rapidly. These neurons are highly organised into networks to transmit and process information. Neurons carry information from the ‘receptors’ in the PNS to the CNS as quickly as possible and, where required, carry back information via ‘effectors’ if an action needs to be taken (Brodal, 2004). In milliseconds, the spinal cord can send a reflexive signal, while information that must be carried to a greater distance to the brain for conscious thought takes slightly longer (Eagleman et al., 2005).
The nervous system is divided into two distinct regions: the Central Nervous System (CNS), which comprises the brain and spinal cord, and the Peripheral Nervous System (PNS), which is made up of sensory and motor neurons and links the CNS to the outside world. The PNS is further divided into the autonomic nervous system (ANS) and the somatic nervous system (Brodal, 2004). The somatic nervous system controls all voluntary and conscious movement, such as raising the arm, through sensory and motor neurons. Sensory neurons carry signals from sensory organs, such as the eyes. The signal is processed, and a signal is sent through motor neurons to the skeletal muscle, causing the muscle to move (Holstege, 1996; Naito et al., 2002). The ANS controls internal organs and glands of the body through two opposing systems, the parasympathetic nervous system and the sympathetic nervous system. These two systems allow the ANS to control how the nervous system responds to the environment and situational changes using a network of neural connections to perform what is known as the ‘fight or flight’ and ‘rest and digest’ responses (Gibbons, 2019). ‘Fight or flight’ is the body’s response to a threat. The sympathetic nervous system responds by increasing muscle tone, blood pressure, respiration rate and metabolism, while decreasing gastrointestinal activity, to optimise the body’s ability to fight or escape (Battipaglia & Lanza, 2014; Gibbons, 2019). In a period without imminent danger, the parasympathetic system acts to decrease the heart rate and increase gastrointestinal activity (Gibbons, 2019).
Nervous System Development
Neural development is a highly sensitive and complex process determined by genetic, biochemical, environmental, and physical events and signals that must occur in a precise order and at a precise time to correctly form the nervous system (Budday et al., 2015). The nervous system begins as a simple layer of tissue. Human embryos consist of three layers that form during gastrulation: the endoderm, ectoderm, and mesoderm. Each layer will go on to become a different part of the body. The outermost layer, the ectoderm, is the precursor for both skin (ectoderm) and the nervous system (neuroectoderm). When nervous system development begins during the 2nd-3rd week of gestation, the ectoderm germ layer is shaped like a disc with cranial and caudal ends. Then, the development of the CNS begins through a process called neurulation, where the neural tube is formed. Neurulation begins when cells in the mesoderm and notochord signal to the ectodermal cells to proliferate and elongate into the neural plate. As the neural plate grows, it invaginates, forming the neural groove along the embryo’s dorsal side. The edges of the neural plate thicken to become the neural folds, which migrate towards each other and converge, creating the hollow tube below the ectoderm called the neural tube (Borsani et al., 2019; Smith & Schoenwolf, 1997).
Following the convergence of the neural folds to form the neural tube, cells from the neural folds separate from the dorsal side of the neural tube to become the neural crest cells. These cells then go through epithelial-mesenchymal transition and migrate to become a variety of PNS cell types, depending on their segment of the neural crest: the cranial, cardiac, vagal and trunk neural crest. The cells in each segment will then migrate to corresponding regions of the neuraxis where they differentiate further into specific cell types. Cranial neural crest cells will migrate dorsolaterally to become the craniofacial mesenchyme and will eventually differentiate into the connective tissue, cartilage, bone, neurons, and pigment cells of the face. Cardiac neural crest cells differentiate into melanocytes, neurons, cartilage, connective tissue and the musculoconnective tissue walls of large arteries and the aorticopulmonary septum of the heart. The vagal and sacral neural crest cells differentiate into the parasympathetic ganglia of the gastrointestinal system, creating peristaltic muscle movement. Trunk neural crest cells can follow two pathways. These cells could migrate dorsolaterally to become melanocytes in the ectoderm, or the cells could migrate ventrolaterally and form the dorsal root ganglia and sensory neurons and cells producing epinephrine in the adrenal gland (Douarin & Dupin, 2003; Gilbert, 2000; Shakhova & Sommer, 2010).
The neural tube is the basis of the nervous system and will continue to differentiate and grow in complexity throughout gestation. When the cranial end of the neural tube fully closes in the fourth week of gestation, bulges in the neural tube differentiate into three vesicles: the Prosencephalon, Mesencephalon and Rhombencephalon. These vesicles will develop into the forebrain, midbrain, and hindbrain of the adult brain respectively. By the fifth week of gestation, these three primary vesicles will develop into five secondary vesicles. The prosencephalon (forebrain) divides into the Telencephalon and Diencephalon. As the embryo and foetus develop, these vesicles will include the cerebrum, thalamus, hypothalamus, basal ganglia, hippocampus, and limbic system structures. The mesencephalon will become the midbrain and does not divide further, but will develop, for example, the crus cerebri, tectum and tegmentum. The rhombencephalon (hindbrain) will divide into the metencephalon and myelencephalon, developing the cerebellum, medulla oblongata and spinal cord, among other structures (Gilbert, 2000; Shoja et al., 2018). All vertebrate brains have these basic regions; however, as human brains are further evolutionarily developed, the cerebrum, or cerebral cortex, of the anterior forebrain, grows large enough to surround much of the brain, hiding the diencephalon (posterior forebrain), the midbrain, and part of the hindbrain from view. In other vertebrates, these structures are clearly visible (Clowry et al., 2010; Geschwind & Rakic, 2013).
As well as promoting the development of the Prosencephalon, Mesencephalon and Rhombencephalon, neural tube closure causes intraventricular fluid pressure to rise, and the brain enlarges. Intracranial pressure is essential to regulate human brain development. Without this pressure, the brain does not enlarge at the correct pace and will not become the highly organised structure of a normal healthy brain. Without intracranial pressure, the brain will fold into the ventricular cavity, resulting in death (Budday et al., 2015).
A precise balance of genetic and embryonic environmental factors is required for the neural tube to close correctly. Neural developmental genes such as Pax3, Sonic Hedgehog, and open brain are essential, as well as correct levels of cholesterol and folic acid in the diet of the mother (Gilbert, 2000). Any complications during neural tube formation can result in Neural Tube Defects (NTDs). NTDs are malformations of the nervous system caused by the neural tube not closing correctly and are the most common cause of congenital defects. If an NTD occurs in the cranial region of the tube it can result in anencephaly or encephalocele, which both have high mortality rates and often result in stillbirths. A caudal NTD can result in spina bifida, where vertebrae over the defect do not develop. There are varying degrees of severity depending on the location and size of the NTD. Spina bifida can result in loss of sensory and motor function in the legs, and even paralysis, though life expectancy is often not affected (Greene & Copp, 2013; Myers & Bennett, 2007).
Neuron Development
For the nervous system to divide and become organised, neurons must develop and grow. Neuron development occurs in multiple stages: Proliferation, neurogenesis, migration, differentiation, synaptogenesis, myelination, and synaptic pruning. These stages can occur concurrently. Proliferation is the production of neurons from stem cells and occurs in the neuroepithelial cells of the neural tube. In humans, neuron proliferation begins in the fifth week of gestation and finishes by gestation week 28.
While proliferation is ongoing, migration begins, where cells migrate from the neural crest to their final destination in the nervous system. Neuronal cell migration begins following neural tube closure and is essential to normal nervous system development as the area of the body a cell migrates to determines the type of cell it will differentiate into. Cell migration also allows cells to form spatial relationships with other cells and form organised structures. The neural tube is made of progenitors (stem cells) called neuroepithelial cells, known as the neuroepithelium. During gestation, neurons formed in the neuroepithelium migrate under tightly regulated conditions depending on cell polarity, cytoskeletal changes, and cell adhesion receptor systems (Rahimi-Balaei et al., 2018). Migration of the neural crest cells requires ‘push and pull’ chemical signals working in tandem. A combination of protein signalling to encourage the cells to move, coupled with the breakdown of the intercellular structures keeping the cells in the neural crest promote cell migration (Gilbert, 2000). The RhoB protein has been shown to regulate the actin cytoskeletal and drive cell migration (Hall, 1998). The Slug protein aids the breakdown of the cell junctions, allowing cells to move away from one another and leave the neural tube. The cell adhesion protein N-cadherin, which links neural crest cells together, is downregulated during cell migration. In trunk neural crest cells, this protein is later re-expressed to link the cells together again in the formation of the dorsal root and sympathetic ganglia. Together, these processes contribute to the successful cell migration of new neurons from the neuronal crest to specified areas of the CNS where they can form neuronal structures and join neuronal circuits. The highly organised six-layered structure of the mature cerebral cortex is due to the orderly migration of neurons during gestation (Gilbert, 2000; Rahimi-Balaei et al., 2018).
When the cells have migrated to their final destination, cell differentiation into progenitor cells provides neurons with neuron-specific features, such as an axon and at least one dendrite, distinguishing neurons from other body cells. Neurons also differentiate into different types of neural cells, such as neurons and glial cells. Synaptogenesis can then begin. Neuronal axons form connections with other neurons to form thousands of connections. Synaptogenesis begins mid-gestation and continues throughout life while neurons form new synapses and connections. Myelination occurs in certain neuronal cell types: oligodendrocytes in the CNS and Schwann cells in the PNS. Myelination significantly increases the speed of electrical signals in the nervous system and occurs gradually throughout life, suggesting myelination occurs as new motor skills are learned. Finally, synaptic pruning can occur throughout life and is the degrading and removal of unused synaptic connections, specific to the individual, to improve learning. Synaptic pruning continues from the time of birth and is mostly completed by adolescence (Budday et al., 2015; Kalat, 2018; Rahimi-Balaei et al., 2018; Tau & Peterson, 2009).
All aspects of the adult CNS can be traced back to embryonic precursors. Another example is the cerebral ventricles that derive from the hollow centre of the neural tube. These are a series of four cavities and tubular spaces in the CNS that contain cerebrospinal fluid (CSF) Lowery & Sive, 2009). CSF circulates through the cerebral ventricles to support cell signalling, and CNS homeostasis and is essential for communication between the CNS and the other body systems like the PNS and immune system (Wichmann et al., 2022).
Conclusion
Humans have the most complex and differentiated nervous system of any species, enabling them to perform complex tasks such as speech, creative thought and other higher cognitive tasks that are considered uniquely human (Lieberman, 1991). As humans are highly evolutionarily developed, the embryonic and postnatal development of the nervous system is a complex and finely balanced process. Throughout gestation, the precise folding of the ectoderm into the neural tube, cell migration and cell differentiation occurs to produce the highly structured and organised human nervous system. Although most neurodevelopment occurs prenatally, postnatal synaptogenesis and synaptic pruning are crucial for learning and other higher cognitive functions that are uniquely human.
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