A
rodent is not stimulated by the environment in a wire cage, and this
affects its brain negatively, particularly the complexity of its
synaptic connections
Environmental enrichment is the stimulation of the brain by its physical and social surroundings. Brains in richer, more stimulating environments have higher rates of synaptogenesis and more complex dendrite arbors, leading to increased brain activity. This effect takes place primarily during neurodevelopment, but also during adulthood to a lesser degree. With extra synapses there is also increased synapse activity, leading to an increased size and number of glial energy-support cells. Environmental enrichment also enhances capillary vasculation, providing the neurons and glial cells with extra energy. The neuropil
(neurons, glial cells, capillaries, combined) expands, thickening the
cortex. Research on rodent brains suggests that environmental enrichment
may also lead to an increased rate of neurogenesis.
Research on animals finds that environmental enrichment could aid
the treatment and recovery of numerous brain-related dysfunctions,
including Alzheimer's disease and those connected to aging,
whereas a lack of stimulation might impair cognitive development.
Moreover, this research also suggests that environmental enrichment
leads to a greater level of cognitive reserve, the brain's resilience to the effects of conditions such as aging and dementia.
Research on humans suggests that lack of stimulation delays and
impairs cognitive development. Research also finds that attaining and
engaging in higher levels of education, environments in which people
participate in more challenging cognitively stimulating activities,
results in greater cognitive reserve.
Early research
Donald O. Hebb in 1947 found that rats raised as pets performed better on problem solving tests than rats raised in cages.
His research, however, did not investigate the brain nor use
standardized impoverished and enriched environments. Research doing this
first was started in 1960 at the University of California, Berkeley by Mark Rosenzweig,
who compared single rats in normal cages, and those placed in ones with
toys, ladders, tunnels, running wheels in groups. This found that
growing up in enriched environments affected enzyme cholinesterase activity. This work led in 1962 to the discovery that environmental enrichment increased cerebral cortex volume. In 1964, it was found that this was due to increased cerebral cortex thickness and greater synapse and glial numbers.
Also starting around 1960, Harry Harlow studied the effects of maternal and social deprivation on rhesus monkey infants (a form of environmental stimulus deprivation). This established the importance of social stimulation for normal cognitive and emotional development.
Synapses
Synaptogenesis
Rats raised with environmental enrichment have thicker cerebral cortices (3.3–7%) that contain 25% more synapses. This effect of environmental richness upon the brain occurs whether it is experienced immediately following birth, after weaning, or during maturity.
When synapse numbers increase in adults, they can remain high in number
even when the adults are returned to impoverished environment for 30
days
suggesting that such increases in synapse numbers are not necessarily
temporary. However, the increase in synapse numbers has been observed
generally to reduce with maturation.Stimulation affects not only synapses upon pyramidal neurons (the main projecting neurons in the cerebral cortex) but also stellate ones (that are usually interneurons). It can also affect neurons outside the brain, such as those in the retina.
Dendrite complexity
Environmental enrichment affects the complexity and length of the dendrite arbors (upon which synapses form). Higher-order dendrite branch complexity is increased in enriched environments, as can the length, in young animals, of distal branches. Environmental enrichment rescues harmful effects of stress on dendritic complexity.
Activity and energy consumption
Animals in enriched environments show evidence of increased synapse activation. Synapses tend to also be much larger. Gamma oscillations become larger in amplitude in the hippocampus.
This increased energy consumption is reflected in glial and local
capillary vasculation that provides synapses with extra energy.
Glial cell numbers per neuron increase 12–14%
The direct apposition area of glial cells with synapses expands by 19%
The volume of glial cell nuclei for each synapse is higher by 37.5%
The mean volume of mitochondria per neuron is 20% greater
The volume of glial cell nuclei for each neuron is 63% higher
Capillary density is increased.
Capillaries are wider (4.35 μm compared to 4.15 μm in controls)
Shorter distance exist between any part of the neuropil and a capillary (27.6 μm compared to 34.6 μm)
These energy related changes to the neuropil
are responsible for increasing the volume of the cerebral cortex (the
increase in synapse numbers contributes in itself hardly any extra
volume).
Motor learning stimulation
Part of the effect of environmental enrichment is providing opportunities to acquire motor skills. Research on rats learning an “acrobatic” skill shows that such learning activity leads to increased synapse count.
Maternal transmission
Environmental enrichment during pregnancy has effects upon the fetus, such as accelerating his or her retinal development.
Neurogenesis
Environmental enrichment can also lead to the formation of neurons (at least in rats) and reverse both the loss of neurons in the hippocampus and memory impairment from chronic stress. However, its relevance has been questioned for the behavioral effects of enriched environments.
Mechanisms
Enriched environments affect the expression of genes that determine neuronal structure in the cerebral cortex and hippocampus. At the molecular level, this occurs through increased concentrations of the neurotrophinsNGF, NT-3, and changes in BDNF. This alters the activation of cholinergic neurons, 5-HT, and beta-adrenolin. Another effect is to increase proteins such as synaptophysin and PSD-95 in synapses. Changes in Wnt signaling have also been found to mimic in adult mice the effects of environmental enrichment upon synapses in the hippocampus. Increase in neurons numbers could be linked to changes in VEGF.
Rehabilitation and resilience
Research
in animals suggests that environmental enrichment aids recovery from
certain neurological disorders and cognitive impairments. There are two
mains areas of focus: neurological rehabilitation and cognitive reserve,
the brain's resistance to the effects of exposure to physical, natural,
and social threats. Although most of these experiments used animal
subjects, mainly rodents, researchers have pointed to the affected areas
of animal brains to which human brains are most similar and used their
findings as evidence to show that humans would have comparable reactions
to enriched environments. The tests done on animals are thus meant to
represent human simulations for the following list of conditions.
Neurological rehabilitation
Autism
A
study conducted in 2011 led to the conclusion that environmental
enrichment vastly improves the cognitive ability of children with autism. The study found that autistic children who receive olfactory and tactile stimulation along with exercises
that stimulated other paired sensory modalities clinically improved by
42 percent while autistic children not receiving this treatment
clinically improved by just 7 percent.
The same study also showed that there was significant clinical
improvement in autistic children exposed to enriched sensorimotor
environments, and a vast majority of parents reported that their child's
quality of life was much better with the treatment.
A second study confirmed its effectiveness. The second study also
found after 6 months of sensory enrichment therapy, 21% of the children
who initially had been given an autism classification, using the Autism
Diagnostic Observation Schedule, improved to the point that, although
they remained on the autism spectrum, they no longer met the criteria
for classic autism. None of the standard care controls reached an
equivalent level of improvement. The therapy using the methodologies is titled Sensory Enrichment Therapy.
Alzheimer's disease
Through
environmental enrichment, researchers were able to enhance and
partially repair memory deficits in mice between ages of 2 to 7 months
with characteristics of Alzheimer's disease. Mice in enriched environments performed significantly better on object recognition tests and the Morris Water Maze
than they had when they were in standard environments. It was thus
concluded that environmental enrichment enhances visual and learning
memory for those with Alzheimer's.
Furthermore, it has been found that mouse models of Alzheimer's disease
that were exposed to enriched environment before amyloid onset (at 3
months of age) and then returned to their home cage for over 7 months,
showed preserved spatial memory and reduced amyloid deposition at 13
months old, when they are supposed to show dramatic memory deficits and
amyloid plaque load. These findings reveal the preventive, and
long-lasting effects of early life stimulating experience on
Alzheimer-like pathology in mice and likely reflect the capacity of
enriched environment to efficiently stimulate the cognitive reserve.
A human study suggests that enriched gardens contribute to better
cognitive function and independence in activities of daily living,
compared to conventional sensory gardens.
Huntington's disease
Research has indicated that environmental enrichment can help relieve motor and psychiatric deficits caused by Huntington's disease. It also improves lost protein levels for those with the disease, and prevents striatal and hippocampal deficits in the BDNF, located in the hippocampus.
These findings have led researchers to suggest that environmental
enrichment has a potential to be a possible form of therapy for those
with Huntington's.
Parkinson's disease
Multiple
studies have reported that environmental enrichment for adult mice
helps relieve neuronal death, which is particularly beneficial to those
with Parkinson's disease. A more recent study shows that environmental enrichment particularly affects the nigrostriatal pathway, which is important for managing dopamine and acetylcholine levels, critical for motor deficits.
Moreover, it was found that environmental enrichment has beneficial
effects for the social implications of Parkinson's disease.
Stroke
Research done in animals has shown that subjects recovering in an enriched environment 15 days after having a stroke
had significantly improved neurobehavioral function. In addition these
same subjects showed greater capability of learning and larger infarct
post-intervention than those who were not in an enriched environment. It
was thus concluded that environmental enrichment had a considerable
beneficial effect on the learning and sensorimotor functions on animals
post-stroke.
A 2013 study also found that environmental enrichment socially benefits
patients recovering from stroke. Researchers in that study concluded
that stroke patients in enriched environments in assisted-care
facilities are much more likely to be engaging with other patients
during normal social hours instead of being alone or sleeping.
Rett syndrome
A
2008 study found that environmental enrichment was significant in
aiding recovery of motor coordination and some recovery of BDNF levels
in female mice with conditions similar to those of Rett syndrome.
Over the course of 30 weeks female mice in enriched environments showed
superior ability in motor coordination to those in standard conditions.
Although they were unable to have full motor capability, they were able
to prevent a more severe motor deficit by living in an enriched
environment. These results combined with increased levels of BDNF in the
cerebellum led researchers to conclude that an enriched environment
that stimulates areas of the motor cortex and areas of the cerebellum
having to do with motor learning is beneficial in aiding mice with Rett
syndrome.
Amblyopia
A recent study found that adult rats with amblyopia improved visual acuity two weeks after being placed into an enriched environment.
The same study showed that another two weeks after ending environmental
enrichment, the rats retained their visual acuity improvement.
Conversely, rats in a standard environment showed no improvement in
visual acuity. It was thus concluded that environmental enrichment
reduces GABA inhibition and increases BDNF expression in the visual
cortex. As a result, the growth and development of neurons and synapses
in the visual cortex were much improved due to the enriched environment.
Sensory deprivation
Studies have shown that with the help of environmental enrichment the effects of sensory deprivation
can be corrected. For example, a visual impairment known as
"dark-rearing" in the visual cortex can be prevented and rehabilitated.
In general, an enriched environment will improve, if not repair, the
sensory systems animals possess.
Lead poisoning
During development, gestation
is one of the most critical periods for exposure to any lead. Exposure
to high levels of lead at this time can lead to inferior spatial
learning performance. Studies have shown that environmental enrichment
can overturn damage to the hippocampus induced by lead exposure.
Learning and spatial memory that are dependent on the long-term
potentiation of the hippocampus are vastly improve as subjects in an
enriched environments had lower levels of lead concentration in their
hippocampi. The findings also showed that enriched environments result
in some natural protection of lead-induced brain deficits.
Chronic spinal cord injuries
Research has indicated that animals suffering from spinal cord injuries
showed significant improvement in motor capabilities even with a long
delay in treatment after the injury when exposed to environmental
enrichment.
Social interactions, exercise, and novelty all play major roles in
aiding the recovery of an injured subject. This has led to some
suggestions that the spinal cord has a continued plasticity and all
efforts must be made for enriched environments to stimulate this
plasticity in order to aid recovery.
Maternal deprivation stress
Maternal deprivation
can be caused by the abandonment by a nurturing parent at a young age.
In rodents or nonhuman primates, this leads to a higher vulnerability
for
stress-related illness.
Research suggests that environmental enrichment can reverse the effects
of maternal separation on stress reactivity, possibly by affecting the
hippocampus, the amygdala and the prefrontal cortex.
Child neglect
In
all children, maternal care is one of the significant influences for
hippocampal development, providing the foundation for stable and
individualized learning and memory. However, this is not the case for
those who have experienced child neglect.
Researchers determined that through environmental enrichment, a
neglected child can partially receive the same hippocampal development
and stability, albeit not at the same level as that of the presence of a
parent or guardian.
The results were comparable to those of child intervention programs,
rendering environmental enrichment a useful method for dealing with
child neglect.
Cognitive reserve
Aging
Decreased hippocampal neurogenesis is a characteristic of aging.
Environmental enrichment increases neurogenesis in aged rodents by
potentiating neuronal differentiation and new cell survival.
As a result, subjects exposed to environmental enrichment aged better
due to superior ability in retaining their levels of spatial and
learning memory.
Prenatal and perinatal cocaine exposure
Research has shown that mice exposed to environmental enrichment are less affected by the consequences of cocaine exposure
in comparison with those in standard environments. Although the levels
of dopamine in the brains of both sets of mice were relatively similar,
when both subjects were exposed to the cocaine injection, mice in
enriched environment were significantly less responsive than those in
standard environments.
It was thus concluded that both the activating and rewarding effects
are suppressed by environmental enrichment and early exposure to
environmental enrichment can help prevent drug addiction.
Humans
Though environmental enrichment research has been mostly done upon rodents, similar effects occur in primates,
and are likely to affect the human brain. However, direct research upon
human synapses and their numbers is limited since this requires histological
study of the brain. A link, however, has been found between educational
level and greater dendritic branch complexity following autopsy removal
of the brain.
Localized cerebral cortex changes
MRI detects localized cerebral cortex expansion after people learn complex tasks such as mirror reading (in this case in the right occipital cortex), three-ball juggling (bilateral mid-temporal area and left posterior intraparietal sulcus), and when medical students intensively revise for exams (bilaterally in the posterior and lateral parietal cortex).
Such changes in gray matter volume can be expected to link to changes
in synapse numbers due to the increased numbers of glial cells and the
expanded capillary vascularization needed to support their increased
energy consumption.
Institutional deprivation
Children
that receive impoverished stimulation due to being confined to cots
without social interaction or reliable caretakers in low quality orphanages show severe delays in cognitive and social development. 12% of them if adopted after 6 months of age show autistic or mildly autistic traits later at four years of age.
Some children in such impoverished orphanages at two and half years of
age still fail to produce intelligible words, though a year of foster
care enabled such children to catch up in their language in most
respects.
Catch-up in other cognitive functioning also occurs after adoption,
though problems continue in many children if this happens after the age
of 6 months.
Such children show marked differences in their brains, consistent
with research upon experiment animals, compared to children from
normally stimulating environments. They have reduced brain activity in
the orbital prefrontal cortex, amygdala, hippocampus, temporal cortex, and brain stem. They also showed less developed white matter connections between different areas in their cerebral cortices, particularly the uncinate fasciculus.
Conversely, enriching the experience of preterm infants with massage quickens the maturation of their electroencephalographic activity and their visual acuity. Moreover, as with enrichment in experimental animals, this associates with an increase in IGF-1.
Cognitive reserve and resilience
Another source of evidence for the effect of environment stimulation upon the human brain is cognitive reserve
(a measure of the brain's resilience to cognitive impairment) and the
level of a person's education. Not only is higher education linked to a
more cognitively demanding educational experience, but it also
correlates with a person's general engagement in cognitively demanding
activities. The more education a person has received, the less the effects of aging, dementia, white matter hyperintensities, MRI-defined brain infarcts, Alzheimer's disease, and traumatic brain injury. Also, aging and dementia are less in those that engage in complex cognitive tasks. The cognitive decline of those with epilepsy could also be affected by the level of a person's education.
Neurons are typically classified into three types based on their function. Sensory neurons respond to stimuli such as touch, sound, or light that affect the cells of the sensory organs, and they send signals to the spinal cord or brain. Motor neurons receive signals from the brain and spinal cord to control everything from muscle contractions to glandular output. Interneurons
connect neurons to other neurons within the same region of the brain or
spinal cord. When multiple neurons are functionally connected together,
they form what is called a neural circuit.
A typical neuron consists of a cell body (soma), dendrites, and a single axon.
The soma is a compact structure, and the axon and dendrites are
filaments extruding from the soma. Dendrites typically branch profusely
and extend a few hundred micrometers from the soma. The axon leaves the
soma at a swelling called the axon hillock
and travels for as far as 1 meter in humans or more in other species.
It branches but usually maintains a constant diameter. At the farthest
tip of the axon's branches are axon terminals, where the neuron can transmit a signal across the synapse to another cell. Neurons may lack dendrites or have no axon. The term neurite is used to describe either a dendrite or an axon, particularly when the cell is undifferentiated.
Most neurons receive signals via the dendrites and soma and send
out signals down the axon. At the majority of synapses, signals cross
from the axon of one neuron to a dendrite of another. However, synapses
can connect an axon to another axon or a dendrite to another dendrite.
The signaling process is partly electrical and partly chemical. Neurons are electrically excitable, due to maintenance of voltage gradients across their membranes. If the voltage changes by a large enough amount over a short interval, the neuron generates an all-or-nothingelectrochemical pulse called an action potential. This potential travels rapidly along the axon and activates synaptic connections as it reaches them. Synaptic signals may be excitatory or inhibitory, increasing or reducing the net voltage that reaches the soma.
In most cases, neurons are generated by neural stem cells during brain development and childhood. Neurogenesis largely ceases during adulthood in most areas of the brain.
Nervous system
Schematic
of an anatomically accurate single pyramidal neuron, the primary
excitatory neuron of the cerebral cortex, with a synaptic connection
from an incoming axon onto a dendritic spine
Axons may bundle into fascicles that make up the nerves
in the peripheral nervous system (like strands of wire make up cables).
Bundles of axons in the central nervous system are called tracts.
Anatomy and histology
Diagram of the components of a neuron
Neurons are highly specialized for the processing and transmission of
cellular signals. Given their diversity of functions performed in
different parts of the nervous system, there is a wide variety in their
shape, size, and electrochemical properties. For instance, the soma of a
neuron can vary from 4 to 100 micrometers in diameter.
The soma is the body of the neuron. As it contains the nucleus, most protein synthesis occurs here. The nucleus can range from 3 to 18 micrometers in diameter.
The dendrites
of a neuron are cellular extensions with many branches. This overall
shape and structure are referred to metaphorically as a dendritic tree.
This is where the majority of input to the neuron occurs via the dendritic spine.
The axon
is a finer, cable-like projection that can extend tens, hundreds, or
even tens of thousands of times the diameter of the soma in length. The
axon primarily carries nerve signals
away from the soma and carries some types of information back to it.
Many neurons have only one axon, but this axon may—and usually
will—undergo extensive branching, enabling communication with many
target cells. The part of the axon where it emerges from the soma is
called the axon hillock. Besides being an anatomical structure, the axon hillock also has the greatest density of voltage-dependent sodium channels.
This makes it the most easily excited part of the neuron and the spike
initiation zone for the axon. In electrophysiological terms, it has the
most negative threshold potential.
While the axon and axon hillock are generally involved in
information outflow, this region can also receive input from other
neurons.
The axon terminal is found at the end of the axon farthest from the soma and contains synapses. Synaptic boutons are specialized structures where neurotransmitter
chemicals are released to communicate with target neurons. In addition
to synaptic boutons at the axon terminal, a neuron may have en passant boutons, which are located along the length of the axon.
Neuron cell body
The accepted view of the neuron attributes dedicated functions to its
various anatomical components; however, dendrites and axons often act
in ways contrary to their so-called main function.
Diagram of a typical myelinated vertebrate motor neuronNeurology video
Axons and dendrites in the central nervous system are typically only
about one micrometer thick, while some in the peripheral nervous system
are much thicker. The soma is usually about 10–25 micrometers in
diameter and often is not much larger than the cell nucleus it contains.
The longest axon of a human motor neuron can be over a meter long, reaching from the base of the spine to the toes.
Sensory neurons can have axons that run from the toes to the posterior column of the spinal cord, over 1.5 meters in adults. Giraffes
have single axons several meters in length running along the entire
length of their necks. Much of what is known about axonal function comes
from studying the squid giant axon, an ideal experimental preparation because of its relatively immense size (0.5–1 millimeter thick, several centimeters long).
Fully differentiated neurons are permanently postmitotic however, stem cells present in the adult brain may regenerate functional neurons throughout the life of an organism (see neurogenesis). Astrocytes are star-shaped glial cells. They have been observed to turn into neurons by virtue of their stem cell-like characteristic of pluripotency.
Membrane
Like all animal cells, the cell body of every neuron is enclosed by a plasma membrane, a bilayer of lipid molecules with many types of protein structures embedded in it. A lipid bilayer is a powerful electrical insulator,
but in neurons, many of the protein structures embedded in the membrane
are electrically active. These include ion channels that permit
electrically charged ions to flow across the membrane and ion pumps that
chemically transport ions from one side of the membrane to the other.
Most ion channels are permeable only to specific types of ions. Some ion
channels are voltage gated,
meaning that they can be switched between open and closed states by
altering the voltage difference across the membrane. Others are
chemically gated, meaning that they can be switched between open and
closed states by interactions with chemicals that diffuse through the
extracellular fluid. The ion materials include sodium, potassium, chloride, and calcium.
The interactions between ion channels and ion pumps produce a voltage
difference across the membrane, typically a bit less than 1/10 of a volt
at baseline. This voltage has two functions: first, it provides a power
source for an assortment of voltage-dependent protein machinery that is
embedded in the membrane; second, it provides a basis for electrical
signal transmission between different parts of the membrane.
Histology and internal structure
Golgi-stained neurons in human hippocampal tissueActin filaments in a mouse cortical neuron in culture
Numerous microscopic clumps called Nissl bodies
(or Nissl substance) are seen when nerve cell bodies are stained with a
basophilic ("base-loving") dye. These structures consist of rough endoplasmic reticulum and associated ribosomal RNA. Named after German psychiatrist and neuropathologist Franz Nissl
(1860–1919), they are involved in protein synthesis and their
prominence can be explained by the fact that nerve cells are very
metabolically active. Basophilic dyes such as aniline or (weakly) haematoxylin highlight negatively charged components, and so bind to the phosphate backbone of the ribosomal RNA.
The cell body of a neuron is supported by a complex mesh of structural proteins called neurofilaments, which together with neurotubules (neuronal microtubules) are assembled into larger neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment that is byproduct of synthesis of catecholamines), and lipofuscin (a yellowish-brown pigment), both of which accumulate with age. Other structural proteins that are important for neuronal function are actin and the tubulin of microtubules. Class III β-tubulin
is found almost exclusively in neurons. Actin is predominately found at
the tips of axons and dendrites during neuronal development. There the
actin dynamics can be modulated via an interplay with microtubule.
There are different internal structural characteristics between axons and dendrites. Typical axons almost never contain ribosomes,
except some in the initial segment. Dendrites contain granular
endoplasmic reticulum or ribosomes, in diminishing amounts as the
distance from the cell body increases.
Neurons vary in shape and size and can be classified by their morphology and function. The anatomist Camillo Golgi
grouped neurons into two types; type I with long axons used to move
signals over long distances and type II with short axons, which can
often be confused with dendrites. Type I cells can be further classified
by the location of the soma. The basic morphology of type I neurons,
represented by spinal motor neurons, consists of a cell body called the soma and a long thin axon covered by a myelin sheath. The dendritic tree wraps around the cell body and receives signals from other neurons. The end of the axon has branching axon terminals that release neurotransmitters into a gap called the synaptic cleft between the terminals and the dendrites of the next neuron.
Most neurons can be anatomically characterized as:
Unipolar:
single process. Unipolar cells are exclusively sensory neurons. Their
dendrites are receiving sensory information, sometimes directly from the
stimulus itself. The cell bodies of unipolar neurons are always found
in ganglia. Sensory reception is a peripheral function, so the cell body
is in the periphery, though closer to the CNS in a ganglion. The axon
projects from the dendrite endings, past the cell body in a ganglion,
and into the central nervous system.
Bipolar: 1 axon and 1 dendrite. They are found mainly in the olfactory epithelium, and as part of the retina.
Spindle cells, interneurons that connect widely separated areas of the brain
Functional classification
Direction
Afferent neurons convey information from tissues and organs into the central nervous system and are also called sensory neurons.
Efferent neurons (motor neurons) transmit signals from the central nervous system to the effector cells.
Interneurons connect neurons within specific regions of the central nervous system.
Afferent and efferent also refer generally to neurons that,
respectively, bring information to or send information from the brain.
Action on other neurons
A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors.
The effect upon the postsynaptic neuron is determined by the type of
receptor that is activated, not by the presynaptic neuron or by the
neurotransmitter. A neurotransmitter can be thought of as a key, and a
receptor as a lock: the same neurotransmitter can activate multiple
types of receptors. Receptors can be classified broadly as excitatory (causing an increase in firing rate), inhibitory (causing a decrease in firing rate), or modulatory (causing long-lasting effects not directly related to firing rate).
The two most common (90%+) neurotransmitters in the brain, glutamate and GABA, have largely consistent actions. Glutamate acts on several types of receptors, and has effects that are excitatory at ionotropic receptors and a modulatory effect at metabotropic receptors.
Similarly, GABA acts on several types of receptors, but all of them
have inhibitory effects (in adult animals, at least). Because of this
consistency, it is common for neuroscientists to refer to cells that
release glutamate as "excitatory neurons", and cells that release GABA
as "inhibitory neurons". Some other types of neurons have consistent
effects, for example, "excitatory" motor neurons in the spinal cord that
release acetylcholine, and "inhibitory" spinal neurons that release glycine.
The distinction between excitatory and inhibitory
neurotransmitters is not absolute. Rather, it depends on the class of
chemical receptors present on the postsynaptic neuron. In principle, a
single neuron, releasing a single neurotransmitter, can have excitatory
effects on some targets, inhibitory effects on others, and modulatory
effects on others still. For example, photoreceptor cells in the retina constantly release the neurotransmitter glutamate in the absence of light. So-called OFF bipolar cells
are, like most neurons, excited by the released glutamate. However,
neighboring target neurons called ON bipolar cells are instead inhibited
by glutamate, because they lack typical ionotropicglutamate receptors and instead express a class of inhibitory metabotropic glutamate receptors.
When light is present, the photoreceptors cease releasing glutamate,
which relieves the ON bipolar cells from inhibition, activating them;
this simultaneously removes the excitation from the OFF bipolar cells,
silencing them.
It is possible to identify the type of inhibitory effect a
presynaptic neuron will have on a postsynaptic neuron, based on the
proteins the presynaptic neuron expresses. Parvalbumin-expressing neurons typically dampen the output signal of the postsynaptic neuron in the visual cortex, whereas somatostatin-expressing neurons typically block dendritic inputs to the postsynaptic neuron.
Discharge patterns
Neurons have intrinsic electroresponsive properties like intrinsic transmembrane voltage oscillatory patterns. So neurons can be classified according to their electrophysiological characteristics:
Tonic or regular spiking. Some neurons are typically constantly
(tonically) active, typically firing at a constant frequency. Example:
interneurons in neurostriatum.
Phasic or bursting. Neurons that fire in bursts are called phasic.
Fast spiking. Some neurons are notable for their high firing rates,
for example some types of cortical inhibitory interneurons, cells in globus pallidus, retinal ganglion cells.
Cholinergic neurons – acetylcholine. Acetylcholine is released from presynaptic neurons into the synaptic cleft. It acts as a ligand for both ligand-gated ion channels and metabotropic (GPCRs) muscarinic receptors. Nicotinic receptors are pentameric ligand-gated ion channels composed of alpha and beta subunits that bind nicotine. Ligand binding opens the channel causing influx of Na+ depolarization and increases the probability of presynaptic neurotransmitter release. Acetylcholine is synthesized from choline and acetyl coenzyme A.
GABAergic neurons – gamma aminobutyric acid. GABA is one of two neuroinhibitors in the central nervous system (CNS), along with glycine. GABA has a homologous function to ACh, gating anion channels that allow Cl− ions to enter the post synaptic neuron. Cl−
causes hyperpolarization within the neuron, decreasing the probability
of an action potential firing as the voltage becomes more negative (for
an action potential to fire, a positive voltage threshold must be
reached). GABA is synthesized from glutamate neurotransmitters by the
enzyme glutamate decarboxylase.
Glutamatergic neurons – glutamate. Glutamate is one of two primary excitatory amino acid neurotransmitters, along with aspartate. Glutamate receptors are one of four categories, three of which are ligand-gated ion channels and one of which is a G-protein coupled receptor (often referred to as GPCR).
AMPA and Kainate receptors function as cation channels permeable to Na+ cation channels mediating fast excitatory synaptic transmission.
NMDA receptors are another cation channel that is more permeable to Ca2+. The function of NMDA receptors depend on glycine receptor binding as a co-agonist within the channel pore. NMDA receptors do not function without both ligands present.
Metabotropic receptors, GPCRs modulate synaptic transmission and postsynaptic excitability.
Glutamate can cause excitotoxicity when blood flow to the brain is interrupted, resulting in brain damage.
When blood flow is suppressed, glutamate is released from presynaptic
neurons, causing greater NMDA and AMPA receptor activation than normal
outside of stress conditions, leading to elevated Ca2+ and Na+ entering the post synaptic neuron and cell damage. Glutamate is synthesized from the amino acid glutamine by the enzyme glutamate synthase.
Dopaminergic neurons—dopamine. Dopamine
is a neurotransmitter that acts on D1 type (D1 and D5) Gs-coupled
receptors, which increase cAMP and PKA, and D2 type (D2, D3, and D4)
receptors, which activate Gi-coupled receptors that decrease cAMP and
PKA. Dopamine is connected to mood and behavior and modulates both pre-
and post-synaptic neurotransmission. Loss of dopamine neurons in the substantia nigra has been linked to Parkinson's disease. Dopamine is synthesized from the amino acid tyrosine. Tyrosine is catalyzed into levodopa (or L-DOPA) by tyrosine hydroxlase, and levodopa is then converted into dopamine by the aromatic amino acid decarboxylase.
Serotonergic neurons—serotonin. Serotonin
(5-Hydroxytryptamine, 5-HT) can act as excitatory or inhibitory. Of its
four 5-HT receptor classes, 3 are GPCR and 1 is a ligand-gated cation
channel. Serotonin is synthesized from tryptophan by tryptophan hydroxylase,
and then further by decarboxylase. A lack of 5-HT at postsynaptic
neurons has been linked to depression. Drugs that block the presynaptic serotonin transporter are used for treatment, such as Prozac and Zoloft.
Purinergic neurons—ATP. ATP is a neurotransmitter acting at both ligand-gated ion channels (P2X receptors) and GPCRs (P2Y) receptors. ATP is, however, best known as a cotransmitter. Such purinergic signalling can also be mediated by other purines like adenosine, which particularly acts at P2Y receptors.
Since 2012 there has been a push from the cellular and computational neuroscience
community to come up with a universal classification of neurons that
will apply to all neurons in the brain as well as across species. This
is done by considering the three essential qualities of all neurons:
electrophysiology, morphology, and the individual transcriptome of the
cells. Besides being universal this classification has the advantage of
being able to classify astrocytes as well. A method called Patch-Seq in
which all three qualities can be measured at once is used extensively by
the Allen Institute for Brain Science.
A signal propagating down an axon to the cell body and dendrites of the next cellChemical synapse
Neurons communicate with each other via synapses, where either the axon terminal
of one cell contacts another neuron's dendrite, soma or, less commonly,
axon. Neurons such as Purkinje cells in the cerebellum can have over
1000 dendritic branches, making connections with tens of thousands of
other cells; other neurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or two dendrites, each of which receives thousands of synapses.
Synapses can be excitatory or inhibitory, either increasing or
decreasing activity in the target neuron, respectively. Some neurons
also communicate via electrical synapses, which are direct, electrically
conductive junctions between cells.
When an action potential reaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter the terminal. Calcium causes synaptic vesicles
filled with neurotransmitter molecules to fuse with the membrane,
releasing their contents into the synaptic cleft. The neurotransmitters
diffuse across the synaptic cleft and activate receptors on the
postsynaptic neuron. High cytosolic calcium in the axon terminal triggers mitochondrial calcium uptake, which, in turn, activates mitochondrial energy metabolism to produce ATP to support continuous neurotransmission.
An autapse is a synapse in which a neuron's axon connects to its own dendrites.
The human brain has some 8.6 x 1010 (eighty six billion) neurons.
Each neuron has on average 7,000 synaptic connections to other neurons.
It has been estimated that the brain of a three-year-old child has
about 1015 synapses (1 quadrillion). This number declines with age, stabilizing by adulthood. Estimates vary for an adult, ranging from 1014 to 5 x 1014 synapses (100 to 500 trillion).
An
annotated diagram of the stages of an action potential propagating down
an axon including the role of ion concentration and pump and channel
proteins
Nonelectrochemical signaling
Beyond electrical and chemical signaling, studies suggest neurons in healthy human brains can also communicate through:
force generated by the enlargement of dendritic spines
the transfer of proteins – transneuronally transported proteins (TNTPs)
They can also get modulated by input from the environment and hormones released from other parts of the organism, which could be influenced more or less directly by neurons. This also applies to neurotrophins such as BDNF. The gut microbiome is also connected with the brain.
Neurons also communicate with microglia,
the brain's main immune cells via specialised contact sites, called
"somatic junctions". These connections enable microglia to constantly
monitor and regulate neuronal functions, and exert neuroprotection, when
needed.
Mechanisms for propagating action potentials
In 1937 John Zachary Young suggested that the squid giant axon could be used to study neuronal electrical properties.
It is larger than but similar to human neurons, making it easier to
study. By inserting electrodes into the squid giant axons, accurate
measurements were made of the membrane potential.
The cell membrane of the axon and soma contain voltage-gated ion
channels that allow the neuron to generate and propagate an electrical
signal (an action potential). Some neurons also generate subthreshold membrane potential oscillations. These signals are generated and propagated by charge-carrying ions including sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+).
Several stimuli can activate a neuron leading to electrical activity, including pressure, stretch, chemical transmitters, and changes of the electric potential across the cell membrane.
Stimuli cause specific ion-channels within the cell membrane to open,
leading to a flow of ions through the cell membrane, changing the
membrane potential. Neurons must maintain the specific electrical
properties that define their neuron type.
Thin neurons and axons require less metabolic
expense to produce and carry action potentials, but thicker axons
convey impulses more rapidly. To minimize metabolic expense while
maintaining rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to travel faster
than in unmyelinated axons of the same diameter, whilst using less
energy. The myelin sheath in peripheral nerves normally runs along the
axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier, which contain a high density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder that results from demyelination of axons in the central nervous system.
Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes graded neurotransmitter release. Such non-spiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long distances.
Neural coding
Neural coding
is concerned with how sensory and other information is represented in
the brain by neurons. The main goal of studying neural coding is to
characterize the relationship between the stimulus and the individual or ensemble neuronal responses, and the relationships among the electrical activities of the neurons within the ensemble. It is thought that neurons can encode both digital and analog information.
All-or-none principle
As
long as the stimulus reaches the threshold, the full response would be
given. Larger stimulus does not result in a larger response, vice versa.
The conduction of nerve impulses is an example of an all-or-none
response. In other words, if a neuron responds at all, then it must
respond completely. Greater intensity of stimulation, like brighter
image/louder sound, does not produce a stronger signal, but can increase
firing frequency.Receptors respond in different ways to stimuli. Slowly adapting or tonic receptors
respond to steady stimulus and produce a steady rate of firing. Tonic
receptors most often respond to increased intensity of stimulus by
increasing their firing frequency, usually as a power function of
stimulus plotted against impulses per second. This can be likened to an
intrinsic property of light where greater intensity of a specific
frequency (color) requires more photons, as the photons can not become
"stronger" for a specific frequency.
Other receptor types include quickly adapting or phasic
receptors, where firing decreases or stops with steady stimulus;
examples include skin
which, when touched causes neurons to fire, but if the object maintains
even pressure, the neurons stop firing. The neurons of the skin and
muscles that are responsive to pressure and vibration have filtering
accessory structures that aid their function.
The pacinian corpuscle
is one such structure. It has concentric layers like an onion, which
form around the axon terminal. When pressure is applied and the
corpuscle is deformed, mechanical stimulus is transferred to the axon,
which fires. If the pressure is steady, stimulus ends; thus, typically
these neurons respond with a transient depolarization during the initial
deformation and again when the pressure is removed, which causes the
corpuscle to change shape again. Other types of adaptation are important
in extending the function of a number of other neurons.
The word was adopted in French with the spelling neurone. That spelling was also used by many writers in English, but has now become rare in American usage and uncommon in British usage.
The neuron's place as the primary functional unit of the nervous
system was first recognized in the late 19th century through the work of
the Spanish anatomist Santiago Ramón y Cajal.
To make the structure of individual neurons visible, Ramón y Cajal improved a silver staining process that had been developed by Camillo Golgi. The improved process involves a technique called "double impregnation" and is still in use.
In 1888 Ramón y Cajal published a paper about the bird cerebellum. In this paper, he stated that he could not find evidence for anastomosis between axons and dendrites and called each nervous element "an absolutely autonomous canton."This became known as the neuron doctrine, one of the central tenets of modern neuroscience.
In 1891, the German anatomist Heinrich Wilhelm Waldeyer wrote a highly influential review of the neuron doctrine in which he introduced the term neuron to describe the anatomical and physiological unit of the nervous system.
The silver impregnation stains are a useful method for neuroanatomical
investigations because, for reasons unknown, it stains only a small
percentage of cells in a tissue, exposing the complete micro structure
of individual neurons without much overlap from other cells.
The neuron doctrine is the now fundamental idea that neurons are the
basic structural and functional units of the nervous system. The theory
was put forward by Santiago Ramón y Cajal in the late 19th century. It
held that neurons are discrete cells (not connected in a meshwork),
acting as metabolically distinct units.
Later discoveries yielded refinements to the doctrine. For example, glial cells, which are non-neuronal, play an essential role in information processing. Also, electrical synapses are more common than previously thought,
comprising direct, cytoplasmic connections between neurons. In fact,
neurons can form even tighter couplings: the squid giant axon arises
from the fusion of multiple axons.
Ramón y Cajal also postulated the Law of Dynamic Polarization,
which states that a neuron receives signals at its dendrites and cell
body and transmits them, as action potentials, along the axon in one
direction: away from the cell body. The Law of Dynamic Polarization has important exceptions; dendrites can serve as synaptic output sites of neurons and axons can receive synaptic inputs.
Compartmental modelling of neurons
Although
neurons are often described of as "fundamental units" of the brain,
they perform internal computations. Neurons integrate input within
dendrites, and this complexity is lost in models that assume neurons to
be a fundamental unit. Dendritic branches can be modeled as spatial
compartments, whose activity is related due to passive membrane
properties, but may also be different depending on input from synapses. Compartmental modelling of dendrites
is especially helpful for understanding the behavior of neurons that
are too small to record with electrodes, as is the case for Drosophila melanogaster.
Neurons in the brain
The number of neurons in the brain varies dramatically from species to species. In a human, there are an estimated 10–20 billion neurons in the cerebral cortex and 55–70 billion neurons in the cerebellum. By contrast, the nematode worm Caenorhabditis elegans has just 302 neurons, making it an ideal model organism as scientists have been able to map all of its neurons. The fruit fly Drosophila melanogaster,
a common subject in biological experiments, has around 100,000 neurons
and exhibits many complex behaviors. Many properties of neurons, from
the type of neurotransmitters used to ion channel composition, are
maintained across species, allowing scientists to study processes
occurring in more complex organisms in much simpler experimental
systems.
Charcot–Marie–Tooth disease (CMT) is a heterogeneous inherited disorder of nerves (neuropathy)
that is characterized by loss of muscle tissue and touch sensation,
predominantly in the feet and legs extending to the hands and arms in
advanced stages. Presently incurable, this disease is one of the most
common inherited neurological disorders, affecting 36 in 100,000 people.
Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by progressive cognitive deterioration, together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is loss of short-term memory (amnesia),
which usually manifests as minor forgetfulness that becomes steadily
more pronounced with illness progression, with relative preservation of
older memories. As the disorder progresses, cognitive (intellectual)
impairment extends to the domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and functions such as decision-making and planning become impaired.
Parkinson's disease (PD), also known as Parkinsons, is a degenerative disorder of the central nervous system that often impairs motor skills and speech. Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
Demyelination
is the act of demyelinating, or the loss of the myelin sheath
insulating the nerves. When myelin degrades, conduction of signals along
the nerve can be impaired or lost, and the nerve eventually withers.
This leads to certain neurodegenerative disorders like multiple sclerosis and chronic inflammatory demyelinating polyneuropathy.
Axonal degeneration
Although
most injury responses include a calcium influx signaling to promote
resealing of severed parts, axonal injuries initially lead to acute axonal degeneration, which is the rapid separation of the proximal and distal ends, occurring within 30 minutes of injury. Degeneration follows with swelling of the axolemma, and eventually leads to bead-like formation. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. Early changes include accumulation of mitochondria
in the paranodal regions at the site of injury. Endoplasmic reticulum
degrades and mitochondria swell up and eventually disintegrate. The
disintegration is dependent on ubiquitin and calpainproteases
(caused by the influx of calcium ion), suggesting that axonal
degeneration is an active process that produces complete fragmentation.
The process takes about roughly 24 hours in the PNS and longer in the
CNS. The signaling pathways leading to axolemma degeneration are
unknown.
Neurons are born through the process of neurogenesis, in which neural stem cells
divide to produce differentiated neurons. Once fully differentiated
neurons are formed, they are no longer capable of undergoing mitosis. Neurogenesis primarily occurs in the embryo of most organisms.
Adult neurogenesis
can occur and studies of the age of human neurons suggest that this
process occurs only for a minority of cells, and that the vast majority
of neurons in the neocortex
forms before birth and persists without replacement. The extent to
which adult neurogenesis exists in humans, and its contribution to
cognition are controversial, with conflicting reports published in 2018.
The body contains a variety of stem cell types that have the
capacity to differentiate into neurons. Researchers found a way to
transform human skin cells into nerve cells using transdifferentiation, in which "cells are forced to adopt new identities".
At different stages of mammalian nervous system development two
DNA repair processes are employed in the repair of DNA double-strand
breaks. These pathways are homologous recombinational repair used in proliferating neural precursor cells, and non-homologous end joining used mainly at later developmental stages
Intercellular communication between developing neurons and microglia is also indispensable for proper neurogenesis and brain development.
